Summary with Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications - Stahl - 4th edition

What is the process of chemical neurotransmission? - Chapter 1

Neurotransmission is a very nicely working chemical process. This chapter examines the chemical workings of the nervous system.

What is the general structure of a neuron and neurotransmitters?

Neurotransmitters (molecules) ensure the signal transfer between nerve cells (neurons) in the nervous system. This signal transmission takes place in the synapse. The size, length, shape, and localization in the brain determine the function of a neuron. The chemically addressed nervous system is the chemical basis of neurotransmission; namely the way chemical signals are (de) coded, converted and how they move around the body.

The six main neurotransmitters in clinical practice are:

• Glutamate (excitatory)

• GABA (inhibitor)

• Dopamine (DA)

• Serotonin (5HT)

• Norepinephrine / Noradrenaline (NE)

• Acetylcholine.

Many different neurotransmitters from many different neuronal circuits can be involved in the input to a neuron. Understanding this input to neurons within functioning circuits can provide man with a rational basis for selecting and combining medications.

What types of neurotransmission are there?

There are three types of neurotransmission in the nervous system.

• Classic neurotransmission

• Retrograde neurotransmission

• Volume neurotransmission

In classical neurotransmission, the stimulation of a presynaptic neuron (by neurotransmitters, light, medication, hormones, nerve impulses) causes an electrical impulse that is sent to the axon terminal. There, these electrical impulses are converted into neurotransmitters that are released, after which they stimulate the receptors of the postsynaptic neuron. In this case, the communication within the neuron is electrical, but the communication between the neurons is chemical. In the postsynaptic neuron, this chemical information can be converted back into an electrical impulse, but it is also possible that further chemical reactions are triggered.

The postsynaptic neuron can also "talk back" to the presynaptic neuron; this can be done via a third neuron which in turn sends messages to the first neuron (a kind of "circle") or this can be done directly via retrograde neurotransmission. Chemicals are returned from the (original) postsynaptic neuron to the (original) presynaptic neuron. This substance is then transported in that neuron to the cell nucleus. There are three groups of retrograde neurotransmitters: endocannabinoids (ECs), nitric oxide (NO), and growth factors (NGFs). It is not yet clear exactly what these retrograde neurotransmitters do in the pre- and postsynaptic neuron.

A third form of neurotransmission is volume neurotransmission or nonsynaptic diffusion neurotransmission. The synaptic cleft "leaks" chemical substances during normal neurotransmission, as it were, and so they can reach nearby other receptors. This happens, for example, with DA in the prefrontal cortex. Since there are few DA reuptake pumps there, the DA gets scattered and can reach nearby receptors of the same neuron (but not the same synapse) or even receptors of another nearby neuron, where it causes a response. The inhibition of monoamine neurons works via this same mechanism: when neurotransmitters are released by a monoamine neuron, over time neurotransmitters leak to the inhibitory autoreceptors on the same neuron. As soon as the neurotransmitters bind to them, the neuron stops sending neurotransmitters. This is how the neuron regulates itself.

What is the process of excitation-secretion coupling?

This is the process of converting an electrical impulse in the presynaptic neuron into a chemical signal at the synapse. When the electrical impulse enters the presynaptic axon terminal, it causes the release of the chemical neurotransmitter stored there. This is done as follows: electrical impulses open ion channels, both the voltage-sensitive sodium (= sodium) channels (VSSCs) and the voltage-sensitive calcium channels (VSCCs), by changing the potential of the membrane. Due to the influence of sodium in the presynaptic neuron, the electrical signal from the action potential moves through the axon until it reaches the presynaptic terminal. There, calcium flows into the nerve terminal causing the blisters (vesicles) to release their chemical contents in the synapse.

What are signal transduction cascades?

Neurotransmission can also be seen in a larger whole; from the genome of the presynaptic neuron to the genome of the postsynaptic neuron and then back again. Such processes involve a series of chemical messages and are called signal transduction cascades. This always involves multiple messengers, altering the biochemical nature of the cell. The first messenger is a neurotransmitter, hormone, or neurotrophin that attaches to a receptor. This triggers a reaction in the postsynaptic neuron where a chemical second messenger (second messenger) is created. This in turn activates a third messenger (third messenger), a kinase. This kinase adds a phosphate group to a fourth messenger protein, making it an active phosphate protein. This phosphate protein can trigger various biological responses in the neuron. It is possible to reverse this reaction through another signal transduction cascade that, instead of kinase, activates phosphatase (an enzyme that breaks down phosphate) and thus deactivates the fourth messenger.

The main signal transduction cascades are:

• G-protein linked systems, where the second messenger is a chemical.

• Ion channel linked systems, where the second messenger is an ion.

• Hormone linked systems, where the first messenger is a hormone.

• Neurotrophin linked systems, where the first messenger is a neurotrophin.

Signal transduction cascades can last from hours to days. They can cause a gene to be turned on or off. Not as much is known about all signal transduction cascades, but the effect of G-protein linked systems is quite clear.

There are two possible goals of signal transduction: activation of phosphate proteins or expression of genes. Activation of phosphate proteins can alter the synthesis and release of neurotransmitters, but also affects ion channel conduction and the overall activity of a neuron. However, activation can also be reversed by the third messenger phosphatase. This activation or deactivation of fourth messengers plays an important role in the regulation of chemical neurotransmitter processes.

Another important goal is genetic expression. Neurotransmission can turn genes on or off and thus determine expression. Some genes function as a kind of front troops. These immediate-early genes respond quickly to the input of a neurotransmitter. Once these genes are activated, they produce proteins (fifth messengers) that together form a leucine zipper (sixth messenger / sixth messenger) that activates a much larger group of late genes.

What is the Epigenetics System?

Epigenetics is a parallel system that determines whether a particular gene is actually turned into a specific RNA or protein, or whether it is ignored. Thus, brain development depends not only on which genes are or are not inherited, but also whether abnormal genes will or will not express themselves. Neurotransmitters, genes themselves, drugs / medication and the environment regulate which genes are or are not expressed and thus influence all events in the brain.

Epigenetic mechanisms turn genes on or off by modifying the structure of chromatin in the cell nucleus. The character of a cell is determined by chromatin, a substance made up of nucleosomes (octet proteins, called histones, around which the DNA is wrapped).

Neurotransmission is a very nicely working chemical process. This chapter examines the chemical workings of the nervous system.

What are the working mechanisms of psychotropic drugs? - Chapter 2

Psychiatric drugs have different working mechanisms, but they all have a profound effect on neurotransmission. Although there are more than 100 psychotropic drugs, there are few places where all of these drugs work. To be precise, about one third target a neurotransmitter transporter (30%), about one third target g-protein-linked receptors (30%), and about one third target ligand-dependent ion channels (20%), voltage gated ion channels (10%) and enzymes (10%). These three locations are discussed in this chapter.

How does the mechanism targeting a neurotransmitter transporter work?

Neurotransmitter transporters are receptors, mainly present on the presynaptic neuron, that bind to neurotransmitters and then transport them across the membrane back into the presynaptic neuron. In this way, the amount of neurotransmitters in the synaptic cleft is controlled and neurotransmitters can be recycled. There are two types of neurotransmitter transporters:

Plasma membrane transporters transport the neurotransmitter from the synaptic cleft in the neuron and consist of solue carrier (SLC; solute transporter) families 6 and 1.

Intracellular synaptic vesicular transporters: place the neurotransmitter incorporated into the neuron into the synaptic vesicles. They consist of SLC families 18, 32 and 17.

Monoamine reuptake mechanisms use unique presynaptic transporters for each monoamine, but the same vesicular transporter for all three monoamine neurons. There are three SLC6 family of monoamine transporters that are very commonly targeted by psychotropic drugs. Serotonin (5HT) uses SERT as a presynaptic transporter, norepinephrine (NE) uses NET, and dopamine (DA) uses DAT. They are then placed into synaptic vesicles by the same vesicle transporter VMAT2 (vesicular monoamine transporter 2). While all presynaptic transporters are specifically designed to carry one of the three monoamine neurotransmitters, they also have a soft spot for other amines and so they may "piggyback" a bit. Besides their standard monoamines, NET also has affinity with DA, DAT with amphetamines, and SERT with MDMA, for example.

Transporting the neurotransmitter to the presynaptic neuron takes energy. This energy is provided by transporters in the SLC6 gene family that link the "downward" transport of sodium with the "upward" transport of monoamine. The monoamine transporters are actually sodium-dependent co-transporters. This is made possible by linking monoamine transport to the activity of the enzyme sodium-potassium ATPase (more commonly known as the sodium-potassium pump), which creates the down-transport for sodium by continuously pumping sodium out of the neuron. This downward transport of sodium allows monoamines (often in combination with potassium or chloride) to be pumped into the cell. If there is no sodium, ATPase does not work and therefore no monoamines or other substances are pumped into the cell.

An allosteric binding site is a site on a transporter where specific other molecules and ions (ligands) can form a chemical bond. This means that a psychiatric drug (eg an antidepressant) can bind to a transporter to affect its transport, without being transported into the neuron itself. For example, the antidepressant Fluoxetine (a 5HT reuptake blocker) binds to an allosteric binding site on SERT, preventing 5HT from binding and pumping it back into the neuron. This has the effect that the amount of 5HT in the synaptic cleft increases enormously. As a result, 5HT has a longer and greater effect on postsynaptic receptors. Since 5HT has a positive effect on mood, an excess of 5HT in theory leads to an improved mood or even euphoria. Many antidepressants and drugs, especially MDMA, work in this way.

The remaining (non-monoamine) neurotransmitter transporters of the SLC6 & SLC1 families are affected by only one psychiatric drug. There are no drugs that affect the acetylcholine (choline transporter) and glutamate (EAAAT 1-5) transporters, but there is one anticonvulsant (tiagabine) that affects the GABA transporters (GAT1-4). It increases GABA levels, which in turn can have a positive effect on anxiety, sleep disturbances and pain.

Not all neurotransmitters are regulated with reuptake transporters. Histamine does not have a presynaptic transporter. Neuropeptides do not have this either. The inactivation of these substances is therefore done exclusively by enzymes.

Transport of the neurotransmitter back into a vesicle is performed by vesicular transporters. The vesicular transporter for 5HT, NE and DA is VMAT2. Other neurotransmitters have different vesicular transporters (Ach = VAChT, GABA = VIAAT, Glu = VGluT1-3). The neurotransmitters enter the vesicle through a proton ATPase. This so-called proton pump continuously pumps positively charged protons out of the synaptic vesicle. The positively charged neurotransmitters then enter the vesicle, so that the charge inside the vesicle remains the same.

VMATs are affected by psychotropic drugs. Amphetamines, for example, affect the reuptake transporters, but also the vesicular transporters of DA. Normally released DA is taken up back into the neuron by DAT and then stored in synaptic vesicles by VMAT. Amphetamine stops the DA from entering the vesicles, leading to an increase in intracellular DA (it cannot escape from the presynaptic neuron). This accumulation of DA eventually causes all channels to open to let the DA out of the cell and even the reuptake pumps to pump DA out of the cell instead of into it.

How does the mechanism targeting a g-protein linked receptor work?

Another important target of psychotropic drugs and drugs are the receptors linked to G proteins. Many psychotropic drugs often act only on certain subtypes of these receptors while natural neurotransmitters work on all subtypes. A neurotransmitter is, as it were, a key that can open all the rooms in a hotel, while the psychoactive drugs represent specific keys that can only open one room. Drugs interact with subtypes of G-protein linked receptors in many different ways across an agonist spectrum:

• Agonists: stimulate receptors. An agonist can increase (positive effect) or decrease (negative effect) the activity of a receptor. Neurotransmitters are often full agonists. Drugs can act directly as agonists, but also indirectly by increasing the concentration of neurotransmitters (agonists).

• Antagonist: an antagonist blocks the activation by agonists on a receptor and is therefore not (!) The opposite of an agonist. The antagonist ensures that no altered activation occurs. Antagonists are neutral and return the starting state. This can be useful if undesirable overstimulation occurs due to the action of agonists (eg in case of side effects of medication).

• Partial agonists: also bind and activate, but only have a partial effect on the receptor compared to a full agonist. Partial agonists are also called stabilizers because in the absence of agonists they slightly increase the signal transduction and in the presence of agonists slightly decrease the signal transduction so that it remains at the same level.

• Reverse agonists: A reverse agonist has an opposite effect on the activity of the receptors; a reverse agonist thus also has the opposite effect of an agonist of that receptor.

The absence of an agonist does not necessarily mean that nothing is happening. In the absence of an agonist, signal transduction can still take place, just at a much slower rate. This is called constitutive activity. This is also achieved due to the presence of an antagonist. In essence, antagonists do not have any influence on the natural signal transduction of a receptor.

How does the mechanism that targets enzymes work?

Some drugs can inhibit enzymes. Enzyme activity is the conversion of one molecule, namely the substrate, into another molecule, namely the product. In the presence of an enzyme inhibitor, the enzyme cannot bind to substrates and therefore no product can be formed. The inhibitors of an enzyme are unique and selective. Inhibitors can be reversible or irreversible. Irreversible inhibitors are sometimes referred to as "suicide inhibitors" because they render the enzyme permanently unusable. With reversible inhibitors, substrates can still adhere to them, but whether this happens depends on the strength of the affinity for the enzyme of the inhibitor and the substrate. The stronger the affinity of the inhibitor, the more difficult it is to get rid of. The stronger the affinity of the substrate, the better it can remove any inhibitors from the enzyme. The amount of the substrate or inhibitor present also plays a role. Three enzymes are known to be the target of psychiatric drugs: monoamine oxidase (MAO), acetylcholinesterase, and glycogen synthase kinase (GSK).

Cytochrome P450

Pharmacokinetic actions are mediated via the hepatic and gut drug metabolism system, also known as the cytochrome P450 (CYP) enzyme system. Pharmacokinetics is the study of the way the body responds to medication, especially its absorption, distribution, metabolism and excretion. The CYP enzymes and the pharmacokinetic actions they represent must be contrasted with the pharmacodynamic actions of medication. Pharmacodynamic actions are responsible for the therapeutic effects and side effects of drugs. However, many psychotropic drugs also target the CYP drugs metabolizing enzymes. CYP = enzymes follow the same principle of enzymes that transform substrates into products. There are several CYP systems and more than 30 known CYP enzymes. Not everyone has the same CYP enzymes; enzymes from these individuals are polymorphic.

An important CYP enzyme is 1A2. Various antipsychotics and antidepressants are substrates for 1A2. An inhibitor of 1A2 is the antidepressant fluvoxamine. 1A2 can also be caused or increased in activity by smoking.

Another CYP enzyme important for many psychotropic drugs is 2D6. Many antipsychotics and some antidepressants are substrates for 2D6 and several antidepressants are also inhibitors of this enzyme. 2D6 converts risperidone and vanlafaxine into active drugs, instead of inactive metabolites. Asenapine is an inhibitor of 2D6 and can increase drug levels that are substrates of 2D6.

The CYP enzyme 3A4 metabolizes various psychotropic drugs and various HMG0CoA reductase inhibitors (statins) to treat high cholesterol. Several psychotropic drugs are weak inhibitors of this enzyme, including the antidepressants fluvoxamine and nefazodone, and the active metabolite of fluoxetine and norfluoxetine. Medicines such as carbamazepine, rifampin and some reversible transcriptase inhibitors for HIV / AIDS can induce 3A4.

Psychiatric drugs have different working mechanisms, but they all have a profound effect on neurotransmission. Although there are more than 100 psychotropic drugs, there are few places where all of these drugs work. To be precise, about one third target a neurotransmitter transporter (30%), about one third target g-protein-linked receptors (30%), and about one third target ligand-dependent ion channels (20%), voltage gated ion channels (10%) and enzymes (10%). These three locations are discussed in this chapter.

How can ion channels be used in psychotropic drugs? - Chapter 3

Ions are electrically charged particles that influence the potential of a cell's membrane. They can only pass through the cell membrane through ion channels. The main ion channels regulate calcium, sodium (sodium), chloride and potassium (potassium). Two types of ion channels can be distinguished:

• Ligand-dependent ion channels that can be opened by neurotransmitters. These channels are also called ionotropic receptors and ion channel linked receptors. A ligand is a drug, neurotransmitter or hormone that can bind to a receptor.

• Voltage-dependent ion channels can be opened by the voltage in the membrane

How can ligand dependent ion channels be used?

Ligand dependent ion channels are a form of receptors that form an ion channel. Since ionotropic receptors directly affect the influx or outflow of ions, drugs acting on these types of receptors have an almost immediate effect. Ligand-dependent ion channels include several long chords of amino acids joined together as subunits around an ion channel. These subunits contain multiple binding sites for everything from neurotransmitters to ions and drugs / drugs. That is, these complex proteins have several sites where some ions pass through a channel and others bind to the channel.

Many ligand-dependent ion channels are composed of five protein subunits and are therefore called pentameric. The subunits of pentameric subtypes of ligand-dependent ion channels each have four transmembrane regions. These membrane proteins enter and exit the membrane four times. When five copies of these subunits are selected, they come together to form a fully functional pentameric receptor with the ion channel in the center. Pentameric ionotropic receptors have many different subtypes.

Ionotropic glutamate receptors have a different structure compared to the pentameric ionotropic receptors. The ligand-dependent glutamate ion channels comprise subunits that have three complete transmembrane regions and in addition a fourth re-entrant loop. When four copies of these subunits are selected, they together form a fully functional ion channel surrounded by the four re-entrant loops. Thus, tetrameric ion channel subtypes are analogous to pentameric ion channel subtypes, but have only four instead of five subunits. Receptor sites are in different locations on each of the subunits; some binding sites are located in the channel, but many are located in different locations outside the channel.

As with the G-protein linked receptors, the ligand-dependent ion channels also have an agonist spectrum that influences the activity of the receptor. Drugs / drugs can produce corresponding changes in these receptors to create any state from full agonist, to partial agonist, and from silent agonist to reverse agonist.

The receptors have the ability to adapt, especially when there is chronic or excessive exposure. Desensitization can result from continued exposure to an agonist; the receptor then no longer responds to the agonist, even though it is still present. Desensitization can initially be reversed by removing the agonist. However, if an agonist remains present longer, the receptor changes from a state of desensitization to a state of inactivation. Inactivation is a state that is not directly reversible by agonist removal; it takes hours after removal of the agonist to return to a resting state in which the receptor is again sensitive to exposure to the agonist.

Ligand-dependent ion channels are regulated not only by neurotransmitters, but also by molecules that can bind to the ion channel at other sites. These ligands are called allosteric modulators. Allosteric modulators are ineffective in the absence of a neurotransmitter; so they only work in the presence of a neurotransmitter. There are two types of allosteric modulators:

• Positive Allosteric Modulators (PAMs): these boost the action of the neurotransmitter and thus enhance the neurotransmitter. This results in an action even greater than that of a full agonist.

• Negative Allosteric Modulators (NAMs): These block the action of the neurotransmitter.

A receptor can be affected by both a PAM and a NAM. Examples of PAMs are benzodiazepines that boost the action of the inhibitory neurotransmitter GABA, which is responsible for its sedative and sleep-inducing effect. A NAM at this site would provide reverse agonist action. An example of a NAM is magnesium. This ensures that glycine and glutamate cannot bind to NMDA glutamate receptors and this receptor does not become active.

How can voltage-dependent ion channels be used?

The opening and closing of these ion channels is regulated by the voltage of the membrane. An action potential (or electrical impulse in a neuron) is activated by the sum of different neurochemical and electrical events. Psychiatric drugs mainly act on the sodium (VSSC: voltage-dependent sodium channels) and calcium channels (VSCC: voltage-dependent calcium channels). VSSCs and VSCCs are the same in many ways. They both have a pore that forms the channel through which the ions can move in and out of the cell.

A VSSC has three different states:

• open and active: where maximum ion current is possible.

• quick stop: the channel is closed with a "pore inactivator", with which the ion flow can be stopped quickly.

• closed channel: where a change to the channel itself causes it to close; this is possible for a more stable idle state.

Binding on sodium channels could reduce seizures (seizures), stabilize mood, and lead to pain relief. Binding on calcium channels could lead to anxiety reduction, pain relief, and sleep improvement.

Many aspects of VSCCs and VSSCs are the same. Both have subunits with six transmembrane segments. Both also wind four of their sub-units together to form a pore, in this case an α unit. There are several subtypes of VSCCs. The most interesting specific subtypes of VSCCs are those that are presynaptic, that regulate neurotransmitter release, and that are targets of certain psychotropic drugs.

What happens to the ion channels during neurotransmission?

Ligand-dependent and voltage-dependent ion channels work together during neurotransmission. When an action potential arises in a neuron, it sends an impulse through the axon via VSSCs. These open one by one to let in sodium. The electrical impulse eventually reaches the axon terminal, where the VSCCs respond to the action potential by opening and letting in calcium. This influence of calcium leads to the fusion of the synaptic vesicles with the membrane, releasing the neurotransmitters into the synaptic cleft. This process is called the excitation-secretion coupling.

Ions are electrically charged particles that influence the potential of a cell's membrane. They can only pass through the cell membrane through ion channels. The main ion channels regulate calcium, sodium (sodium), chloride and potassium (potassium).

What causes and treatments are there for schizophrenia and psychoses? - Chapter 4

The terms psychosis and schizophrenia are often misused. There is a huge stigma attached to psychotic disorders and it is therefore important to be fully aware of what a psychosis actually means. In this chapter the causes and pharmacological treatments of psychosis are discussed.

What is a psychosis and what are the symptoms?

Psychosis is a syndrome, that is, a composition of symptoms. Psychosis means in a minimal sense that there are delusions and hallucinations. In addition, it often also contains symptoms such as disjointed speech, chaotic behavior and gross distortions of reality. It affects the way people think, feel, communicate, interact with others and see reality. There are many disorders in which psychosis may be present, including various dementias, intoxications and various physical illnesses.

There are three types of psychosis with some typical symptoms:

• Paranoid psychosis: paranoid phenomena, hostile attitudes, and megalomania.

• Disorganized Psychosis: Disorganization, disorientation, and excitement.

• Depressed psychosis: apathy, flattening, and guilt.

Perceptual and motor disorders can be part of any kind of psychosis.

Schizophrenia consists of a number of types of symptoms:

• Positive symptoms: symptoms that are not normally present. They reflect an over-activation of normal functions.

• Negative symptoms: symptoms that are normally present: They reflect a reduction in normal functions.

• Cognitive symptoms: problems with executive functions and other higher mental processes.

• Affective symptoms: emotional symptoms. Often these are anxiety, depression, apathy and suicidality.

• Aggressive symptoms: can include verbal or physically aggressive symptoms

Negative symptoms are not only part of the schizophrenia syndrome; they can also be part of a "prodrome," which begins with subsyndromal symptoms that do not meet the diagnostic criteria of schizophrenia and occur before the onset of full schizophrenia syndrome. Prodromal negative symptoms are important to be able to detect and monitor high-risk patients over time, so that treatment can be started at the first sign of psychosis.

The symptoms characteristic of schizophrenia are not unique to this disorder. Negative symptoms are, however, fairly unique to schizophrenia. But disorders like autism and Alzheimer's also consist of cognitive symptoms, and disorders like bipolar disorder and Alzheimer's can also have positive symptoms. Affective symptoms have also been associated with anxiety disorders. Finally, aggressive and hostile symptoms occur with many other disorders, especially impulse regulation disorders.

Schizophrenia symptoms may be linked to certain areas of the brain. The positive symptoms in particular have long been thought to be localized in mesolimbic circuits, especially in circuits involving the nucleus accumbens-part of the brain's reward circuitry.

What is the role of dopamine?

Dopamine (DA) probably plays the most important role in the development of psychosis. DA is made by first converting tyrosine into DOPA which is then converted into DA. DA is then stored in vesicles by a VMAT. DA's action is ended by

DAT (the DA reuptake pump) that removes the DA from the presynaptic slit. DAT is not present in the same density everywhere (e.g. low density in prefrontal cortex). In addition, COMT plays a major role: an enzyme that destroys DA extracellularly (outside the cell) and MAO that destroys DA both intra- and extracellularly.

There are several DA receptors, including D2. DA D2 receptors can be presynaptic; they then function as autoreceptors that only let DA through when they themselves (as autoreceptor) are not occupied. D2 autoreceptors can also be somadentritic (so on the soma / at the dendrites). When DA binds to the neuron here, the receptor causes the release of DA into the synaptic cleft to be stopped.

There are five DA paths (pathways). The four about which something is known:

1. Mesolimbic DA pathway: This pathway runs from the ventral tegmental region to the nucleus accumbens and is involved in pleasurable feelings, including substance use euphoria. Hyperactivity of this mesolimbic dopamine pathway is likely to cause psychotic symptoms. All drugs that work antipsychotic are D2 blockers and thus ensure, among other things, a reduction in the effect of DA in this path. The mesolimbic DA pathway may also be involved in negative symptoms: symptoms such as loss of motivation and interest in things and anhedonia and lack of pleasure may indicate impaired functioning of the mesolimbic DA pathway. This idea is supported by observations of patients treated with antipsychotics, especially conventional antipsychotics; this treatment can produce an exacerbation of negative symptoms, which are very similar to the negative symptoms of schizophrenia.

2. Mesocortical DA Path: This path runs from the ventral tegmental area to two areas in the prefrontal cortex, namely the DLPFC and the VMPFC (ventromedial prefrontal cortex). This pathway may affect cognitive functions and affective symptoms. Cognitive and negative symptoms of schizophrenia are said to arise from a lack of DA activity from DLPFC projections. Affective and negative symptoms are said to arise from a lack of DA activity from VMPFC projections.

3. Nigostriatal DA Path: This path runs from the substantia nigra to the basal ganglia or striatum. It is part of the extrapyramidal nervous system and regulates motor function and movement. DA deficiency in this pathway causes movement disorders such as parkinsonism, extrapyramidal disorders (EPS) and dystonia. Blockage of the D2 receptors of this pathway could lead to tardive dyskinesia.

4. Tuberoinfundibular DA pathway: This pathway runs from the hypothalamus to the anterior pituitary gland (the hormone-producing part of the pituitary gland) and controls prolactin secretion. Decreased DA activity here leads to a reduced inhibition of prolanctin, which in turn leads to glactorrhea (secretion of milk from the breasts), amenorrhea (loss of menstruation) and impotence. These problems arise with the use of some antipsychotic drugs.

5. The fifth DA pass, which is still under much research, is the thalamic DA path; this path innervates the thalamus in primates. It arises in several places in the brain, including the periaqueductal gray matter, the ventral mesencephalon, various hypothalamic nuclei, and the lateral parabrachial nucleus. This pathway may be involved in sleep and arousal mechanisms by filtering information that flows through the thalamus to the cortex and other areas of the brain. There is currently no evidence that there is abnormal functioning of this pathway in schizophrenia.

What is the role of glutamate in schizophrenia?

Glutamate plays an important role in schizophrenia. It is also currently the main target of new psychopharmacological drugs for future treatments for schizophrenia and depression. Glutamate is an amino acid and the main excitatory neurotransmitter in the central nervous system (glutamate is referred to as the "master switch"). In addition to a neurotransmitter, it also works as a building block for proteins. It is considered the brain's "master switch", as it can excite and turn on virtually all neurons in the central nervous system (CNS).

Upon release from the presynaptic neuron, glutamate is taken up into the glial cell via EAAT (Excitatory Amono Acid Transporter). There, glutamate is converted by an enzyme into glutamine. This glutamine is then transported to the cell by a transporter where it is converted back to glutamate in the presynaptic neuron, where it is stored in vesicles by the vesicular glutamate transporter (vGluT) until it can be released. An important receptor for glutamate is the NMDA receptor. Glutamate has the presence of glycine or co-transmitters

D-serine is required to act on the NMDA receptor. These co-transmitters come mainly from nearby glial cells. In addition, there are metabotropic glutamate receptors. These are present both pre- and postsynaptic. Metabotropic glutamate receptors are G-linked receptors. The metabotropic glutamate receptors can be divided into three groups; groups II and III can be presynaptic and function as autoreceptors that stop further glutamate release. Agonists targeting these glutamate receptors can thus reduce glutamate release (e.g., mood stabilizers). Group I metabotropic glutamate receptors are mainly postsynaptic and interact with other postsynaptic glutamate receptors.

NMDA and other glutamate receptors (such as AMPA) are ligand dependent ion channels.

Glutamate has an excitatory effect and appears to be able to "turn on" almost any neuron. There are seven major glutamate pathways to discover:

• Cortico-brainstem glutamate projection: descending pathway that travels from the cortical pyramidal neurons in the prefrontal cortex to central nuclei in the brainstem (raphe nuclei, locus coeruleus, ventral tegmental area, substantia nigra) and regulates neurotransmitter release there.

• Cortico-striatal glutamate pathways: from the prefrontal cortex to the striatum and nucleus accumbens. These paths terminate at GABA neurons destined for a relay station in another part of the striatal complex called the globus pallidus.

• Hippocampal-accumbens glutamate pathway: This path projects from the hippocampus to the nucleus accumbens. Specific theories link this path to schizophrenia. Like the cortico-striatal and cortico-accumbens glutamate pathways, this path also ends on GABA neurons in the nucleus accumbens, which in turn project onto a relay station in the globus pallidus.

• Thalamo-cortical glutamate pathways: ascending from the thalamus to the pyramidal neurons in the cortex, often to process sensory information. This is the way back from the CSTC loop, as it were.

• Cortico-thalamic glutamate pathway: descending from the prefrontal cortex to the thalamus, where it can direct the way neurons respond to sensory information.

• Cortico-cortical glutamate pathways: a complex of many of these pathways exist within the cortex. On the one hand, pyramidal neurons can excite each other within the cerebral cortex via direct synaptic input from their own neurotransmitter glutamate (direct cortico-cortical glutamate pathways) and on the other hand, a pyramidal neuron can excite another neuron via indirect input, namely via interneurons that Releasing, inhibiting GABA (indirect cortico-cortical glutamate pathways).

The NMDA receptor hypofunction hypothesis of schizophrenia: ketamine and PCP

This hypothesis proposes that the symptoms of schizophrenia are caused by a reduced functioning of the NMDA receptors. This hypothesis has been hypothesized because the NMDA antagonist drug PCP (phencyclidine) or ketamine causes the same positive symptoms as in schizophrenia. Hypothetically, genetic abnormalities also make NMDA receptors and their synapses hypofunctional to cause schizophrenia. Amphetamine, which releases DA, also produces a psychotic condition of delusions and hallucinations in normal people; these delusions and hallucinations are equivalent to the positive symptoms of schizophrenia. What makes the NMDA receptor hypofunction hypothesis of schizophrenia so appealing is that unlike amphetamine, which produces only positive symptoms, PCP and ketamine also cause the cognitive, negative, and affective symptoms of schizophrenia. In addition, this hypothesis may also explain the DA hypothesis of schizophrenia, namely as a downstream consequence of hypofunctioning NMDA receptors.

The NMDA receptor hypofunction hypothesis of schizophrenia: erroneous NMDA synapses on GABA interneurons in the prefrontal cortex

A current leading theory suggests that schizophrenia may be caused by abnormalities in the formation of glutamate synapses at a particular site, namely at particular GABA interneurons in the cerebral cortex. There seems to be something wrong with the genetic programming of these specific GABA interneurons located in the prefrontal cortex and containing a calcium that binds to a protein called parvalbumin. These parvalbumin-containing GABA interneurons appear to have hypofunctioning NMDA receptors on their dendrites, defective synapses, synapses between the glutamate neuronal axons and the GABA interneuronal dendrites, and thus erroneous glutamatergic information entering the GABA interneuron. This so-called "disconnectivity" can be genetically programmed from a variety of faulty genes, all of which converge on the formation between these particular NMDA synpases. When parvalbumin-containing GABA interneurons fail to function properly, they do not properly inhibit the major glutamatergic pyramidal neurons in the prefrontal cortex, causing these glutamate neurons to become hyperactive. This hypothetically disrupts the functioning of downstream neurons, especially DA neurons. In this way, one diseased synapse in a neuronal circuit can affect the entire circuit.

A combination of the NMDA receptor hypofunction hypothesis with the DA hypothesis

The NMDA receptors in the glutamate projection within the cortico brainstem are hypoactive in schizophrenia. Glutamate release normally acts as a brake on the mesolimbic DA system. However, when NMDA receptors in the cortical brainstem glutamate projections are hypoactive, there will be no further inhibition of DA in the mesolimbic system. This leads to hyperactivity in that area. The DA hyperactivity of these downstream medolimbic DA neurons is associated with the positive symptoms of schizophrenia, but is actually hypothetically caused by disconnectivity in upstream glutamate neurons, namely defective and hypofunctional neuro-developing glutamate innervation of parvalbumin containing GABA interneurons on NMDA receptor containing synapses. It is also possible that the disconnectivity of upstream glutamate neurons in the hippocampus contribute to downstream mesolimbic DA hyperactivity through a four-neuron circuit. The loss of adequate glutamate function on parvalbumin-containing GABA interneurons in the hippocampus could lead to hyperactive glutamate output from glutamate neurons projecting through this circuit on the mesolimbic DA neurons in the ventral tegmental region, resulting in DA hyperactivity. and positive schizophrenia symptoms. The bottom line is that excessive upstream glutamate output from either the prefrontal cortex or the hippocampus can contribute to downstream DA hyperactivity and positive schizophrenia symptoms.

In addition, the cortical-brain stem glutamate projection communicates directly with the mesocortical dopamine pathway in the ventral tegmental area, normally leading to excitation. However, when NMDA receptors in the cortical brainstem glutamate projection are hypoactive, no excitation takes place and the mesocortical DA pathway also becomes hypoactive. This may explain the cognitive, negative and affective symptoms.

How is schizophrenia explained from genetics?

Schizophrenia appears to be mainly explained by "disconnectivity" of neurons, particularly in the hippocampus and prefrontal cortex, and in particular at glutamate synapses with NMDA receptors becoming hypofunctional. Things like stress and traumatic experiences are examples of 'experience-dependent' development of synaptic connections, something that is abnormal in people with schizophrenia and has to do with both the experiences the patient has (had) and the genes that respond to these experiences. . The best evidence that environment also plays a role is that only half of the monozygotic twins of patients with schizophrenia also have schizophrenia. So having identical genes is not enough to develop schizophrenia. The best evidence for the role of disconnectivity genes is the convergence of evidence indicating multiple genes that regulate not only neuronal connectivity in general, but in particular glutamate synapse formation and removal.

Abnormal genetic programming during critical neural developmental periods can cause the wrong neurons to be selected for survival, neurons to migrate incorrectly, neurons innervate the wrong targets, and myelination of neurons to under- or incorrectly occur. Dysbindine, DISC-1, ErbB4 and neuregulin are all involved in synapse formation. Deviations from this can cause abnormal synapses to form. Dysbindine, DISC-1 and neuregulin are involved in the formation of normal synapses. All three affect the number of NMDA receptors passing through the postsynaptic membrane, the binding of NMDA receptors within that membrane, and NMDA receptor endocyctosis, which removes receptors from the postsynaptic membrane. Other risk genes involve specific proteins - for example DAOA and RSG4 - that directly regulate glutamate synapses and, if abnormal, may contribute to the negative effects of disconnective and dysfunctional NMDA-glutamate synapses. Under normal circumstances, NMDA receptors in glutamate synapses will elicit long-term potentials (LTP), a process involved in learning and memory. LTP leads to synapse strengthening. However, when these genes deviate, it can lead to hypofunctioning NMDA receptors, resulting in a reduction in LTP and thus reduced learning and memory.

Neuroimaging in Schizophrenia

Some studies show underactivity in the prefrontal cortex in schizophrenia patients. Other studies show a lot of activity. The explanation for this is that prefrontal dysfunction in schizophrenia is not so much related to hyper- or hypoactivation but mainly to being "out of tune". In cognitive tests (such as the n-back test), it appears that schizophrenia patients require more activation of brain areas to achieve normal results. Incidentally, this can be the same for brothers or sisters of patients, even if they themselves have no symptoms. Research into the reaction to threatening faces shows that in schizophrenia patients often no increased activity in the amygdala can be seen in such faces, while this is the case in healthy subjects. Conversely, in schizophrenia patients there is overactivity with neutral faces, while healthy subjects do not have it. So there seem to be deviations in the recognition of emotions.

The receipt of the released neurotransmitter by the postsynaptic neuron also has an effect on the ion channels. For example, when glutamate binds to an AMPA receptor, it opens its sodium channels. This depolarizes the membrane and thus causes an action potential. In this way, the voltage-dependent NMDA receptors open which allow calcium influence. This combination of AMPA and NMDA action is called long-term potentiation and probably has a lot to do with learning, synaptogenesis and other neurological functions.

The terms psychosis and schizophrenia are often misused. There is a huge stigma attached to psychotic disorders and it is therefore important to be fully aware of what a psychosis actually means. In this chapter the causes and pharmacological treatments of psychosis are discussed.

How do antipsychotics work? - Chapter 5

Anti-psychotic drugs may have the most complex pharmacological mechanism of all psychotropic drugs. In this chapter you will get an idea of ​​how antipsychotics (also called neuroleptics) work with different neurotransmitter systems. This allows you to understand how a medicine works and how side effects come about.

How Do Conventional Antipsychotics Work?

Conventional antipsychotics (also known as classic, first-generation, or typical antipsychotics) all act primarily as an antagonist at D2 receptors. The therapeutic effect of this medication is mainly due to the blocking of D2 receptors in the mesolimbic dopamine pathway, which causes the positive symptoms to decrease. The disadvantage of these classic antipsychotics is that they block the D2 receptors all over the brain and therefore cause many side effects. The mesolimbic system includes the nucleus accumbens; an area that plays an important role in positive experiences, such as desire, motivation and reward. Thus, blocking of D2 receptors in the mesolimbic system also blocks reward mechanisms, leading to apathy, anhedonia, decreased motivation, interest, and enjoyment in social interactions. Conventional antipsychotics also block the D2 receptors in the mesocortical dopamine pathway, which may already be dopamine (DA) deficient in schizophrenia. This can amplify negative and cognitive symptoms.

What is the influence of antipsychotics on DA pathways?

Nigrostriatal dopamine pad

This path is normal in untreated schizophrenia. The blockade of D2 receptors by the administration of classical antipsychotics leads to motor Parkinson-like side effects, called extrapyramidal symptoms (EPS). Over time, this can then lead to upregulation of the D2 receptors, leading to irreversible tardive dyskinesia (facial and tongue movements including grimacing and chewing as well as movements in the legs and arms). If D2 receptor blockade is stopped in time, tardive dyskinesia may be reversed. This reversal is theoretically due to a "resetting" of the D2 receptors by an appropriate decrease in the number or sensitivity of these D2 receptors in the nigostriatal pathway after a patient has stopped taking the antipsychotic that blocked the receptors. However, after long-term treatment, the D2 receptors cannot be reset, leading to irreversible tardive dyskinesia, even when antipsychotics are discontinued. In addition to tardive dyskinesia, another disorder is associated with D2 receptor blockade in the nigrostriatal pathway, namely the rare but potentially fatal neuroleptic malignant syndrome (extreme muscle stiffness, high fever, coma, and even death).

Tuberoinfundibular dopamine pad

This path is normal in untreated schizophrenia. Blockage of D2 receptors by classical antipsychotics leads to an increased prolactin level, also called hyperprolactinaemia, which causes side effects such as breast milk secretion (galactorrhoea) and absent menstruation (amenorrhea). Hyperprolactinaemia can thus adversely affect fertility, especially in women.

The foregoing shows that the use of classical antipsychotics entails dilemmas. While these drugs positively affect positive symptoms, they block not only the D2 receptors in the mesolimbic DA pathway, which is good, but also in all other pathways, which can have harmful consequences. This dilemma may have been partly addressed by atypical antipsychotics and is one of the reasons why atypical antipsychotics have largely replaced classic antipsychotics.

What are the other activities of classical antipsychotics?

• Blockage of muscarinic (M1) cholinergic receptors: Side effects include dry mouth, blurred vision, constipation, and drowsiness. DA and acetylcholine have a reciprocal relationship in the nigrostriatal pathway. Normally, DA suppresses acetylcholine activity. Because D2 antagonists reduce the activity of DA, there is an increase in acetylcholine activity. This causes EPS. EPS is thus related to a deficiency of DA and an excess of acetylcholine. You can use an anti-cholinergic substance to counteract this side effect. Unfortunately, this substance does not reduce the risk of tardive dyskinesia. In addition, it causes side effects such as dry mouth, blurred vision, urinary retention and cognitive dysfunction.

• Blockage of histamine-1 (H1) receptors: This causes side effects such as drowsiness and weight gain.

• Blockage of alpha-1 (α1) adrenergic receptors: This causes low blood pressure (hypotension), dizziness and drowsiness.

Conventional antipsychotics differ in terms of their ability to block different receptors. For example, the popular conventional antipsychotic haloperidol has relatively little anticholinergic or anti-histamine binding activity, while the classic conventional antipsychotic chlorpromazine has potential anticholinergic and anti-histamine binding. Because of this, conventional antipsychotics differ somewhat in their side effects. A somewhat old-fashioned way to classify conventional antipsychotics is "low potency" versus "high potency". Low potency drugs require higher doses than higher potency drugs, but low potency drugs have more additional properties than high potency drugs, such as greater anticholinergic, anti-histamine, and α1 antagonist properties, and are therefore likely to be general. more narcotic.

What are the characteristics of atypical antipsychotics?

Atypical antipsychotics have the clinical profile of similar positive symptom anti-psychotic actions, but lower extrapyramidal symptoms and less hyperprolactinaemia compared to conventional antipsychotics. Atypical antipsychotics are also called second-generation antipsychotics and are also defined as serotonin dopamine antagonists (SDA), with the same serotonin 5HT2A receptor antagonism associated with D2 antagonism. In addition, they sometimes act as a partial agonist or as an antagonist with rapid dissociation. They do not amplify the negative symptoms and have few EPS side effects. To understand the mechanism of action of atypical antipsychotics and how it differs from conventional antipsychotics, it is necessary to have a somewhat detailed understanding of the neurotransmitter serotonin and its receptors.

Serotonin

Serotonin is listed as 5HT. Synthesis of 5HT starts with the amino acid tryptophan which is converted by two enzymes to 5HT. After synthesis, 5HT is delivered to the synaptic vesicles with a vesicular monoamine transporter (VMAT2) until neurotransmission occurs. Outside the neuron, 5HT can be degraded by the enzyme MAO or transported back by the presynaptic transporter pump SERT which takes 5HT from the synapse and returns it to the presynaptic terminal where it is stored in vesicles for new use.

5HT has many different receptors, both presynaptic and postsynaptic. Presynaptic 5HT receptors are autoreceptors; these can be autoreceptors on the end of the axon that block further 5HT release from the own neuron or 5HT somatodendritic autoreceptors that block 5HT release when 5HT binds to the soma or dendrites. In addition, there are a large number of postsynaptic 5HT receptors (5HT1 to 7) that can trigger many different actions

5HT2A receptors are located in different areas of the brain. When located on cortical pyramidal neurons, they are excitatory and thus can promote downstream glutamate release. Glutamate regulates downstream DA release, so stimulating or blocking 5HT2A receptors can thereby regulate downstream DA release as well. Cortical 5HT1A receptors also regulate downstream DA release.

5HT2A receptors

5HT2A stimulation of cortical pyramidal neurons by serotonin hypothetically blocks downstream DA release in the striatum. This is done via stimulation of glutamate release in the brain stem, triggering the release of GABA. The release of DA from neurons in the striatum is thus inhibited.

5HT2A antagonism in the cortex hypothetically stimulates downstream DA release in the striatum. This occurs by decreasing glutamate release in the brainstem, which prevents the release of GABA on DA neurons from being triggered. Thus, release of DA from neurons downstream in the striatum is inhibited, which theoretically should alleviate EPS.

5HT2A receptors theoretically regulate DA release from nigrostratial DA neurons through additional mechanisms in additional brain regions. That is, 5HT nurons whose cell bodies are located in the midbrain raphe can stimulate nigrostriatal DA neurons at the level of the DA neuronal cell bodies in the substantia nigra as well as at the DA neuronal axon terminals in the striatum. This stimulation can be done via a direct connection between the 5HT neuron and the DA neuron, as well as via an indirect connection with a GABA interneuron. 5HT2A receptor stimulation by 5HT at both ends of substantia nigra neurons hypothetically blocks DA release in the striatum. On the other hand, 5HT2A receptor antagonism by an atypical antipsychotic at the same sites hypothetically stimulates downstream DA release in the striatum. Such release of DA into the striatum could alleviate EPS. 5HT1A receptors also regulate DA release in the striatum.

One way to show the difference in clinical effects of the atypical antipsychotics compared to conventional antipsychotics is to contrast what happens to DA D2 binding in the striatum when a pure D2 antagonist is given versus when an atypical antipsychotic that is equal or greater potential to block 5HT2A receptors with D2 antagonism is presented. In the case of a pure D2 antagonist, such as a conventional antipsychotic, the amount of D2 receptor antagonism in the striatum is the same in the limbic region and in the pituitary gland. This gives you EPS and hyperprolactinaemia at the same dose that you get anti-psychotic effects, namely when all of these D2 receptors in all of these brain areas are substantially blocked. There is little or no leeway between therapeutic effects and side effects. However, in the case of an atypical anti-psychotic, the amount of D2 antagonism in the striatum is reduced by the same dose at which the drugs have anti-psychotic effects. This creates a framework between the dose that produces anti-psychotic effects and the dose that produces EPS or elevated prolactin levels.

The atypical antipsychotics can be categorized in many ways. In the book they are organized as either the "pines", the "down", or "two pipes and a rip". While no atypical antipsychotic has exactly the same pharmacological binding profiles as any other atypical antipsychotic, it is easy to see that for the "pines" and "down" 5HT2A receptor binding always occurs on the left side of D2 binding. This binding property of greater 5HT2A than that of D2 is what makes these drugs atypical antipsychotics and creates the "framework" of atypical antipsychotic effects associated with low EPS.

5HT1A partial agonism

To understand how 5HT1A partial agonism can also reduce EPS, it is important to understand how 5HT1A receptors function in different brain regions and how they regulate DA release in the striatum.

5HT1A receptors on pyramidal neurons in the cortex hypothetically stimulate downstream DA release in the striatum by reducing glutamate release in the brainstem. As a result, no GABA can be triggered on DA neurons here. Thus, DA neurons are inhibited, just as in the case of a 5HT2A antagonist. This would theoretically cause DA release in the striatum and thus reduce EPS.

5HT1A receptors may be postsynaptic not only across the brain, but also presynaptic to the dendrites and cell bodies of 5HT neurons in the midbrain raphe. When 5HT is detected on presynaptic somatodendritic 5HT1A receptors on neuronal dendrites and on the neuronal cell body, an autoreceptor function is activated that causes a slowing of neuronal impulse flow through the 5HT neuron and a reduction in 5HT release from the axon terminal. Pre- and postsynaptic 5HT1A receptors work together to promote DA release in the striatum, and when both are stimulated by certain atypical antipsychotics, this should theoretically reduce EPS.

Some atypical antipsychotics have influential 5HT1A partial agonist properties, especially the 'two pips and one rip - namely aripiprazole, brexpiprabole and cariprazine - have 5HT1A partial agonist effects that are no more potent than 5HT2A antagonist effects, but comparable to D2 antagonist effects. .

5HT1B / D receptors

Presynaptic receptors are autoreceptors and detect the presence of 5HT, causing a cessation of further 5HT release and 5HT neuronal impulse current. When 5HT is detected in the synapse by presynaptic 5HT receptors at axon terminals, it occurs through a 5HT1B / D receptor, also referred to as a terminal autoreceptor. In the case of this autoreceptor, the 5HT possession of this receptor causes a blockade of 5HT release. On the other hand, drugs that block the 5HT1B / D autoreceptor can promote 5HT release, potentially leading to antidepressant effects.

5HT2C receptors

These receptors are postsynaptic and regulate both DA and norepinephrine (NE) release. 5HT2C receptors suppress DA release, rarely more from the mesolimbic system than from the nigrostriatal pathways. This produces an antipsychotic without EPS. Stimulating 5HT2C receptors are also used in obesity, as it has led to weight loss in both preclinical and clinical studies. Blocking 5HT2C receptors stimulates DA and NE release in the prefrontal cortex, and pro-cognitive, but especially antidepressant, effects have been shown in animals.

5HT3 receptors

These receptors are postsynaptic and regulate inhibitory GABA interneurons in different brain regions, which in turn regulate the release of a number of neurotransmitters (5HT, acetylcholine, NE, DA and histamine). 5HT3 receptors are also involved in vomiting and possibly also in nausea. Blocking 5HT3 receptors in the chemoreceptor trigger zone of the brainstem is an established therapeutic approach to relieve chemotherapy induced nausea and vomiting. Blocking these receptors on GABA interneurons increases the release of 5HT, DA, NE, acetylcholine and histamine in the cortex.

5HT6 receptors

These receptors are postsynaptic and may be the main regulators of acetylcholine release and cognitive processes. Blocking this receptor promotes learning and memory in animals.

5HT7 receptors

These receptors are postsynaptic and are important regulators of 5HT release. When these receptors are blocked, 5HT release is disinhibited, especially when 5HT7 antagonism is combined with 5HT reuptake inhibition. New 5HT7 selective antagonists are thought to be regulators of circadian rhythms, sleep and mood in animals.

How do antipsychotics work as a partial agonist?

There are new antipsychotics that act as partial agonists. They stabilize DA neurotransmission in a state between silent antagonism and full stimulation. DPAs would thus be the happy medium between the effect of D2 blocking as in classical antipsychotics on the one hand and the effect of DA itself on the other. They would decrease the too high DA output in the mesolimbic system such that there are no positive symptoms but not so much that no pleasure or reward is experienced, and they would increase the DA output in the mesocortical system so that no negative symptoms are more.

What links are there between anti-psychotic binding properties and clinical effects?

The atypical antipsychotics have perhaps the most complicated pattern of binding to neurotransmitter receptors of any drug in psychopharmacology. Here is an overview of some other receptor interactions of atypical antipsychotics and an overview of potential links between pharmacology and clinical effects where possible. Note: these are hypothetical links.

Antidepressants in bipolar and unipolar depression

Atypical antipsychotics also have antidepressant effects, both on their own and in combination with other antidepressants. The effects associated with antidepressant influences are those that exist for proven antidepressants, although not every atypical antipsychotic with a potential antidepressant mechanism acts as a proven antidepressant. Additional mechanisms associated with antidepressant effects shared by several atypical antipsychotics include 5HT and / or NE reuptake inhibition (quetiapine) and Alpha-2 (α2) antagonism (mirtazapine and various 'pines' and 'dons') .

Antimanic effects

All antipsychotics are effective in the case of psychotic mania, but atypical antipsychotics seem to have a greater effect on non-psychotic mania.

Anxiolytic effects

A somewhat controversial use of atypical antipsychotics is for the treatment of various anxiety disorders. Some studies suggest an effect of various atypical antipsychotics for generalized anxiety disorder. Perhaps most controversial is the use of atypical antipsychotics in post-traumatic stress disorder (PTSD). Side effects, high costs and the use of regulatory consent have limited this use of atypical antipsychotics.

Narcotic-hypnotic and calming effects

Anesthesia is caused by the blocking of one or more of three specific receptors: M1-muscarinic cholinergic receptors, H1-histamine receptors, and α1-adrenergic receptors. Blocking of central α1-adrenergic receptors is associated with anesthesia, while blocking of peripheral α1-adrenergic receptors is associated with postural hypotension. Blocking central DA, acetylcholine, histamine or NE can lead to sedation and cognitive problems. Medicines that combine potent effects on both D2, 5HT2A and 5HT1A receptors - including potent anti-histamine effects (clozapine, quetiapine, olanzapine and iloperidone), potent anticholinergic effects ('pines', clozapine, quetiapine and olanzapine), and strong α1-adrenergic antagonisms (clozapine, quetiapine, risperidone and iloperidone) are the most narcotic.

Cardiometabolic Effects:

The following risk spectrum exists among antipsychotics:

• High metabolic risk: clozapine, olanzapine

• Mean metabolic risk: risperidone, paliperidone, quetiapine, iloperidone (for weight only)

• Low metabolic risk: ziprasidone, aripiprazole, luradisone, iloperidone, asenapine, and possibly brezpiprazole and cariprazine

Blockage of the 5HT2C-5HT receptor and the H1 histamine receptor can lead to weight gain. This is partly due to the increased appetite that this causes. Even without gaining weight, some antipsychotics can cause changes in insulin and cholesterol, which can lead to cardiovascular disease and diabetes. When prescribing atypical antipsychotics, the following parameters should be monitored: weight, cholesterol, glucose and blood pressure.

What are the pharmacological properties of individual antipsychotics?

Below is an overview of some of the differences between 17 selected antipsychotic medications.

- slightly increased, ++ greatly increased, +++ very much increased

What prescription for psychosis are there?

1. Atypical Antipsychotics (SDA or DPA).

2. If no effect: Clozapine or classic antipsychotic.

3. Against aggressiveness: benzodiazepines or sedative antipsychotic (depot).

4. Against negative symptoms: atypical antipsychotic (SDA or DPA)

If there is no compliance with medication, medicines that can be given in the form of a deposit are preferred. In emergency situations, conventional antipsychotics are given intra-muscularly. When switching drugs, it is important to gradually increase and decrease (titrate). Often a benzodiazepine is given throughout the switch and tapered off once the patient has stabilized. If nothing works, you can prescribe two drugs at the same time: atypical + atypical or conventional + atypical.

Future options include pre-symptomatic / prodromal drug delivery and drugs targeting glutamate via NMDA antagonists against excitotoxicity.

Anti-psychotic drugs may have the most complex pharmacological mechanism of all psychotropic drugs. In this chapter you will get an idea of ​​how antipsychotics (also called neuroleptics) work with different neurotransmitter systems. This allows you to understand how a medicine works and how side effects come about.

What are the causes and treatments for mood disorders? - Chapter 6

This chapter deals with disorders characterized by an abnormal mood: depression, mania or both. Mood disturbances are probably associated with dysregulation of three monoamine neurotransmitters, namely DA, NE and 5HT.

What are the characteristics of mood disorders?

Mood can range from manic, to hypomanic, to normophore (normal) and from dysthymia to depression. Bipolar disorder is characterized by four distinct episodes: manic, depressed, hypomanic, and mixed (fully manic and fully depressed at the same time). Mania and normal mood or depression can sometimes alternate very quickly, this is called rapid cycling. Cyclothymic disorder is when someone switches between hypomanic and dysthymic periods. Major depression is the most common disorder and is characterized by the occurrence of at least one major depressive episode. Dysthymia is a less severe form of depression, but lasts a long time (more than two years) and is often stable. A double depression consists of a dysthymic period in which a depressive period occurs.

As for bipolar disorder, there are a number of types:

• Bipolar disorder ¼ consists of depressive episodes that respond well to antidepressants but relapse quickly.

• Bipolar 1/2 disorder is also called schizobipolar and consists of the positive symptoms of psychosis with manic, hypomanic, or depressive episodes.

• Bipolar I Disorder is defined as at least one manic or mixed episode.

• Bipolar I½ consists of hypomanic episodes without depressive episodes.

• Bipolar II is defined as one or more depressive episodes and at least one hypomanic episode.

• Bipolar disorder II½ consists of alternations between hyperthymic (between hypomanic and normophore) and dysthymic states followed by major depression.

• Bipolar III Disorder consists of major depressive episodes followed by drug-induced hypomanic or manic episodes.

• Bipolar III ½ disorder is a drug use disorder in which the drugs cause episodes of hypomania.

• Bipolar IV Disorder consists of stable hyperthymic episodes with depressive episodes.

• Bipolar V disorder consists of mixed epids that do not have the full criteria for mania.

• Bipolar VI disorder is a disorder consisting of alternating depressive episodes characterized by limited attention, irritability, decreased motivation and poor sleep.

It is important to be able to distinguish a bipolar depressive episode from a unipolar depressive episode. This is because bipolar episodes do not respond well to antidepressants and better to mood stabilizers. Bipolar depressive disorder differs from unipolar depressive disorder in that it is more likely to sleep, eat, fear, motor disorders, lability, psychotic symptoms and suicidal thoughts. In addition, the disorder often starts earlier in life, has an abrupt onset, and there are behavioral problems such as many job changes and relationship problems.

What is Norepinephrine?

Norepinephrine (NE) or norepinephrine is made from the amino acid tyrosine, which enters the neuron terminal by means of a tyrosine transporter. In the neuron it is processed by three enzymes: first it is made into DOPA, the enzyme DOPA makes decarboxylase (DDC) DA from it and then the third enzyme, DA β-hydroxylase (DBH), converts it into NE. The NE is then packaged into vesicles via VMAT2 and stored for neurotransmission.

After neurotransmission, the activity of NE can be terminated by two enzymes that destroy NE: MAO (A or B) which is located both presynaptic and elsewhere and COMT which is mainly present extracellularly. NE can also be re-absorbed by the NE re-recording pump NET. In addition to this transporter, there are many other receptors for NE, classified as α1A, α1B and α1C plus α2A, α2B and α2C and β1, β2 and β3. α2 receptors can be presynaptic and postsynaptic, the remaining (α1 and β) receptors can only be postsynaptic. Presynaptic α2 receptors regulate NE release and are thus autoreceptors; they stop issuing NE if they are busy.

Monoamine interactions

NE has bidirectional control over 5HT: it can inhibit (via α2 receptors) or stimulate (via α1 receptors) 5HT release. NE neurons travel from the locus coerleus to the midbrain raphe, where they release NE at postsynaptic α1 receptors on 5HT neuronal cell bodies. This directly stimulates 5HT neurons and acts as an accelerator of 5HT release. This causes release of 5HT from the downstream axons of the 5HT neurons. NE neurons also stimulate the axon terminals of 5HT neurons. Here, NE is released directly onto postsynaptic α2 receptors which then inhibit 5HT neurons, inhibiting 5HT release.

Monoamine and other hypotheses of depression

The classic hypothesis is that depression is caused by a monoamine deficiency. In the case of mania, the opposite may apply: an excess of monoamine neurotransmitters. The entire tri-monoaminergic system (So: SE, DA and NE) would function poorly. There is little evidence for the monoamine hypothesis. That is why attention has shifted to the receptors. The monoamine receptor hypothesis states that a lack of activity of the neurotransmitters leads to an upregulation of the receptors, increasing the need for monoamines. This leads to depression. There is little evidence for this either. It appears that there is mainly a lack in the down signal transmission of the neurotransmitter and the postsynaptic neuron. It may also be related to the neurotrophin BDNF (brain-derived neurotrophic factor); this normally ensures gene viability but could be suppressed under stress and lead to atrophy and possibly also apoptosis of fragile neurons in the hippocampus, leading to depression. Despite the fact that the classical and the receptor hypotheses provide a very simplified representation of reality, these hypotheses have led to a better understanding of the functioning of these three neurotransmitters. We do not know exactly how depression develops, but we have been given ideas on how it might be resolved. After all, all known antidepressants work in such a way that they increase neurotransmission of one or more of these monoamines.

Modern theories suggest that mood disorders are caused by a "conspiracy" between many vulnerable genes and many environmental stressors, leading to a breakdown in information processing in specific brain circuits.

One of the vulnerable genes for depression is the gene that codes for the 5HT transporter, SERT (serotonin reuptake pump). SSRI and SNRI antidepressants target this. The type of SERT you are born with determines in part whether your amygdala is more likely to overreact to anxious faces, whether you are more likely to develop depression when exposed to multiple life stressors, and how likely you are to respond positively to an SSRI / SNRI during depression.

What are the symptoms of a major depressive episode according to the DSM?

• Core symptom (at least one of them):

gloomy mood (↓ NE, SE and DA in amygdala and VMPFC)

• apathy: the lack of interest, emotion, motivation or enthusiasm. Especially occurs in elderly patients with depression. (↓ NE and DA in Nucleus Accumbens, VMPFC, DLPFC, Hypothalamus)

In addition, at least four of the following symptoms:

• change in appetite / weight (↓ SE in hypothalamus)

• altered sleep pattern (↓ NE, SE and DA in hypothalamus, thalamus, basal forebrain)

• psychomotor change: agitation or delay (↓ operation of motor circuits in striatum, PFC, cerebellum)

• fatigue (mental: ↓ NE and DA in PFC, physical: ↓ NE and DA in striatum and nucleus accumbens)

• sense of guilt / worthlessness (↓ SE in amygdala and VMPFC and orbitoFC)

• reduced executive functioning (↓ DA and NE in DLPFC)

• suicidal thoughts (↓ SE in amygdala and VMPFC and orbitofrontal PFC)

Decreased positive affect: depressed mood, loss of pleasure, loss of interest, loss of energy, decreased alertness and self-confidence. This could be related to the dysfunction of DA systems and possibly also to NE. Increased negative affect: depressed mood, guilt, aversion, fear, hostility, irritation, loneliness. This may be related to the malfunctioning of 5HT systems and possibly also NE.

What is a manic episode according to the DSM?

Core symptom (at least one of them):

• Elevated, happy mood (↑ NE, SE and DA in Amygdala, VMPFC and OFC)

• irritable mood (↑ NE, SE and DA in Amygdala, VMPFC and orbitoFC)

In addition, three or more of the following symptoms:

• exaggerated self-esteem (↑ NE, SE and DA in DLPFC and OFC)

• increased activity and arousal (↑ SE and DA in striatum)

• decreased need for sleep (↑ NE, SE and DA in basal forebrain, thalamus and hypothalamus)

• increased distractibility (↑ NE and DA in DLPFC)

• urge to speak (↑ SE and NE in OFC)

• thought flight (↑ NE, SE and DA in DLPFC and OFC)

• risky behavior (↑ SE and NE in OFC)

Neuroimaging in mood disorders

In depressed patients, the resting activity of the DLPFC is lower compared to non-depressed subjects, while the resting activity in the amygdala and in the VMPFC of depressed patients is high compared to others. Emotional symptoms such as happiness or sadness are regulated by VMPFC and the amygdala; two areas that have a higher activity in depressed people. Tests in which emotions are aroused show that the activity in the amygdala is overactive with sad emotions but less active with happy emotions. Impulsive symptoms of mania (risky behavior, urge to talk) are regulated by the OFC. In manic people this area is hypoactive.

In general, the following effects are assumed:

DA dysfunction => positive affect ↓

5HT dysfunction => negative affect ↑

NE dysfunction => both

Overview of the three monoamine neurotransmitters:

This chapter deals with disorders characterized by an abnormal mood: depression, mania or both. Mood disturbances are probably associated with dysregulation of three monoamine neurotransmitters, namely DA, NE and 5HT.

How do antidepressants work and how should they be used? - Chapter 7

There are many different classes and individual antidepressants. It describes how various antidepressants work and how - in what order and in what combination - they can be used.

What are the general principles of antidepressants?

• Response: At least 50% reduction in symptoms through treatment.

• Remission: almost or complete reduction of symptoms after treatment.

• Relapse: The depression returns before a remission is reached or within the first months after a remission

• Recurrence: the depression returns after a longer period of remission.

About one third of patients respond within eight weeks of starting the first drug treatment. Only two-thirds of all patients achieve complete remission of their symptoms after one year of treatment with four different types of antidepressant. Patients who continue drug therapy are much less likely to relapse. This is also where the biggest problem lies: almost one third of the patients stop the medication prematurely. Many people stop before the drug has even had a chance to work.

When complete remission is not achieved, the remaining symptoms are often insomnia, fatigue, pain, difficulty concentrating and lack of interest.

Depressed mood, suicidal thoughts and psychomotor retardation are usually reduced by medication.

When antidepressants cause remission, the chance of relapse is relatively low compared to people who do not achieve complete remission. However, the risk of relapse remains high and increases as patients need more treatments to enter remission.

The risk-effect ratio of the treatment is most favorable in adult patients. In young people, it is less beneficial because of an increased risk of suicide. Older people usually respond less well to antidepressants and experience more side effects.

How Do Antidepressants Work?

There are different classes of antidepressants, but they all have the same principle, which is to boost the synaptic activity of one or more of the three monoamines; DA, 5HT and NE. Often this is done by blocking one or more presynaptic transporters, namely the DAT, the NET and the SERT. This is consistent with the monoamine hypothesis of depression (What are the causes and treatments for mood disorders? - Chapter 6).

The antidepressant effect of the medication is not noticeable as quickly as the increase in the monoamines. This may be due to receptor sensitivity. The increase in the neurotransmitter level only leads to adjustments in the receptor sensitivity after some time, namely downregulation, or the receptors becoming less sensitive. This down regulation provides the antidepressant effect. However, the side effects are present almost immediately, but it is usually observed that as the antidepressants take effect, the tolerance to the side effects increases. This makes sense because the better you feel, the better you can deal with the negative effects of the medication. On the other hand, the side effects are actually less because there is desensitation (down regulation) of the receptors.

The adjustments in receptor number and sensitivity may be due to changes in gene expression, such as increased synthesis of the neurotrophin BDNF and increase of various proteins.

What is the function of selective Serotinin Reuptake Inhibitors (SSRIs)?

The idea is that in depressed patients there is a 5HT deficiency, which means that the number of 5HT receptors is up-regulated. As a result, there are many more 5HT1A and postsynaptic 5HT receptors, so there is a lot of inhibition of 5HT and a lot of 5HT is needed to stimulate a postsynaptic receptor. SSRIs prevent 5HT re-uptake by blocking the transporter SERT. This increases the concentration of 5HT. This takes place not only in the presynaptic axon terminal, but also at the somatodendritic part of the 5HT neuron (near the cell body). It is striking that at the start of the treatment the 5HT concentration mainly increases around the cell body and less at the end of the axon. The somatodendritic 5HT1A autoreceptors desensitize (downregulate) due to the increased amount of 5HT in that area. As a result, there is no longer inhibition and an impulse comes back into the neuron, which results in 5HT being released from the axon. So then there may be an increase of 5HT in the synaptic cleft. Some time has already passed. The increase of 5HT in the synaptic cleft may lead to desensitization of the postsynaptic 5HT receptors, which is thought to be associated with a reduction in side effects.

Side effects can include anxiety, restlessness, delayed psychomotor skills, mild Parkinson's symptoms, sexual dysfunction and decreased libido. Virtually all side effects can be understood as unwanted actions of 5HT on unwanted receptor subtypes in unwanted pathways.

In summary, the above theory suggests the following: SSRIs work by potent, but delayed disinhibition of 5HT release in the brain's nuclear pathways. Furthermore, side effects would be caused by the acute influence of 5HT on unwanted receptors in unwanted pathways. Finally, the side effects can diminish over time through desensitization of the receptors that mediate the side effects.

What types of SSRIs are there?

What is the function of Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)?

SNRIs prevent the reuptake of 5HT and NE by blocking transporters SERT and NET. Although it has long been thought that medication should primarily be aimed at a specific goal in order to reduce the possible side effects as much as possible, it is now again thought that a multiple effect may be necessary. SNRIs affect DA in the prefrontal cortex in addition to the influence on 5HT and NE. This is because there are few DA transporters in the prefrontal cortex and DA is more diffusely present there. However, DA is also taken up by the NET transporter, thus ending DA activity in NE neurons. Due to the blockage of NET in the prefrontal cortex, there is not only more NE present, but also more DA, which therefore has an even greater radius of action. The bottom line is that NET inhibition increases both NE and DA in the prefrontal cortex. So SNRIs have two and a half mechanisms: boosting 5HT and NE across the entire brain and boosting DA in the prefrontal cortex.

Side effects of SNRIs can include tremors, motor activation, agitation and altered blood pressure.

What other types of antidepressants are there?

• Norepinephrine Dopamine Reuptake Inhibitors (NDRIs): Block NET and DAT (Bupropion).

• Selective Norepinephrine Reuptake Inhibitors (NRIs): block NET.

• Agomelatine: Has agonist effects on melatonin 1 (MT1) and MT2 receptors and antagonist effects on 5HT2C receptors (chapter 5).

• Alpha-2 antagonist actions and mirtazapine: Improve the release of monoamines and have an antidepressant effect. α2 antagonists stop the blockage of NE and 5HT release. Mirtazapine with 5HT2 antagonistic properties should enhance the release of various neurotransmitters, which in turn may contribute to antidepressant actions.

• Serotonin Antagonist / Reuptake Inhibitors (SARIs): Block 5HT2A and 5HT2C receptors as well as SERT. It is important here that 5HT2A and 5HT1A receptors have an opposite effect; 5HT on 5HT2A receptors has an excitatory effect and 5HT on 5HT1A has an inhibitory effect. Medication that blocks the 5HT2A receptor enhances the inhibitory effect of 5HT1A receptors. Due to the blocking of SERT, there is more 5HT that mainly works on 5HT1A. 5HT1A receptors stimulate gene expression by signal transduction via a second messenger system. 5HT on the 5HT2A receptors blocks this signal transduction. Thus, by blocking 5HT2A and enhancing 5HT1A, the regulation of neurotrophic factors is helped, which would lead to a reduction in depressive symptoms. In addition, the blocking of 5HT2A and the action of 5HT1A can prevent glutamate release to dysfunctional pyramidal neurons.

How do the classic MAO blockers antidepressants work?

Classic antidepressants inhibit the enzyme MAO. MAO consists of two subtypes, MAO-A and MAO-B. MAO-A breaks down 5HT, NE and DA. MAO-B breaks down DA, and 5HT and NE only when present in high dose. Selective MAO-A inhibition leads to more 5HT and NE and to a lesser extent DA, because this is also broken down by MAO-B. Inhibition of MAO-A is thus an effective antidepressant strategy. Selective MAO-B inhibition leads to slightly more DA, but since MAO-A also breaks down DA, this is only a small increase. MAO-B inhibition therefore has little antidepressant effect. The slight increase in DA can work well for other disorders, such as Parkinson's disease. Combined blocking of MAO-A and MAO-B leads to a large increase in 5HT, NE and DA. The disadvantage of MAO blockers is the risk of hypertension (high blood pressure) after ingestion of food containing tyramine. Tyramine causes NE to be released. Normally, NE cannot reach dangerous amounts because it is destroyed by MAO. When MAO is blocked, there is a risk that the amount of NE becomes too high. Too much NE can cause vasoconstriction (vasoconstriction) and thus increase blood pressure.

Tyramine can be found in food that has been spoiled or fermented, but also in:

• Dried, smoked or fermented meat, poultry or fish.

• Broad beans.

• Old cheeses.

• Non-pasteurized or draft beer.

• Marmite and sauerkraut.

• Soy and tofu products.

The potentially fatal hypertensive reaction that can arise from too much tyramine is characterized by (back) headache, palpitations, nausea, sweating and enlarged pupils. Selegiline is a selective MAO-B inhibitor that does not entail dietary restrictions at low doses. On the other hand, it only inhibits MAO-B and not MAO-A, and is therefore not an antidepressant. At high doses, it does inhibit MAO-A, and thus acts as an antidepressant, but then users must again pay attention to the amount of tyramine they ingest. One solution is to give selegiline transdermally; this means that both MAO-A and MAO-B are inhibited in the brain, but MAO-A is not inhibited in the gut. This means that no dietary restrictions are required. RIMAs are another potential new drug that provides inhibition of MAO-A without risk of tyramine reaction because the action on the enzyme is not irreversible and the blockage of MAO stops in the event of NE accumulation. MAO blockers cannot be combined with decongestants, stimulants, and medications that increase the amount of DA, NE, or SE in any way. So it is very dangerous to make a combination with other antidepressants. Also large amounts of SE (leads to hyperthermia) and DA (leads to behavioral problems and agitation) can be fatal. Because of the risk of 5HT poisoning, a complete wash-out (usually after 5-7 days) of a serotonergic drug is required before starting an MAOI. When switching from a MAO inhibitor (MAOI) to a SERT inhibitor, wait at least 14 days.

How do Tricyclic Anti-Repressants (TCA) work?

Tricyclic antidepressants were mainly so named because of the chemical structure consisting of three rings. They block the readmission pumps for NE (NET), or for both NE and 5HT (SERT). In addition, some TCAs have antagonist effects on 5HT2A and 5HT2C receptors. They have a good antidepressant effect, but as a drawback serious side effects:

• Drowsiness and weight gain (due to antihistamine action on H1)

• Dry mouth, blurred vision, drowsiness and constipation (due to blockade M1-muscarinic cholinergic receptor)

• Hypotension, somnolence and dizziness (due to blockade of the α1-adrenergic receptor)

• In case of overdose: coma, seizures, cardiac arrhythmias and possible death (due to blockage of voltage-sensitive sodium channels (VSSCs))

What are supplements to antidepressants?

Today, more and more drugs, devices, and procedures are used on their own or in combination with standard antidepressants to enhance antidepressant action in patients who do not achieve complete remission. Now a number of natural products, hormones, neurostimulation therapies and psychotherapies will be discussed as alternatives or in addition to antidepressants.

L-5-Methyltetrahydrofolate (L-methylfolate): monoamine modulator

An important regulator of a critical co-factor for monoamine neurotransmitter synthesis, tetrahydrobiopterin (BH4). The monoamine synthetic enzyme that requires BH4 as a co-factor are both tryptophan hydroxylas (the rate-limiting enzyme for 5HT synthesis) and tyrosine hydroxylase (the rate-limiting enzyme for DA and NE synthesis). Low levels of L-methylphodate from genetic and / or environmental / nutritional causes could theoretically lead to low monoamine synthesis and thus contribute to depression or to the resistance of some patients to antidepressant treatment that rely on continuous monoamine synthesis work, such as SSRIs / SNRIs.

A second mechanism involving L-methylfolate affects monoamine levels. Methylation of genes suppresses these levels. L-methylfolate provides the methyl group for this process, so when L-methylfolate is limited, repression of various genes could also be limited. So when the gene suppression for the enzyme COMT is limited, more copies of this enzyme are made and the enzyme activity increases, causing DA levels to drop, especially in the prefrontal cortex. This could adversely affect information processing and cause symptoms such as cognitive dysfunction.

The effects of two or more high-risk genes working together to increase the risk of a disease or disorder is also called epistasis.

S-adenosyl-methionine (SAMe)

L-methylfolate is converted to methionine and eventually to SAMe, the direct methyl donor for methylation reactions. High SAMe doses could be effective in addition to antidepressants in patients with major depression.

Thyroid

Throid hormones act by binding to nuclear ligand receptors to form a nuclear ligand-activated transcription factor. Abnormalities in this hormone have been associated with depression and can be used as add-on medications to antidepressants. Thyroid hormones can boost monoamine neurotransmitters.

How else can depression be treated?

1. Electroconvulsion therapy (ECT) is very effective in persistent depression. It is the only antidepressant that works quickly. The underlying mechanism is unknown.

2. Transcranial Magnetic Stimulation (TMS): magnetic influence from the outside, whereby signals are generated in the brain.

3. Deep brain stimulation (DBS) is an experimental treatment for the most severe forms of depression. The stimulation device is a pulse generator (type of pacemaker) that is implanted in the chest. One or two pipes run directly into the brain. These leads end with an electrode on the areas of the brain involved in a particular disorder. The pulse generator gives short, repeated signals that run through the leads to the electrodes. Currently, electrodes are placed in the subgenual region of the anterior cingulate cortex, part of the centromedial prefrontal cortex (VMPFC), in the treatment of depression. The short, repetitive signals from DBS may boost monoamine activity, relieving depressive symptoms.

4. Psychotherapy: Can be thought of as epigenetic "drugs", or therapeutic agents that respond epigenetically in a way that is similar to or complementary to drugs. So it is probably just as effective as antidepressants.

How is the right treatment chosen?

Theoretically, following the evidence is the best way to select a treatment for depression. Unfortunately, there is little evidence that one option is better than the other. A general principle that most patients and doctors agree on, namely when to switch to another antidepressant and when additional treatments are needed.

The most modern psychoframacological way to treat depression is a symptom-based approach to select or combine a range of antidepressants. This strategy leads to the construction of a portfolio of multiple therapies to treat all individual symptoms of unipolar depression until the patient achieves complete and sustained remission. First, symptoms are constructed into a diagnosis, and then deconstructed into a list of specific symptoms. Then these symptoms are linked to the brain circuits that may be involved in the symptoms and then to the known neuropharmacological regulation of these circuits by neurotransmitters. Finally, available treatment options are selected that target these neuropharmacological mechanisms in order to eliminate symptoms one by one. When symptoms persist, treatment with a different mechanism is added or the current treatment is replaced.

How do antidepressants work in women?

Estrogen levels change throughout a woman's life cycle. These changes have also been linked to the onset or recurrence of depressive episodes. During the fertile years, women are 2-3 times more likely to develop depression than men. The issue of treating pregnant women is a tricky one. Treating and not treating the depression carries risks for both mother and child. There are no clear guidelines, but clinicians are advised to assess the risks and benefits of treatment on a case-by-case basis. There are also no fixed guidelines with regard to the period just after pregnancy during which mothers breastfeed (a period in which there is a risk of postnatal depression). Again, a cost-benefit analysis must be made on a case-by-case basis.

How are antidepressants chosen based on genetic testing?

Genotyping is currently about to be introduced into routine mental health practice. Until then, it is already possible to obtain genotyping from different laboratories for various genes that may be linked to psychiatric diagnoses and drug responses. For example, different genetic forms of the cytochrome P450 (CYP) enzyme system can be obtained to predict high or low drug levels of substrate drugs. These CYP genotypes, in combination with therapeutic drug monitoring of drug levels, may be able to explain the side effects and lack of therapeutic effects in some patients.

Antidepressant combinations as a standard for the treatment of unipolar major depressive disorder?

Given the disappointing number of patients who achieve complete remission after major depressive episode or who can maintain remission over a longer period of time, the paradigm of prescribing a series of monotherapies is rapidly changing to one in which multiple pharmacological mechanisms are prescribed simultaneously. In this sense, the same pattern is followed as with bipolar disorder. The question is not whether multiple pharmacological mechanisms should be administered simultaneously in patients with treatment-resistant depression, but whether multiple mechanisms and / or medications should be given earlier in treatment or perhaps even from the beginning. Possible combinations are:

• Triple-action combo: NDRI in combination with SSRI or SNRI.

• Calfornia rocket fuel: Combination of SNRI and mirtazapine.

• Arousal combinations: Combination of a stimulant (such as lisdexamfetamine) or modafinil with an SNRI.

What are the options for the future?

Various drugs are currently being tested, such as glucocorticoid antagonists, CRF-1 antagonists and vasopressin-1B antagonists. Triple reuptake inhibitors (TRIs) or serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs) are currently being tested to confirm that if one mechanism is good (eg SSRI), and two mechanisms are better (eg SNRI), it may be most effective is to target all three mechanisms of the trimonoamine neurotransmitter system.

It appears that combining multiple modes of monoaminergic influence may improve effectiveness for some patients with depression. One of the most interesting developments in recent years has been the observation that infusions of sub-anesthetic ketamine doses can exert an immediate antidepressant effect in patients with treatment-resistant unipolar or bipolar depression, and can immediately reduce suicidal ideation.

There are many different classes and individual antidepressants. It describes how various antidepressants work and how - in what order and in what combination - they can be used.

How do mood stabilizers work? - Chapter 8

In this chapter, the pharmacological concepts of mood stabilizers are discussed. There are many ways in which mood can be stabilized and thus many types of drugs that are used for this.

What is a mood stabilizer?

Originally, a mood stabilizer was a drug that counteracts mania and thereby stabilizes the manic portion of bipolar disorder. Today, there are more types of mood stabilizers, including lithium-like drugs, anti-seizure drugs, and atypical anti-psychotics. These drugs all work in one way or another to counteract the symptoms of bipolar disorder. So you have mania-directed therapies, the so-called stabilization from above, and therapies aimed at depression, the so-called stabilization from below.

How does lithium work?

Lithium has been used for fifty years. It is an ion of which the function is not exactly known, but it is suspected that it affects signal transduction, perhaps through the inhibition of second messenger enzymes or by interacting elsewhere in a transduction cascade. It is effective against mania, especially euphoric mania. It also prevents suicide. It is less effective against the depressive phase of bipolar disorder. Known side effects of lithium include nausea, vomiting, diarrhea, weight gain, hair loss, acne, tremors, sedation, impaired cognitive function and poor coordination. It has long-term adverse effects on the kidneys and thyroid glands. Due to weight gain, it is important to monitor parameters such as BMI. It is important to find a dose with lithium that is above the therapeutic threshold, but below the level that causes side effects. Lithium works well as a maintenance medication, but also for the acute phase.

How do anti-seizure drugs work as mood stabilizers?

Based on the idea that mania triggers more episodes of mania and that a seizure triggers other seizures, an attempt has been made to reduce manic phases in the same way as they reduce seizures in epilepsy. This proved effective in some cases:

Antiepileptics with uncertain or questionable effects in bipolar disorder:

How do atypical antipsychotics work?

These sometimes work for non-psychotic mania as well. Probably due to the D2 antagonist effect. They also work well against depression, probably due to their action on 5HT2A and 5HT1A receptors. The A1 inhibition is likely to counteract the insomnia commonly seen in bipolar disorder. Not all atypical antipsychotics work equally well for everyone. Risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole have proven anti-manic activity. Quetiapine and possibly lurasidone are also effective for bipolar depression.

What other drugs are used in bipolar disorder?

• Benzodiazepines: These are sometimes used to reduce agitation and provide tranquility.

• Modafinil and armodafinil: These are also called stimulants and block the DA transporter (DAT).

• Hormones and natural products:

1. Omega-3 Fatty Acids EPA and DHA: EPA is an essential fatty acid and can be metabolized to DHA. Omega-3 fatty acids may inhibit PKC (protein kinase C). The effect of these fatty acids has not yet been proven effective in bipolar disorder.

2. Inositol: a natural product associated with second messenger systems and signal transduction cascades, especially for the phosphatidyl inositol signals, which are related to various neurotransmitter receptors, such as the 5HT2A receptor. Possibly as effective as an antidepressant add-on, such as proven mood stabilizers such as lamotrigine and risperidone. Further research is needed

3. L-methylfolate: May boost monoamine neurotransmitter function in bipolar disorder, but little research has been done on it.

4. Thyroid hormone: T3 in particular is said to stabilize mood in some patients with bipolar disorder. This has not yet been well researched and somewhat controversial.

How do mood stabilizers work in clinical practice?

Most patients require a combination of agents. It is important to learn the mechanisms of action of the known and recognized mood stabilizers, familiarize yourself with the evidence for the effectiveness and safety of these agents in monotherapy trials, and then construct a unique portfolio of treatments per patient. Research shows that lithium or valproic acid along with an atypical antipsychotic is an effective combination. In addition, there are a number of other well-functioning combinations:

• Atypical lithium combo: atypical antipsychotic + lithium

• Atypical valproate combo: atypical antipsychotic + valproate

• Li-Vo: lithium + valproate

• La-Vo: lamotrigine + valproate

• La-Li: lamotrigine + lithium

• La-Li-Vo: lamotrigine + lithium + valproate

• Lami-quel: lamotrigine + quetiapine

• Boston bipolar brew: a combination of mood stabilizers without an antidepressant

• California careful cocktail: a combination of mood stabilizers + antidepressant

• Tennessee mood shine: antidepressant + atypical antipsychotic

Options for the future:

• New antipsychotics and new anti-epileptics.

• New ways to increase GABA action or block glutamate.

In this chapter, the pharmacological concepts of mood stabilizers are discussed. There are many ways in which mood can be stabilized and thus many types of drugs that are used for this.

Where do anxiety disorders come from and how are they treated? - Chapter 9

This chapter focuses on various brain circuits and neurotransmitters that are mainly related to the amygdala and that underlie anxiety disorders.

What are Anxiety Disorders?

The symptoms of anxiety disorders often overlap with those of major depression, especially sleep problems, difficulty concentrating, fatigue and psychomotor / arousal symptoms. In addition, every anxiety disorder has a large overlap with other anxiety disorders. Anxiety disorders often coexist with other disorders such as depression, other anxiety disorders, substance abuse, ADHD, bipolar disorders, pain disorders, sleep disorders, and more. Anxiety disorders have two core symptoms: fear and worry. Anxiety is regulated by the amygdala and manifests itself in panic or phobias. Concerns are regulated by the CSTC loops and manifest themselves in exaggerated concern, anxiety about the future, and obsessions. Overactivity of neurons in the amygdala or CSTC underlies an anxiety disorder.

What is the relationship between the amygdala and fear?

The processing of a fear response is regulated by numerous neuronal connections that flow in and out of the amygdala. Each compound uses specific neurotransmitters that act on specific receptors. It is known about these compounds that not only are various neurotransmitters involved in the production of anxiety symptoms in the amygdala, but also that many anxiolytic drugs act on these specific neurotransmitter systems to relieve the anxiety symptoms. The neurobiological regulators of the amygdala - including the neurotransmitters GABA, 5HT and NE, VSCCs, and anxiolytics that act on these neurotransmitters to mediate their therapeutic actions - are discussed further in this chapter.

What is the relationship between CSRC loops and concerns?

Concerns are linked to CSTC feedback loops in the prefrontal cortex. Various regulators and neurotransmitters - including 5HT, GABA, DA, NE, glutamate and VSCCs - modulate these circuits. These overlap very much with many of the same neurotransmitters and regulators that modulate the amygdala. Since various genotypes for the enzyme COMT regulate the availability of DA in the prefrontal cortex, differences in DA availability may have a potential impact on the risk of worry and anxiety disorders and may help determine whether you were 'born with worry' and thus are vulnerable to developing an anxiety disorder. DA is just one of the potential regulators of health circuits and CSTC loops.

What is the neurotransmitter GABA?

GABA is one of the important neurotransmitters involved in anxiety and is affected by anti-anxiety medications. GABA is an inhibitory neurotransmitter; it thus reduces activity in the amygdala and the CSTC loops, among others. GABA activity can be terminated by GAT. Inside the cell, GABA can be destroyed by the enzyme GABA-Transaminase (GABA-T). There are three main GABA receptors: GABA-A, GABA-B and GABA-C. GABA-A and GABA-C are ligand dependent ion channels. GABA-A receptors play a critical role in mediating inhibitory neurotransmission and are the target of various anti-anxiety agents (eg, benzodiazepines and alcohol). There are two types of GABA-A receptors:

Benzodiazepine sensitive GABA-A receptors: These mediate phasic inhibition, which occurs in bursts triggered by excessive levels of GABA. Benzodiazepines increase this phasic postsynaptic inhibition in overactive neurons in the amygdala or in the CSTC loop, reducing anxiety and worry.

Benzodiazepine-insensitive GABA-A receptors: These are extra-synaptic and take up the GABA that is diffusely distributed in the synapse. These benzodiazepine insensitive GABA-A receptors mediate tonic inhibition.

Benzodiazepines increase the effect of GABA. GABA by itself can increase the frequency of opening the chloride channel, but only to a limited extent. The combination of GABA and benzodiazepines may increase the frequency of opening inhibitory chloride channels, but does not affect the conduction of chloride across individual chloride channels or the duration of the channel opening. The end result is more inhibition, and more inhibition would produce more anxiolytic action. This process occurs because benzodiazepines act as agonists at the allosteric modulator binding site of GABA; thus they act as PAMs when GABA binds to agonist binding sites. With flumazenil, the positive allosteric modulation of benzodiazepines can be reversed in people with an anxiety disorder, thus acting as a reverse agonist in them.

How do α2-delta ligands act as anxiolytics?

Gabapentin and pregabalin, also known as α2δ ligands, block the release of excitatory neurotransmitters, such as glutamate, when neurotransmission is excessive and causes anxiety and worry in the amygdala and CSTC circuits. α2δ ligands have different mechanisms of action compared to 5HT reuptake inhibitor or benzodiazepines, and thus may be useful in patients who do not respond well to SSRIs / SNRIs or benzodiazepines. Α2δ ligands can also be combined with SSRIs / SNRIs or benzodiazepines in patients who partially respond to medication but do not go into remission.

What is the relationship between 5HT and anxiety?

5HT is a crucial neurotransmitter that innervates both the amygdala and all elements of CSTC circuits, thus regulating both anxiety and worry. Antidepressants that increase 5HT output by blocking SERT are also effective in reducing anxiety symptoms in the following anxiety disorders; generalized anxiety disorder, panic disorder, social anxiety disorder and post-traumatic stress disorder. These antidepressants include both SSRIs and SNRIs. Buspirone, a 5HT1A partial agonist, is considered a general anxiolytic, but not a treatment for anxiety disorder subtypes. The potential anxiolytic actions of buspirone could be due to 5HT1A partial agonist actions on both presynaptic and postsynaptic 5HT1A receptors, leading to enhanced serotonergic activity in projections on the amygdala, prefrontal cortex, striatum and thalamus. SSRIs and SNRIs theoretically do the same. The potential mechanism of action of 5HT1A partial agonists thus appears to be analogous to that of antidepressants and different from that of benzodiazepines.

What is the role of noradrenergic hyperactivity in anxiety disorders?

NE provides input in the amygdala as well as in other areas. It plays an important role in fear responses. Noradrenergic hyperactivity can cause anxiety, panic attacks, tremors, sweating, nightmares and irritability. Medication that leads to NET inhibition (NRIs, SNRIs) could thus lead to a reduction in anxiety. Other noradrenergic anxiolytic medications are α1 blockers.

Fear Conditioning or Fear Extinction?

Anxiety conditioning takes place because the amygdala remembers, as it were, which stimuli were present during the fear experience. Exposure to those stimuli therefore induces fear. Fear conditioning can be inhibited by repeated experience in which the stimulus is experienced without negative consequences. As a result, the response to the stimulus becomes less and less. This is often referred to as fear extinction, but it may not be accurate. The VMPFC and the hippocampus may learn new things and send that to the amygdala so that it suppresses the fear response, but that doesn't mean that this fear response is gone. The fear experience is forgiven, but not forgotten. In the output it therefore depends on which synapses are the most robust. To help with this, NMDA co-agonists D-cycloserine work well. Taking this medication during exposure to the stimulus without negative experience (eg exposure therapy) helps to strengthen the "non-anxious" synapses. Giving beta-blockers right after a trauma would actually counteract the strengthening of synapses, so that no fear conditioning arises.

Once fear conditioning has set in, it is difficult to return. Yet there may be two ways to neutralize fear conditioning, namely through extinction or by blocking the reconsolidation process. The first way reduces the response to a dreaded stimulus. The dreaded stimulus is presented repeatedly with no adverse consequences. While extinction can greatly reduce the fear response, the original fear conditioning is not really forgotten. Rather than reversing the synaptic changes that occur in fear conditioning, it appears that yet another new way of learning with modified synaptic changes is taking place in the amygdala. Anxiety extinction may occur through activation of the input from the VMPFC and hippocampal glutamate neurons in the lateral amygdala that synapses on an inhibitory GABA interneuron located within the cell mass of the amygdala. This creates a gate in the central amygdala where fear output occurs when the fear conditioning circuits predominate, and no fear output when the fear extinction circuits predominate.

Fear extinction seems more unstable than fear conditioning. Also, fear conditioning can return when the old fear is presented in a context that is different from the context in which fear extinction was taught. This process is also called renewal. New approaches to treating anxiety disorders are looking for a way to facilitate fear extinction, rather than suppress a fear conditioning triggered fear response (which is what current anxiolytic drugs do).

Blocking fear memory reconsolidation is a second mechanism that could be an effective treatment for people with anxiety disorders. When fear is first conditioned, this memory is consolidated through a molecular process. Reconsolidation is the state in which reactivation of a consolidated fear memory renders it unstable. It requires protein synthesis to keep memory intact. Beta blockers disrupt both the recollection of fear memories and the formation of fear conditioning. More research is needed to determine how psychotherapy can be used.

How are anxiety disorders treated?

• Generalized Anxiety Disorder: SSRI / SNRI and Benzodiazepines

• Panic disorder: SSRI / SNRI and benzodiazepines.

• Social anxiety disorder: SSRI / SNRI and benzodiazepines. If there is no effect, possibly beta or MAO blockers.

• PTSD: SSRI / SNRI. Preferably no benzodiazepines due to comorbid substance abuse.

This chapter focuses on various brain circuits and neurotransmitters that are mainly related to the amygdala and that underlie anxiety disorders.

What is pain and how is it treated? - Chapter 10

The treatment of chronic pain disorders by means of pychopharmaceuticals is a relatively new field in psychopharmacology. There are debates about the symptomatic and physiological overlap between pain disorders and mental disorders, mainly depression and anxiety disorders. This chapter examines the clinical and biological aspects of pain and how it can be treated with many of the same agents that we also use for anxiety or depression.

What is pain and what are the causes?

Pain is an unpleasant sensory and / or emotional experience, which is caused by actual or possible tissue damage or is described in terms of tissue damage. Thus, actual tissue damage is not necessary and pain is defined as a human and subjective experience. There are different types of pain:

• Acute pain: has a vital function of indicating damage to the body and leaving an injured part of the body alone. This pain subsides, is a natural process, has a clear cause and responds well to treatment

• Chronic pain: when the cause is unclear or cannot be remedied, the pain sometimes persists and is referred to as chronic pain. This pain often does not go away, is pathological and difficult to treat.

The causes of chronic pain can be divided into three categories:

• Peripheral: cause outside the central nervous system (brain and spinal cord). Responds well to NSAIDs (nonsteroidal anti-inflammatory drugs) and opiates.

• Central: cause within the central nervous system. Responds well to SNRIs, α2δ ligands, TCAs and anti-epileptics.

• Mixed: cause both within and outside the central nervous system. Mainly responds well to central treatments, but both types help.

What is the relationship between normal pain and nociceptive nerve activation?

Nociception is the process by which a nociceptor, a nerve specialized in sensing stimuli with a harmful influence, detects a noxious stimulus and generates an action potential to transmit a signal to the higher nociceptive centers in the brain. Primarily afferent neurons detect sensory input, including pain. Nociception starts with transduction; the process by which specialized membrane proteins located on the peripheral projections of these neurons detect a stimulus and generate a voltage change on their peripheral neuronal membranes. A sufficiently strong stimulus will depolarize the membrane to activate VSSCs and trigger an action potential to the central terminals of the neuron in the spinal cord. Nociceptive impulses from primary afferent neurons into the central nervous system can be reduced or stopped by blocking the VSSCs.

There are three different types of primary afferent neurons (PANs):

• Aβ fibers: detect small movements, light touch, hair movement and vibrations.

• Aδ fibers: detect harmful mechanical stimuli and non-harmful thermal stimuli.

• C fibers: are only activated by harmful mechanical, thermal or chemical stimuli.

Abnormal central processing of these neurons can create the subjective experience of pain in mental disorders (such as fibromyalgia, depression, irritable bowel syndrome or anxiety).

All cell bodies of these PANs lie in dorsal horn ganglia and they synapses on projection neurons in the dorsal horn in the spinal cord. These projection neurons send the signal through the spinal cord to your brain. The spinothalamic tract runs from the spinal cord (spino) to the thalamus (thalamicus) and provides information about the intensity and location of acute (vital) pain. This can be blocked by 5HT, opiates and SNRIs, which ensures that no conscious pain sensation takes place in the brain. These local narcotics block the VSSCs, stopping the action potential.

What is Neuropathic Pain?

Neuropathic pain is chronic pain that arises from damage or malfunctioning of (part of) the nervous system, for example due to illness or trauma. This changes the electrical activity of neurons, which leads to a sensation of pain.

At any place in the nervous system, the nociceptive pain signal can be modulated to make the signal weaker or stronger. Segmental central sensitization is a process thought to be caused when plastic changes occur in the dorsal horn, particularly in pain disorders such as phantom pain. This kind of neuronal plasticity in the dorsal horn is also referred to as activity dependent or use dependent, as it calls for constant firing of the pain pathway in the dorsal horn. As a result of this constant pain input, it ultimately produces exaggerated or sustained responses to any harmful input - a phenomenon sometimes referred to as "wind-up" - and painful responses to normally harmless input (allodynia). In segmental central sensitization, peripheral damage is combined with central sensitization on the spinal cord segment which receives nociceptive input from the damaged area of ​​the body. "Suprasegmental" central sensitization is linked to plastic changes that occur in areas of the brain within the nociceptive pathway, particularly the thalamus and cortex, in the presence of known peripheral causes, or in the absence of identifiable triggering events.

The spectrum of mood and anxiety disorders with pain disorders

A large group of overlapping disorders can be emotional symptoms, painful physical symptoms, or both.

Fibromyalgia: chronic pain syndrome with the symptoms of tenderness of muscles, joints and ligaments, without pathology in the structure. For diagnosis, there must be sensitivity to at least 11 of the 18 specific trigger points where ligaments and muscles are attached to bone. Other symptoms include fatigue and non-restorative sleep, difficulty concentrating and mental fatigue ("fibro-fog", cognitive symptoms). The cause of fibromyaglia is unknown, it may be related to viral infections, toxins, or emotional or physical trauma. Most people diagnosed with fibromyalgia have a comorbid anxiety or mood disorder, a functional somatic syndrome, or both.

Results from preliminary reports suggest that chronic pain could "shrink" the brain in the dorsolateral prefrontal cortex (DLPFC), contributing to cognitive dysfunction in certain pain states, such as fibromyalgia and lower back pain. These findings suggest a possible structural consequence of suprasegmental central sensitization. Abnormal pain processing, exaggerated pain responses and persistent pain could be linked to deficits in the DLPFC circuit and the regulation of this circuit by DA. It could provide a possible explanation for the cognitive difficulties associated with chronic pain, particularly with fibromyalgia fibromyalgia. Chronic pain syndromes thus cause not only pain, but also problems related to fatigue, concentration, sleep, anxiety and depression.

How Is Chronic Pain Treated?

Descending spinal synapses in the dorsal horn

The periaqueductal gray (PAG) is the site of origin and regulation of much of the descending inhibition that projects through the spinal cord onto the dorsal horn. The PAG integrates input from nociceptive pathways and limbic structures, such as the amygdala and limbic cortex, and directs output to brainstem nuclei and the rostroventromedial medulla to direct descending inhibitory pathways. There are three main downhill braking paths:

• Descending endorphins pathway: Endorphins are released and act through the presynaptic mu-opiod receptors to inhibit the nociceptive PANs in the hind horn.

• Descending spinal norepinephrine (NE) path. See below.

• Descending spinal serotonergic (5HT) pathway. At 2 and 3, either noradrenergic or serotonergic neurons are released which inhibit the activity of the hind horn neurons. This prevents harmless bodily input from reaching the brain and being interpreted here as pain. If this inhibition is insufficient, irrelevant nociceptive input may be interpreted as pain. This is likely to happen with IBS and fibromyalgia.

An SNRI can increase norepinifrinergic and serotonergic neurotransmission in the descending spinal pathways to the posterior horn. Therefore physical input cannot reach the brain and cannot be interpreted as pain.

In severe injuries, descending inhibition leads to the release of endogenous opiates, 5HT and NE. This reduces the release of nociceptive neurotransmitters in the hind horn. It also reduces the transmission of nociceptive impulses to the brain, making pain less perceived. This process makes it possible to escape from a dangerous situation with a serious injury. Descending facilitation replaces descending inhibition to restore balance; the pain is again strongly perceived.

Targeting sensitized circuits in chronic pain disorders

When chronic pain occurs at the segmental level, it can likely be linked to the various neurotransmitters released here, with the mechanisms of neurotransmitter release calling for presynaptic depolarization and activation of N-type and P / Q-type VSCCs. When this occurs at suprasegmental levels in the thalamus and cortex, it is likely linked to release of mainly glutamate via the same N-type and P / Q-type VSCCs. The idea is that low neurotransmitter release does not create a pain response because there is not enough neurotransmitter release to stimulate the postsynaptic receptors. However, normal amounts of neurotransmitter release cause a complete nociceptive pain response and acute pain. In the state of central sensitization, there is excessive and unnecessary sustained nociceptive activity causing neuropathic pain. Blocking VSCCs with the α2δ ligands gabapentin or pregabalin inhibits release of various neurotransmitters in the dorsal horn or in the thalamus and cortex and has been shown to be an effective treatment for a variety of disorders causing neuropathic pain.

Targeting additional symptoms in fibromyalgia

The combination of α2δ ligands and SNRIs has not yet been properly investigated. Yet they are often used together in clinical practice and appear to provide additional improvement in pain relief. The combination seems to relieve pain even more than either of the two alone, although both are effective in relieving fibromyalgia pain. α2δ ligands may reduce anxiety symptoms in fibromyalgia and improve fibromyalgia slow-wave sleep disorder. SNRIs may be useful in reducing depression and anxiety symptoms in fibromyalgia and in treating fatigue and cognitive symptoms associated with fibromyalgia (fibro-fog)

Executive functioning problems are generally linked to inefficient information processing in the DLPFC, where DA neurotransmission is important in regulating brain circuits. Other strategies for improving fibro-fog in patients with fibromyalgia include the same strategies used to treat cognitive dysfunction in depression, including modafinil, armodafinil, NRIs and NDRIs. SNRIs, sometimes supplemented with modafinil, stimulants or bupropion, may also be useful for physical and mental fatigue in fibromyalgia patients. Second-line treatments for fibromyalgia pain may include mirtazapine and tricyclic antidepressants, as well as tricyclic muscle relaxants (cyclobenzaprine). Sleep medications, such as benzodiazepines, hypnotics, and trazodone, can help relieve sleep disturbances in fibromyalgia. In addition to the α2δ ligands, a number of other anti-epileptic drugs can be used for chronic neuropathic pain, including fibromyalgia. These drugs are thought to target VSSCs rather than VSCCs, and thus appear to have a different mechanism of action than α2δ ligands, and may be effective in patients with inadequate response to α2δ ligands. Other complementary or experimental treatments for various chronic pain disorders include botulinum toxin injections, cannabinoids, NMDA antagonists and various new anti-epileptics.

The treatment of chronic pain disorders by means of pychopharmaceuticals is a relatively new field in psychopharmacology. There are debates about the symptomatic and physiological overlap between pain disorders and mental disorders, mainly depression and anxiety disorders. This chapter examines the clinical and biological aspects of pain and how it can be treated with many of the same agents that we also use for anxiety or depression.

What are sleep disorders and how are they treated? - Chapter 11

This chapter deals with the psychopharmacology of sleep and wake disorders. The detection and treatment of sleep-wake disorders is becoming an increasingly important part of a psychiatric evaluation. Sleep disorders are so important and pervasive in all aspects of life that it is necessary to resolve them as soon as possible.

Which systems are involved in sleeping and awake?

The arousal spectrum ranges from insufficient arousal (sleep) to excessive arousal (psychosis). Arousal is affected by histamine, DA, NE, 5HT and acetylcholine. Two systems involved in arousal, sleep and wake:

• CSTC loops regulate arousal by controlling the thalamic filter, among other things. This filter determines whether sensory information such as sound or light is passed on to the brain. Only important information is passed on during sleep, otherwise everything would wake you up. Thus, treatment of insomnia is to strengthen the filter by GABA enhancers. The treatment of drowsiness is actually reducing the filter by increasing DA.

• Sleep / wake switch on hypothalamus: whether you are awake or asleep is determined by the sleep / wake switch. This switch looks like a kind of seesaw: if the right side is down you are asleep, if the left side is down you are awake. The bud is located in the ventrolateral preoptic (VLPO) nucleus of the hypothalamus and the bud is in the tuberomammilar nucleus (TMN) of the hypothalamus. This switch is regulated by histamine (from the TMN) and GABA (from the VLPO). Histamine release promotes wakefulness and GABA promotes sleep. Hypocretin / orexin is a neurotransmitter that stabilizes the sleep / wake switch and, as it were, sits on the active (sleep or wake) side of the seesaw, so that you do not suddenly switch from sleep to wake. The suprachiasmatic nucleus of the hypothalamus also aids in stabilization because this structure is activated by light and is thus, as it were, the inner clock of your body.

Disorders characterized by excessive daytime sleepiness can be conceptualized as having the sleep / wake switch off during the day. Awake-promoting treatments, such as modafinil, can restore balance to wakefulness by promoting the release of histamine from TMN neurons.

Disorders characterized by insomnia can be conceptualized as having the sleep / wake switch on during the night. Insomnia can be treated with drugs that promote GABA activity, thus inhibiting the waking promoter, or with drugs that block histamine action and thus act as postsynaptic H1 receptors.

Disorders characterized by a disturbance in the circadian rhythm can be conceptualized as either 'phase delayed', where the wake promoter and sleep / wake switch start too late in a normal 24-hour cycle (often in depression or during adolescence) , or 'phase advanced', where the wake promoter and sleep / wake switch start too early in a normal 24-hour cycle (often in older people). With phase delayed circadian rhythms, someone is active at night and sleepy in the morning. So there is no activity in the morning and too much activity in the evening. This can be remedied by using a daylight lamp in the morning and taking melatonin in the evening, so that the SCN is reset and the sleep-wake button turns on earlier. With "phase advanced" circadian rhythms, someone wakes up too early and is very tired at night. A daylight lamp in the evening and taking melatonin in the morning can help.

What is the neurotransmitter histamine?

Histamine is a major neurotransmitter in wakefulness regulation and is therefore the target of many wake-promoting drugs (via downstream histamine release) and sleep-promoting drugs (antihistamines). Histamine is broken down by two enzymes that work together: histamine NMT breaks down histamine and MAO-B converts it into an inactive substance (N-MIAAA). Histamine has different receptors. Histamine 1 and 2 (H1 and H2) are postsynaptic and histamine 3 (H3) is a presynaptic autoreceptor. When histamine binds to postsynaptic H1 and H2, it activates a G-protein linked second messenger system, ensuring normal alertness. Antagonists of H1 and H2 prevent the activation of the second messenger and therefore facilitate sleep. When histamine binds to presyaptic H3 autoreceptors, further histamine release is stopped. Antagonists of these receptors promote wakefulness because they disinhibit the release of histamine.

Histamine also acts on NMDA receptors. Histamine neurons are all from the TMN.

What Is Insomnia and How Is It Treated?

Insomnia or insomnia is the most common sleep disorder. It boils down to excessive nighttime arousal that prevents you from sleeping. The sleep / wake switch is on awake, so TMN is on and histamine inhibits the VLPO. The old guidelines recommend short-term use of hypnotics, whereby the influence of hypnotics must be continuously evaluated. Medicines that work well for insomnia are benzodiazepines, GABA-A PAMs (also called z-drugs, because the names of the medicines start with a 'z': zaleplon, zolpidem, zopiclone), melatonin, 5HT hypnotics (such as the antidepressant trazodone H1 antagonists, DA agonists and α2δ ligands (if insomnia is secondary to another disorder, such as restless legs syndrome. Cognitive behavioral treatments and sleep hygiene may also be effective.)

Some empirical clinical observations have shown that slow-wave sleep deficiency may contribute to a feeling of lack of restorative sleep and daytime fatigue. Patients with pain disorders and a lack of slow-wave sleep may experience an improved subjective experience of their pain during the day; patients with depression and a lack of slow-wave sleep may experience improved symptoms of fatigue, apathy and cognitive dysfunction. So adequate restorative slow-wave sleep may seem positive at first, however, the evidence of how much is enough and the implications of too little slow-wave sleep are not yet known. Some drugs, such as SSRIs / SNRIs, stimulants and stimulant antidepressants (NDRIs) can all interfere with slow-wave sleep, and a limited number of drugs - namely α2δ ligands, GABA reuptake inhibitor tiagabine, 5HT2A / 2C antagonists (including trazodone and GHB) - are known to improve slow-wave sleep.

What is the function of orexin antagonists?

Orexin neurons are located exclusively in certain regions of the hypothalamus (lateral hypothalamic region, perifornic region, and posterior hypothalamus). These neurons make the neurotransmitters orexin-A and orexin-B, which are released from their neuronal projections all over the brain, but particularly in the monoamine neurotransmitter centers in the brainstem. The postsynaptic actions of the orexins are mediated by two receptors called orexin-1 and orexin-2. Orexin-A interacts with both orexin-1 and -2 receptors, but orexin-B interacts only with orexin-2 receptors. The effect of orexin on vigilance is believed to be largely mediated by activation of the TMN histamine neurons expressing orexin-2 receptors. Orexin-2 receptors may therefore play a central role, and orexin-1 receptors play an additional role in sleep / wake regulation. Deficiency of orexins is associated with narcolepsy. Pharmacological blockade of orexin receptors has been explored not only as a novel hypnotic mechanism, but also for weight loss and substance abuse. Some dual Orexin receptor antagonists (DORAs), such as almorexant and suvorexant, appear to be effective in the treatment of insomnia.

What is the cause and treatment of hypersomnia?

Hypersomnia or excessive daytime sleepiness is due to poor arousal during the day. The most common cause is sleep deprivation, and the treatment for this is sleep, not drugs. Other causes are various sleep disorders, mental disorders, medication and medical disorders. Hypersomnia patients have problems with cognitive functioning. Medicines that work well against this are modafinil, stimulants, caffeine, and GHB.

This chapter deals with the psychopharmacology of sleep and wake disorders. The detection and treatment of sleep-wake disorders is becoming an increasingly important part of a psychiatric evaluation. Sleep disorders are so important and pervasive in all aspects of life that it is necessary to resolve them as soon as possible.

What is ADHD and how is it treated? - Chapter 12

ADHD and its pharmacological treatment are part of rapidly evolving psychopharmacology. It is increasingly seen as not just an attention disorder or only occurring in children. This chapter discusses ADHD, its causes and the biological basis for symptom relief through psychotropic drugs.

What are the symptoms of ADHD?

ADHD consists of three symptoms:

• Attention problems

  • Problems with selective attention

  • Problems with sustained attention

• Hyperactivity

• Impulsivity

It is currently believed that all of these symptoms are due to abnormalities in the prefrontal cortex. Specific areas of the prefrontal cortex are connected to specific subcortical brain areas through the CSTC loops. Each specific symptom is related to a specific loop / circuit or structure disrupting that loop. Selective attention problems are linked to the ACC, sustained attention problems are linked to inefficient processing in the DLPFC, hyperactivity in the prefrontal motor cortex and impulsivity in the OFC. Problems with attention and concentration do not only occur with ADHD. These symptoms occur in multiple psychiatric disorders. It turns out that the same brain circuitry involved in ADHD is also central to executive dysfunction in other syndromes. The same treatment can then be applied. These abnormalities are mainly genetic and stem from synapse malformation and abnormal neurotransmission.

Can ADHD be characterized as a disorder or inefficient "tuning" of the prefrontal cortex by DA and NE?

People with ADHD generally have difficulty adequately activating prefrontal cortex areas in response to cognitive attentional and executive function tasks. A number of studies suggest this is due to DA and NE dysregulation, which hinders the normal "tuning" of pyramidal neurons in the prefrontal cortex. In ADHD, imbalances in NE and DA circuits in the prefrontal cortex would cause insufficient information processing in prefrontal circuits, thus causing ADHD symptoms. At the level of NE and DA synapses in the prefrontal cortex, limited signaling in prefrontal cortical DA and NE pathways is reflected by decreased neurotransmission and thus reduced stimulation of postsynaptic receptors. Medicines that can lead to increased release of these two neurotransmitters would hypothetically be beneficial for people with ADHD by bringing prefrontal activity to optimal levels. On the other hand, ADHD may also be associated with excessive signaling in prefrontal cortical DA and NE pathways, particularly in adolescents and adults. That is, stress can activate NE and DA circuits in the prefrontal cortex, leading to high DA and NE release levels, and thus can cause excess phasic NE and DA firing. Thus, both too much and too little stimulation by NE or DA can cause inefficient information processing. In order for the prefrontal cortex to function optimally, cortical pyramidal neurons must be tuned, which means that moderate stimulation of α2A receptors by NE and D1 receptors by DA is necessary. In the prefrontal cortex, α2A and D1 receptors are often located on the spines of cortical pyramidal neurons, and can thus send incoming signals. α2A and D1 receptors are both linked to the molecule cyclic adenosine monophosphate (cAMP). The cAMP molecule links the receptors to the hyperpolarization activation cyclic nucleotide-gated (HCN) cation channels. When NE, or a noradrenergic agonist, binds to an α2A receptor, the activated Gi-linked system inhibits cAMP and closes the HCN channel. This allows the signal to travel through the spine to the neuron. It thus enhances network connectivity with similar neurons. So in general, stimulation of α2A receptors in the prefrontal cortex amplifies an incoming signal. Stimulation of D1 receptors, on the other hand, leads to attenuation of the signal.

Limited DA and NE input would theoretically lead to increased noise and a reduced signal, thus preventing a coherent signal from being sent. This could potentially lead to hyperactivity, attention problems, impulsivity and a combination of these symptoms, depending on the location of the mistuned pyramidal neuron in the prefrontal cortex. Furthermore, a person may exhibit a very different set of symptoms when one neurotransmitter is low while the other is high. By mapping both the levels of DA and NE neurotransmission and the specific area of ​​the possible disturbances, it may be possible to predict the degree and type of symptoms in the future.

What is the relationship between neurodevelopment and ADHD?

ADHD is generally seen as a childhood disorder, but it has also turned out to be an influential psychiatric disorder in adults. Classic ADHD starts around the age of seven and lasts a lifetime. In this case, you probably have the disorder from birth, but since children cannot show sustained and selective attention until they are six or seven, the symptoms for this are not noticeable. At age 6, synapses rapidly increase in the prefrontal cortex, and about half of these are rapidly eliminated in adolescence. The timing of the onset of ADHD suggests that the formation of synapses, and perhaps more importantly, the selection of synapses for removal in the prefrontal cortex during childhood, may contribute to the onset and lifelong pathophysiology of this disorder. Those who are able to compensate for these prefrontal abnormalities through new synapse formation may be those who "outgrow" their ADHD, and this may explain why the prevalence of ADHD in adults is only half the prevalence of ADHD in children and adolescents.

According to current theory, in ADHD neurodevelopmental abnormalities occur in the circuits of the prefrontal cortex. The main genes involved in ADHD are the genes linked to the neurotransmitter DA, although links with the α2A-adrenergic receptor genes, 5HT receptors and some other proteins are also being investigated. Environmental factors, such as preterm birth and smoking during pregnancy, inevitably contribute to ADHD. The prevalence of ADHD in adults is only about half that in children, but it is not recognized as often as in children. This may be because it is much more difficult to diagnose and the symptoms are often not treated. Where half of all children or adolescents with ADHD are diagnosed and treated, only one in five adults with ADHD is diagnosed and treated. In young children there is mainly hyperactivity and impulsivity, but the attention disorders are less noticeable. As children get older, attention problems become more prominent and hyperactivity and impulsivity diminish. ADHD in adults therefore often only consists of attention problems. Adults with ADHD also have a lot of co-morbidity with other diseases, so it is often overlooked. Currently, there is an increasing focus on the recognition and treatment of ADHD in adults, modification of diagnostics and psychopharmacological considerations with regard to the unique features of this disorder in adults.

How Is ADHD Treated?

It can be helpful in managing ADHD to prioritize which symptoms to treat first with psychopharmacological treatments. Treating substance abuse should be at the top of the list, as it can hinder the treatment process. In addition, any mood and anxiety disorders should also be treated first.

Obviously there are problems with this way of setting priorities. For example, many children are first treated for ADHD, without evaluating possible comorbidities, until they appear to be unresponsive to treatment. In adults, it can be so difficult to treat substance abuse, mood disorders, and anxiety disorders that the focus of treatment never shifts to ADHD.

The modern, sophisticated psychopharmacologist always takes into account the presence of ADHD in mood, anxiety and substance abuse disorders, especially in adults, and always focuses on complete symptomatic remission in patients on treatment.

Stimulants

The agitation and motility in ADHD is thought to stem from too low a tonic firing of NE and DA, resulting in too little stimulation of NE and DA receptors in the prefrontal cortex. Stimulants and some noradrenergic drugs work by amplifying the NE and DA signals. Not only too low NE and DA signals lead to ADHD, but also too high signals from these neurotransmitters. The theory is that the stress and distress associated with ADHD can lead to high NE and DA release, which in turn causes inefficient information processing. However, when stress becomes chronic, NE and DA levels eventually plummet again due to exhaustion. However, the signal output remains poor. Ultimately, the appropriate treatment is to increase NE and DA concentrations and thus normalize behavior. Although it is difficult to treat patients with too much DA and NE, too little DA and NE or a combination of these in different pathways. Children and adolescents who have conduct disorder, oppositional defiant disorder, psychotic disorder and / or bipolar mode or mixed conditions in addition to ADHD are the most difficult to treat. Adults who have an anxiety disorder in addition to ADHD are also difficult to treat. Supplementing antidepressants or anxiolytic treatments with a tonic activator of DA and / or NE systems, such as a long-lasting NET inhibitor (NRIs), or an α2A-adrenergic agonist in place of a stimulant, may be an effective long-term approach for comorbid anxiety, depression, or substance abuse with ADHD.

Methylphenidate

This stimulant blocks the transporters of both NE (NET) and DA (DAT) in much the same way that antidepressants do, namely by binding to NET and DAT in places other than where monoamines bind NET and DAT. Methylphenidate thus stops the reuptake pumps, so that no methylphenidate is transported into the presynaptic neuron. Methylphenidate has a d and l isomer; the d isomer has a more potent action than the l isomer on both NET and DAT bond.

Amphetamine

This stimulant also blocks NET and DAT, but in a different way than methylphenidate and antidepressants. Amphetamine is a competitive inhibitor and pseudo-substrate for NET and DAT and binds at the same site where monoamines bind to the transporter. Amphetamine thus inhibits NE and DA reuptake. When amphetamine is given at dosages suitable for the treatment of ADHD, the clinical differences in effect compared to that of methylphenidate are relatively small. However, at high doses of amphetamine - used by stimulant addicts - additional pharmacological actions are triggered. Followed by the inhibition of DAT, amphetamine is transported as a lifter into the presynaptic DA terminal. Once sufficient amounts have been transported into the DA terminal, as is the case with overdose, amphetamine also acts as a competitive inhibitor of the vescular transporter (VMAT2) for both DA and NE. When amphetamine flows back into other synaptic vesicles, it replaces DA here, causing a flood of DA release. When DA accumulates in the cytoplasm of the presynaptic neuron, it causes DAT to change direction, which in turn causes intracellular DA to enter the synapse and open presynaptic channels, releasing another DA current into the synapse. These pharmacological actions of high dose amphetamine are not linked to therapeutic actions in ADHD, but to reinforcement, reward, euphoria and persistent abuse. Amphetamine has a d and an l isomer. The d-isomer has a more potent action than the 1-isomer for DAT binding, but d- and 1-amphetamine isomers are about as potent in their action on NET binding.

Noradrenergic treatment of ADHD

Atomoxetine: This is a selective norepinephrine reuptake inhibitor, or selective NRI. In ADHD patients with weak NE and DA signals in the prefrontal cortex, a selective NRI, such as atomoxetine, increases both NE and DA in this brain region, which enhances the tonic firing of both neurotransmitters, but does not affect NE or DA in the accumbens. Atomoxetine therefore has no possibility of abuse.

α2A adrenergic agonists: α2A receptors are widely distributed throughout the central nervous system (CNS), with high levels in the cortex and locus coeruleus. These receptors are thought to be the primary mediators of the effects of NE in the prefrontal cortex and regulate symptoms of attention problems, hyperactivity and impulsivity in ADHD. There are two direct acting agonists for α2A receptors used to treat ADHD, namely guanfacine and clonidine.

Future treatments

Research is currently being conducted into various H3 antagonists to boost cognitive functioning in people with ADHD. Research is also being done on various α7-nicotinic receptor agonists. Other pro-cognitive mechanisms currently being investigated for their action in ADHD and other disorders are AMPAkines, which boost glutamate neurotransmission AMPA receptors, 5HT6 antagonists and phosphodiesterase 4 (PDE4) inhibitors.

ADHD and its pharmacological treatment are part of rapidly evolving psychopharmacology. It is increasingly seen as not just an attention disorder or only occurring in children. This chapter discusses ADHD, its causes and the biological basis for symptom relief through psychotropic drugs.

What is dementia and how is it treated? - Chapter 13

Dementia cannot be cured, but it can be treated symptomatically to some extent. Recently there have been possibilities to slow down dementia and a lot of research is being done to see if it is possible in the future to stop or even reverse the symptoms of this disorder. This chapter focuses primarily on Alzheimer's disease, as it is the most common type of dementia.

What are the causes, pathology and clinical features of dementia?

Dementia consists of memory loss (amnesia) plus a decrease in either language use (aphasia), motor function (apraxia), recognition ability (agnosia), or reduction in executive functions, such as problem-solving skills and working memory. There may also be a personality change. It is possible to have multiple forms of dementia. Some common dementias are:

• Alzheimer's (60-70%)

• Vascular dementia (10-20%)

• Lewy-Body dementia (15-25%)

Alzheimer's disease is caused by the formation of (outside the cell) amyloid plaques and (inside the cell) neurofibrillary tangles. The idea is that Alzheimer's starts with the abnormal processing of certain proteins (amyloid precursor protein: APP), resulting in toxic forms of Abeta (Aβ) peptides. Aβ peptides have anti-oxidant properties. Alzheimer's disease is a disorder in which toxic Aβ peptides are formed, leading to the deposition of amyloid plaques in the brain, ultimately leading to the ultimate destruction of neurons that are diffusely located across the brain. Thus, Alzheimer's disease may essentially be a problem of too much formation of Aβ amyloid-forming peptides, or too little removal thereof. APP is a transmembrane protein with the C terminal in the neuron and the N terminal outside the neuron. One APP processing pathway does not produce toxic peptides and includes the enzyme α-secretase. APP is cut by α-secretase to form α-APP and amino acid 83 peptide. Amino acid 83 is again divided by γ-secretase into peptides p7 and p3. According to the amyloid casade hypothesis of Alzheimer's dementia, this is where things go wrong in people with Alzheimer's disease:

• α-secretase cuts incorrectly, resulting in β-APP and amino acid 91.

• Amino acid-91 is cut by γ-secretase into two pieces of peptides Aβ-42.

• These toxic Aβ-42 peptides stick together to form oligomers, which interfere with synaptic functions and neurotransmitter actions.

• Aβ oligomers then stick together again, resulting in large clumps of Aβ-42. These are called amyloid plaques. They cause inflammation, release toxic chemicals such as free radicals and cytokines, and activate microglia and astrocytes.

• These activities activate kinases which in turn phosphorysize Tau proteins and tie microtubules into tangles with neurons. The accumulation of amyloid plaques and neurofibrillary tangles leads to neural dysfunction and cell death.

Evidence for the amyloid cascade hypothesis comes from genetic research on Alzheimer's within families. In rare cases, Alzheimer's occurs at a young age and in that case there could be a genetic abnormality. Some of the abnormal chromosomes could be chromosomes 21, 14 and 1. The mutation on chromosome 21 encodes a defect in APP leading to increased β-amyloid deposition. People with Down's syndrome also have an abnormality in this chromosome and almost all of these people develop Alzheimer's at a young age. It is still unclear what the influence of these chromosomes is in Alzheimer's later in life, which is usually not passed on genetically.

What is the relationship between ApoE and Alzheimer's risk?

An alternate version of the amyloid cascade hypothesis is the possibility that something is wrong with the protein ApoE. This is because properly functioning ApoE binds to Aβ-42 and cleans it up, preventing the development of Alzheimer's. A genetic abnormality could cause a malfunctioning version of ApoE so that it cannot bind effectively to Aβ-42. This would not clean up the amyloid build-up.

What are the three stages of Alzheimer's?

In 2011, the Alzheimer's diagnostic criteria were revised in two important respects: (1) the understanding of Alzheimer's has been divided into three stages to reflect the current dynamic sequence model of structural and functional brain changes over time in older people who first functioned normally in the cognitive field, then underwent mild cognitive changes, and eventually developed Alzheimer's disease; (2) the new diagnostic criteria have incorporated biomarkers. The five biomarkers in the new criteria include biomarkers of amyloidosis / amyloid accumulation and biomarkers of neurodegeneration.

Stage 1: preclinical (asymptomatic amyloidosis)

The first plaques appear relatively asymptomatic, but somewhere halfway through, sufficient plaque accumulation appears to trigger neurodegeneration, ultimately leading to dementia. Amyloid biomarkers contribute to the diagnostic process for identifying early stages of Alzheimer's. The first stage of Alzheimer's is considered preclinical and silent, but problems are already setting in - namely the slow, relentless deposition of Aβ peptides in the brain, rather than their elimination via cerebrospinal fluid (CSF), plasma and liver - for to do. This pre-symptomatic stage can be identified using biomarkers. Amyloidosis can also be detected using PET scans. Of particular concern for the eventual progression of presymptomatic Alzheimer's to the next stage of mild cognitive impairment (MCI), some studies suggest that preclinical stage Aβ deposition is already associated with some degree of gray matter atrophy in the hippocampus. and the posterior cingulate gyrus, which can be detected by MRI. Risk factors in this early stage that accelerate the rate or increase in the risk of further dementia are depression, type 2 diabetes, ApoE4 genotype and vascular disease, especially cerebral emboli.

Stage 2: Mild Cognitive Impairment (MCI) (symptomatic, predementia stage of amyloidosis and some neurodegeneration)

Patients with MCI have mild cognitive symptoms, but no dementia. Diagnosis of MCI does not mean that Alzheimer's pathology did not necessarily cause the symptoms, or that MCI patients will inevitably develop dementia. The question is whether this form of memory loss is a precursor or a mild form of Alzheimer's or just "normal old age". It often seems to be the first, as about 80% of people with MCI do have Alzheimer's ten years later. Biomarker studies try to determine which of the MCI patients develop Alzheimer's and who do not. One biomarker for neurodegeneration is the presence of elevated CSF tau (including phospho-tau). This is thought to be associated with neuronal loss in the brains of Alzheimer's patients.

Among all MRI techniques, volumetric MRI is usually chosen as a biomarker for establishing Alzheimer's disease, for measuring the progression of the disorder, and for clinical trials in an attempt to establish effective treatments.

FDG-PET measures synaptic activity. Low amounts of FDG uptake (called hypometabolism) indicate synaptic dysfunction. Combinations of abnormal biomarkers in MCI increase the chance that a patient with MCI will develop dementia. The findings suggest that neurodegeneration, and not amyloidosis, drives the onset of symptoms in the MCI stage of Alzheimer's disease and the progression of symptoms from the MCI stage to the stage of dementia.

Not only can depression be confused with dementia, it can also be a precursor to dementia. Depression in the elderly often manifests itself in cognitive symptoms, such as apathy, loss of interest and delayed information processing, sometimes without apparent gloom. Dementia also often starts with such a depression. It remains controversial whether depression reflects a causal factor for MCI or dementia, is part of MCI, or shares neuropathological features with the dementia stage of Alzheimer's. Some experts suggest that depressive symptoms associated with MCI are an ominous combination, with depression being a prodromal manifestation of dementia. Thus, depression that starts later in life may represent an Alzheimer's symptomatic prodrome, while recurrent depression with another episode at a later age may be related to vascular dementia, or not related to dementia at all.

Stage 3: dementia (amyloidosis with neurodegeneration and cognitive decline)

The last stage of Alzheimer's disease is dementia, and it is characterized by cognitive or behavioral problems that interfere with functioning at work or in daily activities. The new criteria, like the old criteria, classify patients in "probable" and "possible" Alzheimer's, with no changes occurring in those with probable Alzheimer's. In addition, the new criteria have two new categories: probable and possible Alzheimer's with evidence of the Alzheimer's pathophysiological process. To diagnose probable Alzheimer's, "all-cause" dementia must first be diagnosed. Patients who meet these criteria are likely to have Alzheimer's when they also meet the main clinical criteria; Dementia that is deceptive at the time of onset has clearly shown negative impact on cognition over time, presenting either amnestic (difficulties with learning and recall) or non-amnestic (linguistic, visuospatial, or executive dysfunction).

The new category of probable Alzheimer's with evidence of the pathophysiological process includes patients with probable Alzheimer's who have clear positive biomarker evidence of either amyloid deposition / amyloidosis in the brain or downstream neuronal degeneration. The new category of possible Alzheimer's with evidence of the pathophysiological process is for individuals who meet the clinical criteria for dementia other than Alzheimer's, but who have clear positive biomarker evidence or neuropathological evidence of the pathophysiological process of Alzheimer's.

Is Amyloid a Future Alzheimer's Treatment?

The main current utility of biomarker improved early detection of Alzheimer's disease is to identify those at high risk of developing dementia to participate in clinical trials of testing new drugs, and especially different anti-amyloid treatments.

Vaccinations and Immunotherapy

Immunizing the body against beta-amyloid could theoretically not only slow or stop further cognitive deterioration, but could also potentially improve cognitive functioning by removing already formed plaques. Positive tests of amyloid vaccines in animals lead to early clinical trials showing that not only was memory stabilized in Alzheimer's patients, but amyloid plaques were also removed. However, the first vaccine on the Aβ peptide (AN1792) caused encephalitis in 6% of the cases in phase II and the trials had to be discontinued. There are also clinical trials of passive immunization with intravenous immunoglobulin (IVIG) in the hope that it may contain natural antibodies against β-amyloid and promote the removal of β-amyloid in the brain. Further research is needed.

Gamma Secretase Inhibitors

Another strategy to block amyloid plaque formation is to inhibit the enzyme γ-secretase. Various γ-secretase inhibitors (GSIs) are currently under development.

Beta-secretase inhibitors

Inhibitors of the β-secretase enzyme are difficult to synthesize, but it is increasingly under development. These inhibitors could act as a mechanism to prevent beta-amyloid formation.

Acetylcholine as a symptomatic treatment

Acetylcholine is formed in cholinergic neurons from two precursors: choline and acetyl coenzyme A (AcCoA). These two substrates interact with the synthetic enzyme choline acetyl transferase (CAT) to produce the neurotransmitter acetylcholine (ACh). The action of ACh is terminated by one or two enzymes, namely acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE). Both enzymes convert ACh to choline, which is then transported back into the presynaptic cholinergic neuron for resynthesis in ACh. ACh released by CNS neurons is too rapidly and completely destroyed by AChE to be available for transport back into the presynaptic neuron, but the choline formed by the breakdown of ACh is transported back into the presynaptic cholinergic nerve terminal by a transporter similar to the transporters for other neurotransmitters, such as NE, DA and 5HT. Once it is back in the presynaptic nerve terminal it can be recycled to new ACh synthesis. Once synthesized in the presynaptic neuron, ACh is stored in synaptic vesicles after being transported back into these vesicles by the vesicular transporter for ACh (VAChT). There are numerous receptors for ACh. The main subtypes are nicotinic and muscarinic subtypes of cholinergic receptors. These subtypes are also divided into many receptor subtypes, such as M1, M2 and M3 (muscarinic receptor subtypes) and α7, α4 and β2 (nicotinic receptor subtypes).

What is the cholinergic deficiency hypothesis of amnesia in Alzheimer's and other dementias?

Several studies have shown that a deficiency in cholinergic functioning is linked to a disturbance in memory, especially short-term memory.

For example, blocking muscarinic acetylcholine receptors through medication can cause memory loss in healthy subjects. The Meynert nucleus basalis - a region in the basal forebrain - is involved in the production of acetylcholine. These neurons play a major role in memory formation. The short-term memory disturbances in Alzheimer's patients could be due to a degeneration of these cholinergic neurons.

The most successful approach in boosting cholinergic function and improving memory in Alzheimer's patients is to inhibit ACh destruction by blocking the enzyme AChE. This increases the amount of ACh. The improved availability of ACh can affect the clinical outcome of Alzheimer's, from improving memory in some patients, to slowing the impaired functioning of Alzheimer's patients for several months. This medication would be especially effective in the early stages of the disease, because the neurons with postsynaptic receptors for ACh are still intact.

Medication that prevents the breakdown of acetylcholine:

• onezepil: is a selective inhibitor of AChE in pre- and post-synaptic acetylcholine neurons and also acts on peripheral acetylcholine receptors, making it beneficial for gastrointestinal problems for example.

• Rivastigmine: Inhibits both AChE and BuChE.

• Galantamine: Inhibits AChE and acts as a PAM on nicotinic cholinergic receptors.

What is the glutamate hypothesis of Alzheimer's disease?

As mentioned, Alzheimer's predominant explanation is that neurons die from the production of toxic plaques. However, it is still unclear exactly how these plaques cause damage. One theory about this is that there are poisonous knots but also inflammatory reactions. The idea of ​​the glutamate hypothesis is that the plaques release a toxic amount of glutamate, causing excitotoxicity. If amyloid were to reduce the action of the glutamate transporter (which carries away excess glutamate), inhibit glutamate reuptake and / or increase glutamate release, a persistent excess of glutamate would develop. If this continues, it could eventually cause glutamate to be released to the postsynaptic receptor in such harmful amounts that dendrites, and later entire neurons, die. There are indications that this can also lead to the formation of more nodes. This hypothesis is also called the NMDA glutamate hyperactivity hypothesis of Alzheimer's (NMDA is the glutamate receptor).

Memantine is an NMDA antagonist and prevents abnormal activation of glutamate neurotransmission. Based on the NMDA glutamate hypothesis, it could thus alleviate symptoms of Alzheimer's. However, interference from NMDA is risky because it can cause symptoms that resemble the positive and negative symptoms of schizophrenia (think ketamine). Memantine could do this safely by closing off the ion channel when it is left open for too long (as is done in healthy situations by a magnesium ion) and thus causing the continuous flow of glutamate to stop. So it ensures that a resting state arises again. The advantage of memantine is that it provides a block with sustained tonic release of glutamate, but it temporarily clears the block with phasic release. Therefore, it would not have the drawbacks that other NMDA antagonists have.

What other medications can be used for Alzheimer's?

A number of psychopharmacological agents - including various anti-oxidants, anti-inflammatory drugs, statins, vitamin E, estrogen, the MAO inhibitor selegiline, the anti-dianetic drug rosiglitazone and other peroxisome proliferator-activated receptor gamma (PPARγ) agonists, lithium and other glycogenic synthase kinase (GSK) inhibitors, drugs that block tau phosphorylation, and phosphodiesterase inhibitor - have been tested as potential treatments for Alzheimer's disease, but none have proven effective so far.

Dementia cannot be cured, but it can be treated symptomatically to some extent. Recently there have been possibilities to slow down dementia and a lot of research is being done to see if it is possible in the future to stop or even reverse the symptoms of this disorder. This chapter focuses primarily on Alzheimer's disease, as it is the most common type of dementia.

What are impulsive compulsive disorders? - Chapter 14

In addition to discussing drug addiction, this chapter discusses other 'impulsive-compulsive disorders', including obsessive compulsive disorder (OCD), trichotillomania, gambling, aggression, obesity, and other disorders believed to be partly related to inefficient information processing in the prefrontal cortex / striatal circuit.

What Are the Characteristics of Impulsive Compulsive Disorders?

Impulsivity and compulsivity are endophenotypes, namely symptoms linked to specific brain circuits and presented trans-diagnostically as a dimension of the psychopathology of many mental disorders. Impulsivity is defined as acting without thinking first; the lack of reflection on the consequences of your own behavior; inability to defer reward and preference for immediate interest over more favorable but deferred reward; difficulty inhibiting motor responses, often opting for risky behavior; or lack of willpower to resist temptation. Compulsivity is defined as actions that are inappropriate in a particular situation, but which persist and often eventually lead to undesirable consequences. Compulsions are characterized by the inability to adapt behavior after negative feedback. Habits are a kind of compulsion.

What is the Relationship Between Neurocircuits and Impulsive Compulsive Disorders?

The difficulty in inhibiting impulses and impulses in various mental disorders may be related to a problem in cortical circuits that normally suppress these behaviors. A simple explanation is that impulsivity and compulsivity are hypothetically neurobiological "bottom-up" drives, with impulsivity coming from the ventral striatum and compulsivity from the dorsal striatum. Several areas in the prefrontal cortex act "top-down" to suppress these urges. Inhibitory control is thus exercised top-down by cortical mechanisms, implying that impulsivity and compulsivity could result from a relaxation of this control. Thus, according to this formulation of impulsivity and compulsivity, behavioral output is driven by a balance between dual and sometimes competing neurobehavioral systems. What actually happens depends on the balance between 'top-down' and 'bottom-up', with both impulsivity and compulsivity either caused by either the failure of response inhibition systems (inadequate top-down cognitive control), or due to too much pressure from the bottom up of the ventral striatum for impulsivity, or from the dorsal striatum for compulsivity.

Neuroanatomically, impulsivity and compulsivity are seen as different neuronal loops: impulsivity as an action outcome ventrally dependent learning system and compulsivity as a dorsal habit system. Many behaviors begin as impulses in the ventral course of reward and motivation. Over time, some of these behaviors migrate dorsally due to a cascade of neuroadaptations and neuroplasticities that make up the habit system, eventually turning an impulsive act into compulsive. Several areas of the prefrontal cortex, including the hippocampus and amygdala, appear to be involved in this process. Drug addiction is a well-known example of ventral to dorsal migration.

What is the role of the mesolimbic dopamine circuit?

All drugs that can lead to addiction increase DA in the ventral striatum, also called the nucleus accumbens. This area of ​​the brain is also known as the mesolimbic DA pathway which is said to be overly active in people with psychosis and mediates the symptoms of schizophrenia. The final joint reinforcement and reward pathway in the brain is believed to be the same mesolimbic DA pathway. The mesolimbic DA pathway is very important in addiction and is also referred to as the "pleasure center", where DA is referred to as "pleasure neurotransmitter". All kinds of natural events (including exercise, orgasm, getting compliments) can trigger the mesolimbic DA neurons to release DA and thus create a "natural high". All kinds of neurotransmitters play a role in this, such as:

• Endorphins: the natural morphine / heroin of the brain, as it were.

• Anandamine: the brain's natural marijuana.

• Acetylcholine: the brain's natural nicotine.

• DA: the brain's natural amphetamine / cocaine.

Drugs affect these neurotransmitters, but have the ability to create a much more explosive high than the natural ones can. Also, it now appears that drugs as well as potentially inappropriate behaviors can result in the release of DA which in turn stimulates the reward system. These behaviors are included in the impulsive-compulsive disorder composition and include behaviors such as gambling, internet use, shopping, and even eating. The drugs bypass the brain's natural system for reward and cause a large amount of DA release. Your brain therefore 'thinks' that it is no longer necessary to get your rewards through the natural way, if you can also get it that simply by using drugs. Because you get a direct upregulation of DA receptors through that DA bombardment, "craving" quickly arises: you suddenly have many more DA receptors and they need DA much more than was previously the case. Because of this, you become preoccupied with finding more drugs to meet that demand for DA and the vicious circle of addiction is created.

How does the addiction work?

Impulsive traits and a dysfunctional reward system may contribute to a propensity for drug use and abuse. When drugs are taken regularly, impulsive drug use can harness habit system involvement - which may be more likely in some people than others - triggering neuroplasticity in the compulsivity circuit. This would be the means by which drug intake eventually becomes compulsive in some people.

Stimulants

The speed at which drugs enter the brain determines the degree of the subjective "high". The faster the drugs enter the brain, the stronger the reinforcing effects. This probably has to do with the fact that this triggers phasic DA firing, the kind associated with reward and satiety. Some of these drugs are taken orally in low doses, for example for ADHD. Stimulants that cause DA to be released slowly work by "tuning" inefficient brain circuitry by targeting the prefrontal cortex, enhancing tonic DA firing for motivation and attention, and decreasing impulses and hyperactivity. This while at the same time ensuring that there is enough phasic DA firing for learning and for facilitating appropriate, goal-oriented behaviors / rewards.

While therapeutic actions of stimulants are thought to target the prefrontal cortex to enhance both NE and DA neurotransmission here, the reinforcement effects and misuse of stimulants are thought to target reward pathways, particularly DA release from mesolimbic DA neurons in the nucleus accumbens. It turns out that in the long run, it is not the reward of the drug, but the anticipation of the reward, which is associated with drug seeking, or whatever substance / situation. DA neurons stop responding to the primary reinforcer (e.g., the drug) and instead begin to respond to the conditioned stimulus (e.g., seeing the drug). Conditioned responses are subordinate to desire and compulsive use, and the increased DA migrates to the dorsal striatum.

DA is associated with motivation, and the motivation to buy drugs is the hallmark of addiction. What begins with increased DA release leads to increased activity in the ventral striatum and anterior cingluate cortex (ACC) where reward may end in a compulsive drive with escalating dosages in an attempt to achieve increased reward stimulation in order to avoid DA (resulting from this). Methylphenidate, amphetamines and cocaine inhibit DAT and NET. In addition, cocaine inhibits SERT and acts as a local anesthetic. Too high a dose of cocaine and methamphetamine can lead to unpleasant effects, such as tremors, emotional lability, restlessness, agitation, paranoia, panic and repetitive stereotypical behavior. At even higher doses, these agents can lead to intense anxiety, severe paranoia, hallucinations and physical effects such as depressed breathing and hypertension.

Pharmacological treatments for stimulant addicts are not yet available. A cocaine vaccine may be in development.

Nicotine

Nicotine acts directly on the nicotinic (acetyl) cholinergic receptors in reward system circuits. There are two main subtypes of nicotine receptors present in the brain: the α4β2 subtype and the α7 subtype. By the direct pathway, nicotine binds to α4β2-nicotinic postsynaptic receptors on DA neurons in the ventral tegmental region (VTA). For example, it releases glutamate, which in turn leads to the release of DA in the nucleus accumbens. Nicotine binds by indirect pathway to α7-nicotinic presynaptic receptors on glutamate neurons in the VTA, releasing glutamate to the DA receptor and also releasing DA in the nucleus accumbens. The α4β2 nicotinic receptors adapt to the chronic intermittent pulsatile delivery of nicotine in a way that leads to addiction. That is, in the resting state, α4β2 receptors are closed. Administration of nicotine by smoking a cigarette causes the receptor to open, leading to DA release. Sustained stimulation of the receptor leads to desensitization, so that there is temporarily no response to nicotine (or acetylcholine; ACh); this phenomenon of desensitization occurs about the same time as it takes to smoke a cigarette. (NB: this means that it would not make sense to make a cigarette longer because the effect would then stop anyway). When the receptors sensitize again (after about 45 minutes), craving and withdrawal symptoms arise due to the lack of further DA release. With chronic desensitization, the α4β2 receptors will increase (up-regulation). If one then continues to smoke, there are more receptors, but the effect of smoking is that they will all desensitize by the nicotine. Subsequently, they will cause extra craving during brain sensitization (ie return to a resting state). One pack contains just enough cigarettes to keep your α4β2-nicotine receptors continuously anesthetized.

Treating nicotine addiction is not easy. Craving starts within a month of repeated use. Perhaps even more troubling is the finding that the "diabolic learning" that occurs in response to substance abuse from all types of minors, including nicotine, may be very prolonged after nicotine exposure has stopped. Some studies have shown that these changes can even be lifelong. One of the first successful drugs in the treatment of smoking addiction is nicotine itself. By administering this in another form, such as patches, craving can be reduced without causing an enhancement DA release. When someone still smokes with these patches, an extra large DA release is created and thus reinforcement to smoke again.

Another treatment is varenicline, a selective α4β2-nicotinic ACh receptor partial agonist.

Nicotinic partial agonists (NPAs) stabilize the channel so that it is less open than a full agonist (such as nicotine itself) and so that it does not desensitize. When someone takes this drug, there is a moderate and even release of DA that is not as great as with smoking and is not energizing. When one subsequently smokes while using this drug, the NPA will, as it were, compete with the nicotine (it keeps the receptors occupied) and the effect of the nicotine cannot become so great that reinforcement occurs. Smoking therefore has no rewarding effect.

Yet another treatment approach is to try to reduce craving by boosting DA using the NE-DA reuptake inhibitor (NDRI) bupropion. The idea is that some of the DA is returned downstream to the craving postsynaptic D2 receptors in the nucleus accumbens as these receptors readjust to the lack of DA from the recent nicotine withdrawal. Thus, while smoking, DA is released into the nucleus accumbens, due to the actions of nicotine on α4β2 receptors on the VTA DA neuron. This reduces craving, because DA still reaches the receptor.

Alcohol

Alcohol is sometimes used as a self-medication for disorders. There is a high degree of co-morbidity. It is estimated that 85% of alcohol addicts also have a nicotine addiction.

Alcohol affects various neurotransmitter systems. It increases the (inhibitory) neurotransmission of GABA and decreases the (excitatory) neurotransmission of glutamate. The reinforcing effect of alcohol is due to its effect on the mesolimbic reward system. Not only through the actions on GABA and glutamate, but also on cannabinoid receptors. Alcohol is also said to cause the release of endogenous opiates. This ensures the release of DA in the nucleus accumbens.

Various means are used to treat alcohol addiction. One of these, naltrexone, blocks μ-opiate receptors. These receptors theoretically contribute to euphoria and the "high" from frequent drinking. A μ-opiate antagonist would thus block the pleasure of frequent drinking and enhance abstinence through its action on the reward circuit. This theory is supported by the results of clinical trials. Naltrexone can be administered orally or intramuscally. The advantage of the intramuscular administration is that this only has to be done once a month and not daily as with tablets (whereby motivation must therefore be given daily to continue treatment).

Acamprosate is another drug that is used for alcohol addiction. Like alcohol, it interacts with inhibiting the glutamate system and enhancing the GABA system. Acamprosate is used to support the cessation of chronic alcohol consumption. Long-term alcohol consumption causes changes in the glutamate and GABA system as they anticipate the arrival of alcohol. The moment alcohol is then stopped, these adjustments will lead to a state of glutamate over-excitation and a lack of GABA activity. By blocking the glutamate receptors, Acamprosate will reduce the hyperactivity of glutamate from abstinence.

Disulfiram is the classic drug to treat alcoholism. It is an irreversible aldehyde dehydrogenase inhibitor and, when alcohol is used, results in the build-up of toxic acetaldehyde levels. This creates an aversive experience, including nausea, vomiting and hypotension. The idea behind this is that conditioning the aversive experience reduces the need to drink.

Experimental agents that appear to have promising effects in the treatment of alcoholism are the anti-epileptic drug topiramate, the 5HT3 antagonists and cannabinoid CB1 receptor antagonists. New opiate antagonists, such as nalmefen (Selinco) are also currently under investigation. The psychopharmacological treatments for alcoholism are most effective when integrated into structured therapies.

What are narcotics?

Narcotics include barbiturates. Benzodiazepines and alcohol are also often included in the category of narcotics. Narcotic drugs act as PAM for GABA receptors (see also Where do anxiety disorders come from and how are they treated? - Chapter 9).

Benzodiazepines and barbiturates work the same but in different places. Compared to benzodiazepines, barbiturates have more drawbacks: for example, they are more dangerous in overdose. Barbiturates also give a more intense euphoria, so that they are also more addictive.

Opiates

Opiates include morphine, codeine and heroin. They act as neurotransmitters released in the arcuate nucleus and project to the VTA and nucleus accumbens. The brain itself produces a number of endogenous opiate-like substances. An example of this is enkephalin. Natural endogenous opiates act on a variety of receptor subtypes, including the μ, δ and κ opiate receptors. Exogenous opiates are said to act on the same receptors, but mainly on the μ subtype. Opiates induce a feeling of euphoria, which is empowering. They can also cause a very short euphoria followed by an ultimate sense of calm that can last for several hours. This is followed by drowsiness, mood swings, apathy and delayed motor skills. In overdose, opiates can impair breathing and lead to coma. The acute actions of opiates can be counteracted by synthetic opiate antagonists such as Naltrexone. Regular use of opiates easily leads to habituation and dependence. With abstinence, a syndrome of complaints can then develop, consisting of dysphoria, craving, agitation and signals of autonomic hyperactivity such as tremors, sweating and goosebumps. This occurs especially when suddenly (cold turkey) is stopped. Because the opiate receptors adapt to use, it becomes impossible at some point to function normally without opiates.

Opiate receptors adapted to opiate use can also adjust again after use, but this can be difficult to achieve. Resources that can support this:

• Methadone: a full agonist for opiate receptors. This could help with detoxification.

• Buprenorphine: a partial agonist for opiate receptors (OPA).

• Naloxone: must be injected and in combination with Buprenorphine would prevent a high.

Marijuana

The active ingredient in marijuana is THC (δ9-tetrahydrocannabinol), which binds in the brain in the same places where the endogenous cannabinoids are normally used as retrograde neurotransmitters (see Chapter 3 on retrograde transmission). This leads to DA release. Marijuana can have both stimulant and narcotic effects. In the usual dose it can provide a pleasant, friendly and calming feeling, reduced awareness of time, delayed thinking, reduced short-term memory and the feeling of gaining special insights. At higher doses it can lead to panic and in rare cases psychosis. A problem with long-term use is the so-called a-motivational syndrome, which is characterized by a lack of ambition and "drive". It would also be associated with other limitations in social and occupational functioning, such as shortened attention span, impaired concentration, introversion and limited communication skills. It is known that habituation occurs. Most likely, dependence also occurs.

There are two known cannabinoid receptors: CB1 (in the brain) and CB2 (especially in the immune system). Not only cannabis is said to act on these CB1 receptors, but also alcohol and some other substances including sugars and fats. An endogenous agent of the body that acts on this receptor is anandamide. Anandamide is similar to THC in many ways. Rimonabant is an antagonist to marijuana and could therefore potentially be used in the future for the treatment of addiction.

How do hallucinogens work?

Hallucinogens act on the 5HT synapses. They cause intoxication (a trip) in which sensory perception is altered, including visual hallucinations and increased awareness of both external and internal stimuli. These hallucinations are said to be both psychedelic and psychotomimetic. Psychedelic means that there is heightened sensory perception and the subjective experience that consciousness has expanded. Psychotomimetic means that it imitates a psychosis. Use can also lead to a "bad trip" in which a panic attack is triggered by the hallucinations.

There are two groups of hallucinogenic agents:

1. 5HT-like agents, including classic agents such as LSD and psylocybin (contained in magic mushrooms).

2. NE and DA-like agents such as mescaline.

In addition, there is a group of new "designer drugs" such as MDMA (ecstasy) that are made in laboratories and specially designed as party drugs.

The influence of hallucinogens on the brain is complex. The most obvious action is as an agonist on 5HT2A receptors. There are also clear actions on other 5HT receptors and SERT.

Hallucinogenic agents can quickly lead to habituation. This probably stems from desensitization of 5HT2A receptors. It is striking that the use of these drugs can lead to "flashbacks", in which the symptoms of use suddenly return without using the drug. This can take seconds to hours. It is not clear which mechanism exactly underlies the flashbacks. Hallucinogens are often not addictive.

What are club drugs?

The book mentions the following means:

• Phencyclidine (PCP): NMDA antagonist. Originally intended for anesthesia, but unsuitable because it gives a hallucinatory experience like in psychosis.

• Ketamine (special K): similar to PCP, but this is still used as an anesthetic.

• Gamma hydroxybutyrate (GHB): agonist at GHB and GABA-B receptors.

• Inhalants: For example toluene, directly release DA into the nucleus accumbens.

• “Bath salts”: synthetic stimulants that often contain methylenedioxypyrovalerone (MDPV), but may also contain mephedrone or mehylon. Also referred to as "plant foods," they can cause agitation, paranoia, hallucinations, suicidality and chest pain in addition to reinforcing effects.

Is Obesity an Impulsive Compulsive Disorder?

Obesity occurs when a person's BMI is equal to / greater than 30. Not everyone who is obese has a compulsion to eat, as obesity is also related to genetic and lifestyle factors. Only those obesity driven by an inordinate motivational drive to eat and mediated by a reward circuitry could be considered impulsive-compulsive disorders.

Hunger / motivation to eat and the actual amount of food consumed can both be affected by psychotropic drugs in many people. Bupropion, naltrexone, topiramate and zonisamide all cause weight loss in patients taking these agents for other reasons. Marijuana and atypical antipsychotics work opposite to stimulate hunger and cause weight gain. The neurobiological basis of food and hunger is linked to the hypothalamus and to the connections that make hypothalamic circuits with reward pathways. The hypothalamus controls hunger by using regulators including orexin, α-melanocyte stimulating hormone (α-MSH), neuropeptide Y, and agouti-related peptide.

The hypothalamus controls hunger using two pathways: (1) the hunger-stimulating pathway, the actions of which are mediated by two peptides (neuropeptide Y and agouti-related peptide), and (2) the hunger-suppressing pathway, whose actions are mediated by

pro-opio melanocortin (POMC) neurons that make the peptide POMC. POMC can be broken down into either β-endorphins or α-MSH. α-MSH interacts with melanocyte-4 receptors (MC4Rs) to suppress hunger. Weight gain can be caused by either excessive activity of the hunger-stimulating pathway, or deficient activity of the hunger-suppressing pathway, or both.

A new obesity treatment targeting multiple sites within the hypothalamic hunger pathways is the combination of the stimulant phentermine - already authorized as monotherapy for the treatment of obesity - with the antiepileptic drug topiramate (phentermine / topiramate ER, or Qsymia). ). Phentermine works in the same way as amphetamine and blocks DAT as well as NET and, in the case of high doses, VMAT. When stimulants such as phentermine increase DA and NE levels in the hypothalamus, they reduce hunger and therefore lead to weight loss. However, when phentermine is given on its own in appropriate doses to suppress hunger, there are limitations to the use of this agent. In this way, a user builds up tolerance over time and the lost weight is restored. In addition, a user can become addicted to the drug. Also, higher doses can increase heart rate and blood pressure and cause cardiovascular complications. One solution to these limitations of phentermine monotherapy is to reduce the dose and improve its efficacy by supplementing with topiramate.

Another combination is bupropion / naltrexone (Contrave) and this combination is currently under further investigation. Bupropion works like an NDRI. This mechanism is similar to, but less robust compared to amphetamine or phentermine. When bupropion's NDRI actions take place in the hypothalamus, this would enhance POMC neuron-mediated hunger suppression. However, it additionally activates a β-endorphin / endogenous opioid-mediated negative feedback pathway that moderates the extent to which bupropion can activate the POMC neuron. Preclinical studies show that natrexone supplementation can remove this negative opioid feedback and enhance bupropion's ability to increase POMC neuron firing.

Another recently approved treatment for obesity is the 5HT2C agonist lorcaserine (Belviq). Lorcaserine may work by activating the POMC hunger suppressant.

Future treatments for obesity and impulsive-compulsive eating disorders could possibly include a different combination of agents, namely the anti-epileptic drug zonisamide and naltrexone.

An available treatment for obesity - orlistat - acts peripherally by inhibiting fat absorption. So it doesn't work on the reward circuit, except it causes an aversive response (diarrhea and abdominal bloating) to eating fatty foods. This medicine is not used very often.

Bariatric surgery is also effective, mainly for morbid obesity. It does entail many risks and high costs.

What are Impulsive Compulsive Behavioral Disorders?

Many impulses can develop in impulsive-compulsive disorder when done inordinately often. Gambling addiction is an example of this. While Internet addiction, pyromania, and kleptomania are not considered by many to be disorders, there are those who cannot stop these behaviors and also exhibit tolerance and withdrawal symptoms. Paraphilia and hypersexual disorder are also characterized by the same characteristics of the transition from impulsivity to compulsivity.

Many neurodevelopmental disorders have impulsivity / compulsivity as a symptom dimension, such as ADHD. While increasing DA release in the nucleus accumbens of the ventral striatum using high doses and rapidly applied stimulus can enhance impulsive actions, increasing DA release in the orbitofrontal cortex (OFC) circuits with stimulants in low doses and slow release reduce impulsivity and improve a person's ability to say 'no' to impulsive temptation.

Impulsivity can also occur with mania. Autism and related spectrum disorders can be associated with impulsivity as well as compulsivity. Tourette's syndrome, tic disorders and stereotyped movement disorders consist mainly of compulsivity.

Aggression and violence, both towards others and themselves, are associated with many mental disorders. Especially when aggression and violence are impulsive and evoked quickly and inappropriately, this is increasingly seen as an impulsive dimension of psychopathology. Impulsive violence can occur in a variety of psychotic disorders, including drug-induced psychosis, schizophrenia, bipolar mania and borderline personality disorder. Treating the underlying disorder, often with antipsychotics, can help. Aggression and violence in such disorders can be viewed as an imbalance between top-down "stop" signals and bottom-up urges and "go" signals, as is the case in other impulsive-compulsive disorders. Periodic Explosive Disorder is currently considered an impulsive-compulsive aggression disorder.

Since people with Antisocial Personality Disorder, Dissocial Personality Disorder, Psychopathic Traits and Behavioral Disorder have a mix of manipulative and planned aggression, and impulsive aggression, the cause of any particular episode of violence is very difficult to determine. Childhood Oppositional Behavior Disorder is often associated with impulsive acts.

What is Obsessive Compulsive Disorder (OCD)?

In the case of OCD, many patients experience an intense urge to perform stereotypical, ritualistic acts, even though they see for themselves how pointless and excessive this behavior is. Excessively inflexible behaviors are often thought to be performed to neutralize fear or distress triggered by certain obsessions. However, while OCD patients feel compelled to perform these actions, they are often aware that these actions are more disruptive than helpful. So, rather than conceptualizing compulsive behaviors as goal-directed behaviors to reduce anxiety, these rituals should be viewed as habits unconsciously triggered by a stimulus in the environment. Such habit learning can be reduced or reversed through exposure and response prevention.

First-line treatment for OCD is with one of the SSRIs. While second-line treatments with one of the tricyclic antidepressants with serotonergic properties, clomipramine, SNRIs or MAO inhibitors are all worth considering, the best option for a patient who has not responded well to several SSRIs is to consider very high administering doses of an SSRI, or supplementing an SSRI with an atypical antipsychotic.

An experimental treatment for OCD is deep brain stimulation (see also How do antidepressants work and how should they be used? - Chapter 7).

In addition to discussing drug addiction, this chapter discusses other 'impulsive-compulsive disorders', including obsessive compulsive disorder (OCD), trichotillomania, gambling, aggression, obesity, and other disorders believed to be partly related to inefficient information processing in the prefrontal cortex / striatal circuit.