What does the pharmacological approach to depression look like? - Chapter 3

Depression is the most common psychological disorder. One out of ten adults have ever been diagnosed with depression. In general, 17% of all people, 24% of women and 12% of men. Depression in adolescence and among young adults can lead to suicide, among others. Suicide is number three of leading causes of death.

What is a Major Depressive Disorder?

The diagnostic criteria are described in DSM-IV or DSM-V. At least five of the following symptoms must be experienced for at least two weeks:

• depressed or irritable throughout the day
• reduced level of interest and pleasure
• a clear change in appetite and weight (someone eats lot or someone doesn’t want to eat)
• insomnia or hypersomnia
• motor stiffening or deterioration (this is often seen by others)
• fatigue or reduced energy
• a bad concentration
• feelings of hopelessness, guilt and worthlessness, repeated thoughts of suicide
• most people with a major depression do have comorbid anxiety

Another form of depression is the reactive depression. This is often accompanied by a big change in someone's life. This depression is similar to a major depression, but it only disappears in a few weeks to a month, and in this type the period of depression alternates with periods of normal mood.

What is the pathology of depression?

Monoamine hypothesis

Deviations in serotonin and norepinephrine systems can cause depression. This is known because medications that act on these monoamines (serotonin and norepinephrine) reduce or cause the depression. Evidence for this is the drug Reserpine that was used for high blood pressure, but as a side effect it causes depression. Once the drug was stopped, the depression disappeared again. This is how the monoamine hypothesis of depression came about. In the first version of this one did not know which of the monoamines were responsible for the depression and how this was could be caused. A contradiction to the monoamine hypothesis is the lag time. This is the time between taking the medicine and when the medicine starts to work. In antidepressants, for example, two weeks may pass before changes in symptoms occur.

The current version of the monoamine hypothesis states that depression is the result of neural degeneration in the hippocampus and the frontal cortex. This is because monoamine neurons no longer produce growth factors here. An important protein in this is the Brain derived neurotropic factor BDNF . BDNF is a protein that ensures that cells survive and receptors and new neurons grow. If this does not happen, the neurons in the hippocampus and frontal cortex can no longer communicate properly. Chronic treatment with antidepressants leads to an improvement in activity. However, it takes some time before it recovers. There are genetic characteristics that cause these receptors to work worse so that someone is more susceptible to develop a depression. Chronic stress also leads to a reduction in the production of BDNF, which can lead to depression.

How can depression be treated?

Various medications have been used for the treatment of depression over the years. Only the most important ones are discussed in this chapter.

Tricyclic antidepressants

These are the first medications that were used in the treatment of depression. They were discovered in the 50s of the last century. The use of these medicaments for depression has been accidentally discovered. The naming is derived from the structure. All tricyclic drugs are composed of three molecule rings that are attached together. Additions to this structure give each medicine its own characteristics. The drugs bind to the proteins that enable the reuptake of serotonin and norepinephrine. In this way they influence the time after which these neurotransmitters are taken up again. In this way, the fabrics stay active longer in the synaptic gap. The drugs work after a few weeks and provide an upregulation of the BDNF.

Unfortunately, the tricyclic antidepressants also have side effects. By blocking the histamine receptors, fatigue and drowsiness is common in patients. They can also cause dry mouth, dizziness, high blood pressure, constipation, blurred vision and concentration problems by blocking the ACH receptors. In addition, sleep problems often occur. After an overdose (about 10 times the prescribed amount), cardiac arrhythmias and very high blood pressure can occur. The medications can even lead to death. This is a very dangerous option for depressed patients.   

Monoamine oxidase inhibitors (MAOIs)

These medications were developed at the end of the 1950s. They were first developed to treat tuberculosis, but turned out to cause a mood-induced reaction. Some time later, they were also used for the treatment of depression.

The medications are made from all monoamines. MAOIs ensure the storage and use of neurotransmitters. They can be divided into two groups.

Group 1: MAO-a, including norepinephrine, serotonin and dopamine.

Group 2: MAO-b, including dopamine and phenylamine.

MAOIs permanently deactivate the MAO until the MAO is replaced, which can take several weeks. Later, the MAOIs came up with fewer side effects. The lag time of the MAOIs is two weeks. 

The side effects that the current MAOIs can have, can be very serious. The MAOIs deactivate all MAO in the body, including those in the liver. When eating dairy products, extra large amounts of tyrimine are released, which will be broken down in the liver by MAO. If the tyrimine is not broken down it can increases the norepinephrine levels in the body. An excess of norepinephrine can cause severe headaches, sweating, nausea and even hypertension. Eventually, this can lead to a stroke.

Selective serotonin reuptake inhibitors (SSRIs)

In the 1970s more research came into the differences in behavioural stimulation and mood influences caused by antidepressants. We searched for differences between serotonin and norepinephrine systems. There has been thought that behaviour was influenced by norepinephrine and mood by serotonin. Since that moment, they started to develop agents that only affected the serotonin and at the same time tried to eliminate the side effects on histamine and acetylcholine. In 1988 the first breakthrough came, this was the drug Fluoxetine (better known as Prozac). These drugs are called the second generation of antidepressants. The biggest difference with the medication of earlier days, is that this generation of medicines has been especially developed for the treatment of depression.

SSRIs only block the serotonin receptors. They do this by binding to all subtypes of serotonin transport proteins. For example, serotonin cannot be processed further and remains present in the synaptic cleft. Because they bind to all subtypes, and also to the 5-HT2a serotonin receptors, there are specific side effects of SSRIs. Examples include: sexual dysfunction, reduced appetite, insomnia and agitation. There may also be a condition called the serotonin syndrome. The serotonin syndrome is a reaction to the serotonin that is toxic for the body. This can cause serious side effects and in some cases lead to death. It often occurs in combination with the use of other medications that increase serotonin activity such as other antidepressants (other than SSRIs) or certain herbs. For a long time it has been thought that SSRIs contribute to suicide attempts, but research has shown that this contribution is minimal. SSRIs have been shown to be more effective than the use of a placebo.

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

These drugs focus purely on the neurotransmitters serotonin and norepinephrine. As a result, they have slightly fewer side effects than the first generation of antidepressants. New drugs such as those that are still on the market are only improvements of older ones. People who make a new drug, are always trying to reduce the side effects, reduce the lag time and treat more and more symptoms with one drug.

The SNRIs have an effect on serotonin, norepinephrine and sometimes also on dopamine. Every SNRI works differently. A number of known SNRIs are: Duloxetine, Mirtazapine and Nefazodone. 

Atypical antidepressants

Medications for depression that do not modify the available neurotransmitters in the brain are called atypical antidepressants. Initially, the SNRIs also belong to this group, because they only affect serotonin and norepinephrine. Two known and still used atypical antidepressants are Bupropion and Trazodone.   

Bupropion

Bupropion is just as effective as other antidepressants, only it works in a different way. Instead of focusing on serotonin and norepinephrine, the drug blocks only dopamine receptors. Because it only focuses on dopamine, the side effects that appear at the SSRIs do not occur here. Side effects that do occur with dopamine and are as follows: tremor, restlessness, weight loss, less appetite and seizures. This drug cannot be used in patients with anxiety disorders, panic disorders or manic periods. Bupropion is used in combination with SSRIs to reduce its side effect.

Trazodone

Trazodone belongs to the groups serotonin antagonists and reuptake inhibitors. Trazodone blocks the serotonin reuptake transporters, but it also minimizes the side effects, which you see a lot with the SSRIs.   

How effective are antidepressants?

Not all patients respond to medication. Approximately 40% of patients do not respond to any medication or therapy. Sometimes the effects of the medication may fade over time. It is difficult to say anything about the effects of antidepressants because in many studies the placebo group also made progress. Nevertheless, most studies show that medicines work better than an (active) placebo. With an active placebo, there are substances in the placebo that ensure that the patient gets the side effects of the real medicine and therefore thinks that he really has the original medicine. In contrary to the real drug, the placebo has no effective substances in it.

St. John's wort

The question of whether herbs can also have a healing effect on depression has long been discussed. There are many studies on one herb, the St. John's wort or hypericum perforatum. This is an herb that has been used since time immemorial to heal all kinds of diseases and pain, it is even available in the form of a pill. Research has shown that it is indeed effective in the short term for mild depression, but that it does not apply to chronic or severe depression. The herb works by ensuring that the absorption of the neurotransmitters (serotonin and norepinephrine) and its storage are blocked. 

What is bipolar disorder?

Bipolar disorders are distinguished from other depressions by the presence of manic episodes. A manic episode is a state of euphoria, in which someone can also suffer from delusions and hallucinations. In order to be able to diagnose this, the behavioural fluctuations between a mania and depression must be present for at least four days. Until a mania is detected, the wrong diagnosis of unipolar depression can be made. This is very difficult, given that the medication for the treatment of unipolar depression can worsen the condition of someone with bipolar depression.

Bipolar disorder often occurs late in adolescence and occurs as much in men as in women. In the DSM three types of bipolar disorders are mentioned: bipolar disorder 1, bipolar disorder 2 and cyclothymia. The differences between these can be found in the severity of the symptoms. Thus, for the diagnosis of bipolar disorder 1, one manic or mixed period is necessary. A depression does not have to occur here. In bipolar disorder 2, one depressive period is necessary and at least one manic period. Someone with bipolar disorder 1 still has problems with social intercourse between the mania, while someone with bipolar disorder 2 can function normally in between.

Cyclothymia is a type of chronic bipolar disorder, where there have to be at least two years of fluctuations between mild depression and mania.

Determining a manic episode according to the DSM:

• There must be a period (at least one week) of a deviant, exceptionally joyful or irritable mood.
• During the mood disturbance, at least three of the following symptoms have to be noticed: increased self-image, less sleep needed, excessive talking, having many thoughts, easily distractible, more goal-oriented behaviour and/or an extra sense in activities that can have painful consequences.
• The mood disruption causes limitations in the functioning or dealing with other people in a normal way.

If there is a mixed period, there must be both the manic criteria and the depression criteria and they have to change quickly during at least one week.

Pathology

Little is known about the pathology of bipolar disorder. It has been known for a long time that a genetic component is present. This genetic component gives a chance of developing a bipolar disorder of 70% in identical twins and 12% in bipolar twins. The disorder often appears in families. Recent research has shown that the genes that cause serotonin transporter 5-HTT and BDNF are affected, both in bipolar and unipolar disorders. Manic periods can be linked to certain changes in the brain. For example, there are often enlarged ventricles in patients who have already had multiple manic episodes. There is also a reduction in neurons, which corresponds to the abnormalities in the BDNF.

How can bipolar disorder be treated?

John Cade discovered in 1948 the anti-manic effect of lithium. He believed that mania was caused by a by-product of metabolism. If this product was too much, it would lead to mania. To test this, he collected urine and injected it into guinea pigs. The urine of people with a mania was more toxic, but did not produce mania in the guinea pigs. Through much research, he discovered that lithium carbonate eased mania. It was not until 1970 that the drug was approved for use by the FDA.

The FDA is a company that investigates whether medication can be used and what it may be used for. If it has been said that it can be used since a certain year, it has been approved by the FDA in that year.

Lithium

Lithium is a metal that looks like sodium. Lithium carbonate is the active substance used in the medicine. It is a natural product. The drug is easily absorbed into the blood stream and is difficult to get through the blood-brain barrier. The therapeutic index of lithium is very small and when you take too much, a dose can be fatal.

Only slightly higher doses are prescribed for the control of an acute mania. Lithium poisoning can also occur if someone loses too much salt, for example during exercise. Prolonged use can cause weight gain, thyroid disease, rash, kidney failure and a diminished immune system. That is why patients often stop using lithium. Sometimes the drug is also used in depression because it reduces suicidal tendencies. In addition, it restores the affected parts in the brain. Until now, lithium is the most commonly used drug in bipolar disorders. Because of the side effects, new drugs are being developed.

The new medicines (called anticonvulsants ) are also used in the treatment of seizures and anxiety disorders, in addition to the treatment of bipolar disorders.

Other medications

Valproic acid is an anticonvulsant and comes from 1994. It stimulates the growth of BDNF and the activity of various neurotransmitters such as GABA and dopamine. Valproic acid works faster and is better responded to by patients. The most common side effects are sedation, tremor, ataxia, fainting and weight gain.

Gabapentin has not been approved by the FDA, but is used a lot outside the booklet since 1993. It works very effectively against neuropathic pain. Neuropathic pain can be caused by an autoimmune disease, cancer and the death of neurons. Gabapentin is made to mimic GABA. It reduces the influence of calcium by blocking the voltage-dependent calcium channels.

Lurasidone (Latuda) is an atypical antipsychotic. It has proven effective in fighting depression when used in combination with a mood stabilizer such as lithium. It is a powerful antagonist and works in the same way as many other atypical antipsychotics, only the side effects of this drug are less intense. It is a fairly new drug so not much is known about the long-term effect.