Article summary with Possible role of more positive social behaviour in the clinical effect of antidepressant drugs by Young a.o. - 2014

Introduction

Two important characteristics of antidepressants: 1) they aren’t as effective as an ideal antidepressant would be, and 2) there’s a delay in their maximal effect. A proposed biological mechanism for the delay in onset is that different classes of antidepressants cause slow changes in pre- or postsynaptic mechanisms that increase serotonin function – responsible for mood improvement. Another proposed mechanism is based on a cognitive neuropsychological model suggesting that antidepressants “change the relative balance of positive to negative emotional processing,” resulting in later changes in mood. This paper suggests another mechanism involving serotonin-induced changes in social behaviour that will improve mood.

Serotonin and Social Behaviour in Animals and Humans

Aggression is a more dramatic aspect of social behaviour. A meta-analysis concluded that serotonin “has an overall inhibitory effect on aggression” in various animals. Findings suggest that serotonin may alter social behaviour along the continuum of agnostic to affiliative. Research suggests this may also be true in humans.

Acute tryptophan depletion increases aggressive responses and decreases affiliative behaviour according to lab tests. Conversely, tryptophan supplements may decrease aggression and increase positive social behaviour. Tryptophan given to schizophrenic patients decreased the number of incidents on the ward requiring intervention. Another study gave aggressive patients tryptophan, leading to a decreased need for injections of antipsychotics and sedatives to control agitated/violent behaviour. The first study found tryptophan to decrease quarrelsome behaviour but not affect agreeable behaviours (possible ceiling effect). This was tested in the latter study, where participants were psychiatrically healthy but in the upper levels of the population distribution for irritability. In these individuals, tryptophan decreased quarrelsome behaviours and increased agreeable ones. This change occurred without an effect of tryptophan on their appraisal of the agreeableness of their interaction partners – suggesting a direct effect on behaviour instead of an indirect effect mediated by changes in participants’’ cognitive appraisal of others. This is consistent with the fact that altered serotonin function can influence social behaviour in organisms with primitive nervous systems.

Effect of Antidepressants on Social Behaviour in Healthy Humans

Seretti and colleagues reviewed 30+ studies where the effects of antidepressants were compared with placebo in healthy participants. They concluded that generally there were no effects on mood. The effects that did occur were more consistent when the antidepressants were given (sub)chronically rather than acutely, and effects included alterations in social behaviour.

Knutson and colleagues found SSRI paroxetine to decrease subjective irritability and increase affiliative behaviour on a dyadic lab puzzle task in healthy volunteers. Tse and Bond conducted 5 studies where the effects of antidepressants were compared to placebo given to healthy participants, results as followed:

1. Citalopram increased self-directedness but not cooperativeness.
2. Citalopram had no effect on ratings by roommates, but increased cooperative behaviour in a laboratory game.
3. Reboxetine, but not citalopram, caused participants to show more cooperative communication with a confederate behaving nonsociably and to give more cooperative communications in a mixed-motive game.
4. No effect of reboxetine on behaviour along agreeable-quarrelsome dimension, but roommates considered participants more cooperative and agreeable when receiving reboxetine.
5. Reboxetine had no significant effect on irritability, cooperation, or any other measure.

Variability in results is due to various factors (differences in study design, outcome measures, sample sizes). But several studies found changes consistent with improvements in behaviour along the agreeable-quarrelsome dimension – providing modest support for the idea that antidepressants may decrease agonistic and increase affiliative social behaviours in humans. Reboxetine is suggested to increase serotonin function – serotonin may be a mediator of the effects of antidepressants.

Effect of Antidepressants on Social Behaviour in Patients

Irritability occurs in roughly half of depressed patients, and usually resolves with successful treatment. Reviews suggest that about 1/3 of depressed patients experience anger attacks. One study compared effects of sertraline, imipramine, and placebo on anger attacks in patients with atypical depression and dysthymia. Anger attacks ceased in 50% of patients in active treatment groups compared to 37% in placebo group.

Studies have compared effects of antidepressants and placebo on agonistic behaviour in patients with diagnoses other than depression. One found that fluoxetine decreased anger in patients with borderline personality disorder (BPD), and another found it to decrease irritability and aggression in patients with various personality disorders. However, another study found no effect of SSRI fluvoxamine on aggression in women with BPD. A study treating aggressive schizophrenic inpatients with found that it decreased the frequency of aggressive incidents.

Overall results from various studies support the idea that patients with elevated irritability may respond quicker to treatment with SSRIs than patients with only depressed mood. Results provide evidence that SSRIs can decrease aggression, anger, and irritability.

Social Interactions During Depression and Depressed Mood

Hames and colleagues reviewed interpersonal processes thought to be involved in initiating and maintaining depression. Depressed patients tend to have social skills deficits, seek reassurance excessively while also seeking negative feedback and exhibit both interpersonal inhibition and dependency. Many studies looked at how depressed mood influences social behaviour in interaction partners – no direct evidence that the response of others toward those with depressed moods was mediated directly by irritability/anger associated with depression. But it’s a plausible explanation given that quarrelsome/aggressive behaviours tend to be reciprocated by others.

Complementarity in Social Interactions and its Implications for Mood Regulation

People respond to the behaviours of others in a way governed partly by the specific behaviour of the other. It’s proposed that a person’s interpersonal actions evoke a complementary response leading to a repetition of the person’s original actions and that a certain level of intensity tends to evoke a response of similar intensity. Many studies support the idea that quarrelsomeness tends to evoke quarrelsomeness and agreeableness evokes agreeableness, though the exact response can be modulated by the context. Taken together, research suggests that in most people, more agreeable behaviours toward others will tend to be reciprocated and result in a more positive mood. Vice versa for quarrelsome behaviours – resulting in a negative mood.

Complementarity of behaviours, together with changes in mood/appraisal of others, could contribute to an iterative cycle in everyday life.

Possible Role of Changes in Social Behaviour Along the Agreeable-Quarrelsome Dimension in the Effects of Antidepressants on Mood

Research suggests:

1. Most antidepressants enhance serotonin function
2. Serotonin influences behaviour along the agreeable-quarrelsome dimension
3. Depressed patients tend to be irritable and sometimes have anger attacks
4. People tend to respond to quarrelsome behaviour with quarrelsome behaviour – same for agreeable behaviour.
5. More quarrelsome interactions tend to be associated with negative mood, and agreeable behaviour with positive mood.

Hypothesis based on the effects of antidepressants and serotonin on mood -> changes in social behaviour are a way in which antidepressants can improve mood. The change in mood after each interaction will be small, but after many interactions the effect should be much greater. Consistent with the idea of slow onset of action of antidepressants.

Increases in positive affect associated with more positive social interactions and decreases in negative affect associated with fewer negative interactions may play a role in improvement of mood in depressed patients. But increases in positive affect may be more important than decreases in negative affect. Research show positive and negative affect to be separate dimensions rather than opposites on one continuum. Enhancement of positive social behaviour may be more primary in the action of antidepressants than the inhibition of negative social behaviour.

Role of More Prosocial Behaviour and Other Mechanisms in Mediating the Response to Antidepressants

Slow onset of antidepressants is possibly due to initial inhibit firing of serotonergic neurons, though adaptive changes occurring result in important increases in serotonin function. Research on tryptophan suggests small increases in serotonin release to be enough to promote more positive social interactions. But improvement in mood mediated by changes in social behaviour may be important in initial effects of antidepressants, and may be augmented by direct effects on mood associated with larger increases in serotonin functioning happening later.

Cognitive neuropsychological model of antidepressant action suggests that from initiation of treatment, antidepressants create implicit positive biases in attention, appraisal, and memory and that delay in effects on mood are because of the time it takes for these emotional processing biases to influence mood.

The cognitive neuropsychological and social interaction models suggest that antidepressant alter responses to stimuli. In the cognitive model, change is to a more positive appraisal of neutral and emotional stimuli. In the social model, the stimuli are people whom a depressed patient encounters daily – change is a shift away from quarrelsome and toward agreeable behaviour. The important difference is in how the altered response to a stimulus improves mood. In the cognitive model changes occur in the mind (positive appraisals of stimuli) and in the social model the change is in behaviour.

The models are different but not mutually exclusive. Antidepressants may be moving to more agreeable behaviour while simultaneously reinforcing this change through more positive cognitive appraisal of situations. This initiates a cycle of more positive social behaviour resulting in a clinically significant improvement tin mood. 

Conclusion

Evidence is stronger for increased serotonin function and antidepressants decreasing aggressive behaviour than for increasing agreeable behaviour. There’s inconsistency in results on the effects of antidepressants on behaviour – could be attributed to use of measures. Also a lot of the evidence for agreeable social behaviour is mainly based on studies on healthy rather than depressed people. Lastly, if more positive social interactions are a clinically significant factor in the action of antidepressants, then patients who have more social interactions early in treatment may be expected to respond better to it.