Evidence for and against the Serotonin Hypothesis of Depression

Question: Discuss About Evidence For And Against The Serotonin Hypothesis Of Depression? Answer: Introduction The fundamental idea stating the cause of depression as a serotonin imbalance within the body elicits a discussion that can be justified as a hypothesis, which adequately deserves ample evidence to either support or dispute. The serotonin hypothesis of depression, from Dr. Schildkraust in 1965, states that low levels or lack of serotonin within the brain causes depression, a condition that could be treated by antidepressants. The hypothesis, when compared to an earlier belief, is presently discussed that the mood disorders occurring repetitively in depression are brain infections or disorders that result from a variety of factors such as various degrees of biological, genetic and environmental factors that gradually change in the brain (Sanders, 1988). The serotonin hypothesis of depression over the years has stated that low levels of serotonin in the brain nerve cells cause depression. It has led to the development of antidepressant medication such as the Selective Serotonin Reuptake Inhibitors (SSRIs). SSRIs work to maintain a high level of the neurotransmitter serotonin in the nerve cells of the brain by inhibiting its re absorption into the cells releasing it (Moreno and Kramer, 2002). According to Paul Andrews (2004), a professor of psychology and neuroscience at Mc Master University in Canada, the hypothesis might be incomplete since depression patients often find it hard to recover from the serotonin boosting medications. Many scientists have refuted the use of SSRIs in treatment of depression because when you accurately analyze their use, they put an obstacle in the path towards the recovery of a depressed patient instead of helping them. It occurs because, instead of them helping people to overcome depression, they interfere with the mechanisms of recovery within the brain (Louie and Meltzer, 2004). A decrease in the levels of serotonin (5-HT) has been hypothesized as the main pathogenic factor resulting to depression for almost half a century. SSRIs increase the levels of serotonin in the nerve cell spaces known as the synapses in a quick manner. In spite of this, the effect of the antidepressant will take many weeks to develop. According to Paul Andrews (2004), SSRIs work in repairing damage in the brain by the use of hormones and stress chemicals, a gradual process that takes several weeks (Louie and Meltzer, 2004). Moreover, Clomipramine, a tricyclic antidepressant (TCA), showed a similar antidepressant efficacy with other TCAs. It stopped the serotonin uptake with a higher affinity of more than 100 folds and above than other inhibitors by the noradrenalin uptake. Such pharmacological studies have supported and facilitated the hypothesis of depression. This clinical observation of an increase in the release of serotonin contributes to an anti depressant effect that has been repeatedly supported .Nevertheless, for instance, the efficacy of SSRIs versus placebos(slow) may be strong in a moderately depressed in comparison to severely depressed patients (Sanders, 1988). It is difficult to quantify the amount of serotonin used and released in a safe way by the human brain. This can be estimated from evidence about serotonin levels metabolized by the brain and by inferences from animal studies. The best evidence against the hypothesis of depression states that not less but more serotonin is used and released during an episode of depression. This is to say that patients are left in worse conditions after using antidepressants. Furthermore, many forms of depression are beneficial adaptation to stress and are natural thus this might be against the serotonin hypothesis of depression and the use of antidepressants (Louie and Meltzer, 2004). Meltzer and Louie (1987) argue that a pharmacological lessening of the functions of serotonin enhances depression; nevertheless, the primary cause cannot be entirely attributed to serotonin deficiency. In the scientific literature and the lay media, it is frequently assumed that serotonin deficiency causes depression. This theoretically attractive assumption might be an overgeneralization or be premature. Clinical presentations of depression are wide since they include various syndromes which were initially separate and various disease aspects especially in melancholic versus an endogenous depression ( Meltzer and Louie, 1987, p. 136). In such clinical manifestations that are diverse, depression could represent various overlapping sources of pain that arise from unique and distinct causes. Moreover, symptomatology in depression can also arise from diverse neurological (for example the Alzheimers disease), endocrine (Cushing disease) and immunological causes (e.g. interferon treatment). Stressors of life such as social isolation, financial difficulties, childhood trauma and job insecurity are also significant factors in depression that demonstrate the importance of the environment in depression ( Mannl , 1989). In the past 40 years , several anomalies in regards to putative biomarkers of the central serotonin functions have been repeatedly reported in patients with depression, indicating that a deficiency in serotonin could be evidenced in depression especially the severely depressed or in suicidal patients. Iproniazid, a drug developed to treat tuberculosis, surprisingly showed an antidepressant activity in patients diagnosed with TB and who concurrently suffered from depression. Clinical studies indicated that Iproniziad inhibited the monoamine oxidase (MOA) enzyme A and B. These enzymes are responsible in metabolizing serotonin and subsequent monoamines .Furthermore; it also increased the serotonin concentrations in the brain thus helping in supporting the serotonin hypothesis of depression (Louie and Meltzer, 2004). Tryptophan Levels. In many clinical studies, an acute depletion of tryptophan leads to a frequent occurrence of mild depression symptoms even after treatment with antidepressants, this occurs by lowering the serotonin levels in the brain thus it can be a fundamental aspect in supporting the hypothesis. Tryptophan depletion in the brain is somehow a non-selective tool in probing the hypothesis, furthermore, its studies were not effective in alleviating depression (Fairburn and Smith, 1997). Tryptophan is an amino acid which most likely affects protein synthesis. The decrease in its levels probably affects the brain and mood by starving pathways of metabolism for example by impairing the kynurenic acid synthesis or neurobiological and quinoline substances.50 percent of patients diagnosed and treated with interferon alpha develop symptoms of depression after treatment. Another evidence that correlates with this study indicates that interferon alpha enhances the induction of indole amine 2, 3 dioxygenase, thus leading to the decrease in levels of tryptophan in the brain, therefore decrease in serotonin is involved herein (Fairburn and Smith, 1997). Another drug Imipramine, a tricyclic antidepressant (TCA) prototype, was originally developed to treat schizophrenia but unluckily, the drug failed and it did not induce its antipsychotic effect but favorably showed actions against depression symptoms in patients with schizophrenia. Consequently, imipramine was successfully adopted to induce the antidepressant effect on the body. In the 1960, chemical studies showed that other TCAs and imipramine blocked the serotonin reuptake .Within that same period, reports indicated that the precursors of serotonin, induced antidepressant effects and increased the brain serotonin levels in study animals (Fairburn and Smith, 1997). It has been reported that in particular patients, depression is precipitated by chronic depletion of serotonin due to vesicular monoamine transport inhibitor, reserpin. In high doses, it depletes extracellular and storage levels of serotonin, noradrenalin, and dopamine making it consistent to ascribe depressogenic effects of reserpine to one neurotransmitter. Studies have indicated that the link between depression and chronic reserpine treatment remains contentious. Studies done later on chronic reserpine treatments indicated less frequent depressogenic effects, a factor in varying the findings could be attributed to the differential schedules of dosing. In addition to that, chronic reserpine induces a weak antidepressant effect rather than a pro-depressant effect, so the cause of disagreement still lies in establishing whether the probability of depression is elicited by the deficiency of serotonin in neurotransmission (Stanley, 1985). Biomarkers or indirect measures have been used to probe for the brains serotonin system integrity over the last four decades. A primary metabolite of cerebrospinal fluids serotonin is 5 hydroxyindoleacetic acid. It reflects the levels of 5-HIAA utilized as an index of neurotransmission within the brain. Studies have indicated a correlation between depression and low levels of CSF 5- HIAA and regarded them as inconsistent. The finding that is more robust is the relationship between aggression, suicidality or impulsivity with low 5 HIAA (Stanley, 1985). Acute stimulation of serotonin triggers a secretion of hormone prolactin, there is a complex mechanism involved in the release of the hormone, which is not defined. It appears that the mechanism involved includes oxytocin neurotransmitters .The amount of prolactin in the plasma increases fenfluramine, a brain serotonin biomarker, that challenges prolactin, where lower serotonin levels reflect a blunted response by the hormone ( Stanley, 1985). In depressed patients, low 5HIAA indicates that there is a minimal response of plasma prolactin to fenfluramine. Furthermore, inhibiting plasma prolactin due to activation of fenfluramine is more insightful in severely depressed patients. In addition to that, aggression and suicidality are also present. Increased cortical receptors, 5HT2AR of serotonin have been associated with depression, there is also a link between an increase in frontal 5 HT2ARs receptors and suicide. In contrast to this, there is a decrease in hippocampal receptors 5HT2ARs in chronic depressed people therefore indicating that necessarily, up regulation of serotonin receptors does not occur in depressed patients. A large groups of scientists report a lack of association in the levels of frontal cortex 5HT2ARr and suicide (Louie and Meltzer, 2004). In conclusion, the serotonin hypothesis might not be wrong or true but it might be incomplete. The association of serotonin levels with depression as the primary syndrome is not entirely conclusive. Considering the diversity of symptoms, disease severity in patients and the numerous etiology that underlie depression as a syndrome, its extremely difficult to associate depression to a particular body mechanism such as serotonin depletion within the brain. Nevertheless, when we shift focus to the analysis of severe depression or suicidality, an association of serotonin biomarker findings suggest that the serotonin deficiency could be linked to depression in some populations but the link does not essentially prove to be the cause. SSRI antidepressants reveal a superiority that is convincing over placebos entirely in depression that is severe while in adult depressed patients, studies indicate that antidepressants have the least effect against depression. It is therefore much persuading to include a hypothesis on serotonin deficiency (lack or a low level) as significantly a causal factor in particular subsets of depression patients and not completely all cases of depression. 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