A recent article on depression, in the latest issue of open-access medical journal PLoS Medicine, seems to suggest that the current disease-based model of depression should be replaced by a drug-based model and to treat particular symptoms like sleep deprivation it may be better to administer sedatives like benzodiazepine.

Taking a drug-centred approach to the treatment of depression, we would conclude that no presently known effects of any drugs, including antidepressants, are likely to do more good than harm in the long term. In the short term, sedative effects of drugs may help people who are acutely anxious, highly aroused, or have difficulty sleeping. The common practice of prescribing short-term, low-dose sedative TCAs, for which general practitioners have frequently been criticised, may therefore be a rational one. Similarly, short-term benzodiazepine prescribing may occasionally be justified, bearing in mind the problem of dependency.

To me this seems to be an overkill and a case of throwing the baby with the bath-tub.

While the premise that SSRI’s are not the panacea-for-depression-and-are-not-god-sent-for-the-specific-purpose-of-treating-depression is attractive, the alternative pitted against this that Depression is not a ‘disease’ and is not ‘biological’ in nature is hardly tenable.

There have been studies linking the hereditary aspects of depression (and more so of psychotic diseases like Schizophrenia), both based on twin studies and clustering amongst relatives (or running in families). Genetic studies are on-going to identify the underlying genes or ‘diathesis’ and just like Diathesis-stress model of Schizophrenia, a similar model is proposed for Depression.

Moreover, research is now focused on identifying endophenotypes of depression like sleep-disturbance and linking it to genes/ environmental stressors.

In the PLoS medicine article, many of the arguments are specious and I will try to address them.

1. Monoamine hypothesis.

Independent evidence has not confirmed that there is a monoamine abnormality in depression. For example, the findings of brain imaging studies of serotonin abnormality are contradictory. Some found reduced serotonin 1A receptor binding in drug-free patients who were depressed, consistent with the hypothesis that selective serotonin reuptake inhibitors (SSRIs) improve depression by correcting a deficiency of serotonin activity [4,5]. Other studies, however, have found no difference between patients who are drug-free and controls [6,7] or increased binding potential in depressed patients [7,8]. Postmortem findings of receptor changes in the brains of people who committed suicide have also been inconsistent [9–11]. In some studies, with patients who had recovered from depression, a tryptophan depletion challenge led to a transient increase in depressive symptoms. However, these results have not been confirmed in volunteer studies [12], and the effect appears to be dependent on previous SSRI use [13].

Granted that studies are still inconclusive about how exactly the SSRIs work and whether other neurotransmitters/neuromodulators apart from sertonin are also involved, but it is instructive to note that neurotransmitters/modulators may work differently in different brain regions and may have paradoxical activation profiles in different regions. While Schizophrenia is generally thought to be due to over-activity of Dopamine and Prakinsonism due to under-activity, more informed experts know that in both there is not global excess / deficiency but it is localized in one region (say increase in the reward circuit, while decreasee in some other region) . Thus, the global deficiency-of-sertoninn hypothesis may be, and in my opinion is, wrong; yet the depressive symptoms and the ‘disease’ depression is a fairly clustered set of symptoms that have a biological origin and are either due to chemical imbalances or defective processing/ networking of brain channels.

There are many compelling theories of depression including an evolutionary one based on ‘social-negotiation-hypothesis’ or a cognitive one based on ‘learned helplessness’ and may include diverse mechanisms like invocation of an evolutionary-no-more-relevant-module-and-corresponding-mechanisms/adaptations-that-were-once-suitable, to changing-cognitive-schema-based-on-some-past-failures-and-now-no-more-exploring-to-find-if-the-schema-is-still-relevant mechanisms.

But all explanations will ultimately rely on biology for manifesting into stable symptom clusters. And this may be mediated by changes in the opponent-process mechanism of some emotions or motivational activities like exploration/hunger or rest and relaxation set-points mediated in turn by gated inputs, where the gates may be in the form of neurotransmitter levels and activities. Refer to my earlier postings on opponent-process mecahnisms in relation to color vision.

2. Depression rating scales

These scales contain items that are not specific to depression, including sleeping difficulties, anxiety, agitation, and somatic complaints. These symptoms are likely to respond to the nonspecific sedative effects that occur with most tricyclic antidepressants (TCAs) and some other antidepressants. Hence, changes in rating scale scores may merely reflect drug-induced effects

Sleep difficulties/ somatic complains may not be specific to depression in the sense that they may manifest in situations that are not necessarily due to clinical depression; but that does not prove that they are not relevant as salient depression symptoms. If a drug reduces scores on these dimensions it is definitely helping to relive the symptoms of depression.

3. Animal models of depression

These models, which usually involve biochemical orbehaviorall processes thought to mimic aspects of depression in humans, do not select antidepressants reliably but produce numerous Â?false positivesÂ? with other drugs, including stimulants, opiates, and neuroleptics. They also produce some Â?false negativesÂ? with supposed antidepressant drugs [15].

Animal models of any human psychological condition is still an oxymoron as animals cannot exhibit the complex psychological mechanisms and symptoms that humans can. “Depressed” mouse may just be some mouse with Sertonin related genes knocked out. These mya be good to study the particular endophenotype like effect of sertonin-on-sleep-cycle, but not to totality of depressive symptoms.

4. Antidepressants versus other drugs

Many drugs not normally considered to be antidepressants show comparable effects to antidepressants when given to patients who are depressed in some randomised controlled trials (RCTs) [1,16]. These include benzodiazepines [17], opiates [18], buspirone [19], stimulants [20], reserpine, and other antipsychotics [21].

This may question the crowning of SSRIs as depressants but have nothing to say about depression being disease-based or drug based.

5. Healthy volunteer studies

The fact that antidepressants do not appear to elevate mood in healthy volunteers [22–26] might suggest that they have a disease-specific action. However, because of the nature of depression rating scales (as explained above), it is unclear that antidepressants specifically affect mood in patients who are depressed. Any effect they have over and above placebo may also be attributable to an “amplified” placebo response (see below). Although there are some reports of improved sleep in patients with depression who are given SSRIs versus volunteers’ reports of decreased sleep when given SSRIs [27], in general, side effects in patient studies are consistent with effects on volunteers. For example, TCAs show sedation and cognitive impairment [28,29], while SSRIs show gastrointestinal upset and drowsiness, both in patients and in healthy volunteers [22].

It is clear from above that SSRI’s do have very specific effect on mood when depressed and the drug action on volunteers (lets leave the side-effects aside for a moment) is not the same -viz elevating mood or restoring sleep-cycles – as in the diseased persons. This fits well with opponent process and set-point hypothesis whereby if the underlying chemical is increased beyond normal levels it does not necessarily lead to increase in primary affect.

6. Outcome of depression

There is little evidence outside RCTs that the long- or short-term outcome of depression is changing as a consequence of antidepressant use. Recent sharp increases in antidepressant use have been accompanied by increased prevalence and duration of depressive episodes [30] and rising levels of sickness absence [31]. Naturalistic studies have also shown that depressive episodes are more frequent and last longer among antidepressant users than among nonusers [30] and that sickness absence is more prolonged [32], although severity is likely to explain some of this effect (i.e., it is likely that patients are on antidepressant drugs because they have more severe disease). Follow-up studies of people treated for depression indicate high levels of nonrecovery or relapse [33–35].

The argument is like that if you once recover from viral fever using an antibiotic and on same later day relapse to viral fever again, then the viral fever is not a biological disease. Granted that better methods like CBT/psychotherapy alongwith medication and changes to socio-environments (to reduce stressors) is required to prevent relapse, but relapse is hardly an argument against a ‘disease’ model.

Overall, the ideological rooting of the author in not treating depression/ mental illness as physical phenomenon has resulted in a research that is highly provocative and ignores many other accumulated literature. I too do not side with the Drug companies and am aware of their wrong tactics, but that should not be a reason to take extreme positions that are not viable.

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