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For Those Still Convinced Antidepressants Have Non-Placebo Value

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Even though meta-analyses of antidepressant studies have repeatedly shown that antidepressants’ effects are barely distinguishable from placebo, many opponents of suicide rights still point to meds as a proper course of action for those who wish to die. Those unlucky enough to be hospitalized after a suicide attempt (like me) are still administered antidepressants in hospital – by force, if necessary.

Anyone who still thinks antidepressants have non-placebo value should listen to this 20-minute interview with Dr. Irving Kirsch, the lead investigator on the major meta-analyses of antidepressant drugs.

Major points:

  1. The serotonin hypothesis is “dead in the water.” Studies have repeatedly failed to demonstrate that serotonin deficiency is responsible for depression.
  2. The effects of antidepressants are indistinguishable from placebo, especially when data is included from studies that have not been published because they did not get a positive result. (Dr. Kirsch and others obtained these unpublished studies using the Freedom of Information Act.) Both the publication bias in general, and specific monetary incentives, are implicated.
  3. Antidepressants’ “effects” are independent of the drug mechanism. Antidepressants that work on inhibiting serotonin reuptake have the same effect as antidepressants that work on other neurotransmitters or even other chemicals; that is, their effect is indistinguishable from placebo.
  4. Antidepressant “effects” are independent of dosage.
  5. SSRIs (selective serotonin reuptake inhibitors) show the same level of response as SSREs (selective serotonin reuptake enhancers) – that is, drugs with the opposite mechanism show the same result!
  6. Contrary to my previous suppositions, the antidepressants’ effects are dismal regardless of the severity of depression. Severely depressed patients (who make up most of the study groups!) are not significantly more likely to respond to antidepressants than less severely depressed individuals.

As Dr. Kirsch puts it, “that’s what I call a placebo.”

The next time you see someone recommend drugs as a course of therapy for depression, please point them here, or to the podcast.

Meanwhile, the only drug that consistently cures depression in laboratory studies is only available on the black market.


(In the interests of full disclosure, I take one of these yummy placebos every day – citalopram. Similarly, millions of people feel better every day by using quack therapies such as chiropractic, homeopathy, and prayer. The folks making money off those therapies feel even better.)

Written by Sister Y

March 7, 2011 at 6:12 pm

What the DSM-II Got Right

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The DSM-II, or Diagnostic and Statistical Manual of Mental Disorders, Second Revision, was the diagnostic guide specifying the criteria for psychiatric disorders between 1968 and 1980.

In general, the DSM-II is very suspect. Until 1974, the DSM-II famously listed homosexuality as a mental disorder – specifically, it was listed under Personality Disorders and Certain Other Non-Psychotic Mental Disorders, Sexual Deviations, as DSM-II 302.0, Homosexuality. (Certain wacky Christian fringe groups and many Catholics still think the removal of homosexuality from the DSM was a real shame.) The DSM-II uses quaint terms like “neurosis” and includes controversial diagnoses like “Psychosis with childbirth,” “Involutional melancholia,” and “Depersonalization syndrome.”

More recent revisions of the DSM (DSM-III, DSM-IV, and DSM-IV-TR) are generally considered to contain diagnoses that map more scientifically onto observable real-world phenomena.

Partially due to a realization of ignorance of the etiology of many diseases, revisions beginning with the DSM-III tended to erase etiology from the names and diagnostic criteria of many conditions (except conditions where the etiology is obviously central, such as 292.1, “Psychosis with other syphilis of central nervous system” (psychosis caused by syphilis).

Unfortunately, the refusal to link mental diseases with etiology resulted in a step backwards in the diagnosis and treatment of depression, according to Professor Gordon Parker (“Is depression overdiagnosed? Yes,” British Medical Journal 2007:328).

“Fifty years ago [under DSM-II criteria],” says Professor Parker, “clinical depression was either endogenous (melancholic) or reactive (neurotic). Endogenous depression was a categorical biological condition with a low lifetime prevalence (1-2%). By contrast, reactive depression was exogenous – induced by stressful events affecting a vulnerable personality.” In other words, the DSM-II recognized a type of biologically-determined depression, with a population frequency similar to other major, debilitating psychiatric disorders such as schizophrenia. (In fact, for various reasons including the severity and similar lifetime prevalence as schizophrenia, my reading of this is that endogenous “melancholic” depression, if studied in more detail, would be found to be specifically genetically linked, just like schizophrenia.) Another type of depression, much less severe and much more common, resulted from people “becoming depressed” secondary to negative life events.

Then, in 1980, the DSM-III revisions changed all that. They created a new taxonomy of depression, and rather than exogenous and endogenous, began to classify depression as “major” or “minor,” with no reference to etiology. Only the diagnostic modifier “melancholic features,” which I’ve previously discussed in my essay “Depression, Cognition, and Value,” was left of the endogenous depression distinction.

Unfortunately, the major/minor classification has never been borne out by scientific studies (though the “melancholic features” modifier is scientifically robust). As Professor Parker points out,

Meta-analyses show striking gradients favouring antidepressant drugs over placebo for melancholic depression. Yet trials in major depression show minimal differences between antidepressant drugs, evidence based psychotherapies, and placebo. . . . Extrapolating management of the more severe biological conditions to minor symptom states reflects marketing prowess rather than evidence. Depression will remain a non-specific “catch-all” diagnosis until common sense prevails. [Emphasis mine; citations omitted.]

Scientific studies do not back up diagnoses of “major” and “minor” depressive disorders as true disorders. The DSM-III criteria for major depression has “failed to demonstrate any coherent pattern of neurobiological changes or any specific pattern of treatment response outside in-patient treatment settings,” says Professor Parker. In other words, while the quaint diagnosis of “melancholic depression” under the DSM-II retains some scientific validity, the diagnosis of Major Depressive Disorder under the DSM-IV is not scientifically valid in any of the normal senses.

The implications for suicide rights are several. First, to the extent that everyone who is suicidal is assumed to be suffering from “Major Depressive Disorder,” we are being diagnosed with a disease whose scientific validity is extremely questionable. The laughable overdiagnosis of “Major Depressive Disorder,” coupled with the diagnosis’ failure to “demonstrate any coherent pattern of neurobiological changes or any specific pattern of treatment response,” must shake our confidence in the fashionable hypothesis that all suicide is secondary to a genuine mental disorder. Second, to the extent that our psychiatric establishment chooses to use these diagnostic criteria (Major Depressive Disorder), and since meta-studies generally show little significant difference between antidepressant medications, “evidence-based psychotherapies,” and placebo, if we have depression, we must be said to have an incurable disease. Both citizens in general the those in medical professions should be much more circumspect about their willingness to force people with “Major Depressive Disorder” to remain alive against their will, and especially to forcibly medicate or “treat” this “disease.”

While I think endogenous depression is a “real” disease, unlike DSM-IV Major Depressive Disorder, I do not think that all suicides have endogenous depression – not even close – nor do I think that endogenous depression is always treatable. At best, it is marginally more treatable than DSM-IV Major Depressive Disorder – that is to say, not very. The famous study that found that SSRIs work no better than a placebo found a slightly significant difference between drug and placebo for the most severely depressed people, which could be tracking endogenous depression, but this was primarily due to that group’s much lower response to placebo. From the study:

Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. . . . Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

Written by Sister Y

August 1, 2008 at 10:31 pm

Depression, Cognition, and Value

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Loss of appetite, often coupled with weight loss, is commonly seen in what our medical system defines as depression. It is a diagnostic criterion for a Major Depressive Episode under the DSM-IV. (A Major Depressive Episode is, in turn, the building block for a diagnosis of Major Depressive Disorder.) Spefically, Criterion A3 for Major Depressive Episode is (in the amusingly vague, catch-all language of the DSM-IV):

significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day.

(Interestingly, anorexia or significant weight loss, but not weight gain, is a diagnostic subcriterion for what the DSM-IV calls “melancholic features,” a sort of diagnostic hanger-on to Major Depressive Disorder that requires either a loss of pleasure in almost all activities, or a loss of reactivity to usually pleasurable stimuli. People exhibiting melancholic features are less likely to respond to placebo, says the DSM-IV.)

Some depressed people, the DSM-IV tells us, overeat, and some fail to eat enough. For simplicity, and to illustrate an aspect of depressed cognition, I will consider in this essay only the depressed people whose appetite is reduced.

Why do some depressed people not eat? Is there some mysterious “chemical imbalance” that causes both depressed feelings and reduced appetite (except that the same imbalance causes increased appetite sometimes)? Instead of reaching for a possible explanation why someone might not eat, let’s consider the opposite question: why do non-depressed people eat?

A model of the eating-related introspection of a non-depressed person might look like this:

  1. The person feels hungry (or, perhaps more commonly in wealthy countries, the person feels bored).
  2. The person imagines various options for food.
  3. The person picks something that triggers pleasurable associations, based on a hope that eating will produce pleasurable sensations (satiety, aesthetic interest).
  4. The person eats.

People eat to relieve hunger or boredom, in a sense, but the cognitive path followed by a person in order to eat must have some basis in hope – hope that eating will make the person feel better, hope that the action of acquiring food, chewing, and swallowing will be worth it.

A model of the eating related introspection of a depressed person, on the other hand, might look like this (and I’m taking this from introspection, and exaggerating a bit for clarity):

  1. The person feels hungry or bored.
  2. The person, being depressed, also feels miserable.
  3. The person imagines various options for food.
  4. While the person remembers food relieving hunger, the person, if very depressed, also remembers that food does not relieve misery.
  5. No imaginary food seems that much better than any other, since all will ultimately lead to misery (by failing to relieve the misery).
  6. Why bother?
  7. The person may often fail to eat.

Failure to eat by depressed folks has nothing to do with body image, as in eating disorders. It merely has to do with a lack of hope for getting relief from food – and, ultimately, a lack of recognition of the value of eating (distinct from an intention to starve oneself to death).

Despite some evidence for depressive realism, there is some sense in which we might say that the cognition of severely depressed people may be impaired – especially their decision-making capabilities. We might easily say that a person who can’t decide what to eat, and so fails to eat, is indeed cognitively impaired, rather than being especially wise. (I feel rather silly when it happens to me.) In fact, “diminished ability to think or concentrate, or indecisiveness, nearly every day” (emphasis mine) is DSM-IV Criterion A8 for a Major Depressive Episode.

Recent work in cognitive science has explored the role that emotion plays in decision-making. For example, in “The role of emotion in decision-making: Evidence from neurological patients with orbitofrontal damage,” Brain & Cognition 55 (2004) 30–40, Antoine Bechara reports that

The studies of decision-making in neurological patients who can no longer process emotional information normally suggest that people make judgments not only by evaluating the consequences and their probability of occurring, but also and even sometimes primarily at a gut or emotional level. Lesions of the ventromedial (which includes the orbitofrontal) sector of the prefrontal cortex interfere with the normal processing of ‘‘somatic’’ or emotional signals, while sparing most basic cognitive functions. Such damage leads to impairments in the decision-making process, which seriously compromise the quality of decisions in daily life.

That decisions, in humans, are based on emotion is an empirical fact, to the extent that there is evidence for it. People with impaired capacity to experience emotion are not perfect rational calculators; their decisions appear very strange, and often poor. But that is a mere description of our meat-based decision-making apparatus. It says nothing as to how the best decisions might be made – or, most importantly, what characteristics distinguish the best decisions. To specify that, we need to know what is valuable – for values must be the ultimate criteria for which decisions are good, and which poor. Why do anything? Here psychology must collide with philosophy.

To the extent that a depressed person does not make a normal decision – including the silly case of failing to eat (for lack of a compelling reason, not for lack of resources) – the depressed person is merely revealing his values. To claim that the depressed person is cognitively impaired in a way that would justify intervention into his decisions is to say that his values are incorrect, or that he is not justified in pursuing his values, and should be required to pursue our values instead. We cannot, I think, ethically intervene (force-feed) when a hunger striker decides that she values, say, women’s suffrage over the continued satisfaction of her hunger, even unto death. When a depressed person concludes that nothing is valuable, except perhaps an end to suffering, we are in no better ethical position to intervene – either to force-feed, or to withhold the means for suicide.

Depressed people who overeat are consistent with my model. These people – less severely depressed, perhaps – have not completely given up on food as a source of relief, and may in fact clearly remember receiving positive feelings as a result of food. Therefore, instead of triggering the “eat” response every time one is hungry or bored, the overeating depressed person triggers it in addition every time he feels miserable, leading to increased eating and perhaps weight gain. As I pointed out above, increased appetite is not a feature associated with “melancholic features,” which might, in a vague sense perceptible from the DSM-IV report on response to placebo, indicate a more severe type of depression. This is consistent with overeaters being less “hopelessly” depressed than undereaters.

Written by Sister Y

June 2, 2008 at 5:57 am