The word “placebo,” often denigrated by psychopharmacology skeptics as “the sugar pill” is a very misunderstood concept in psychiatry.
In order to gain approval for prescription in the United States, the Food and Drug Administration (FDA) requires clinical trials of between five and ten thousand patients before approving new medications. The gold standard for clinical trials is the double-blind placebo controlled study, in which half the enrollees are given a capsule or pill containing an inert substance (placebo), while the others receive active drug. From the outset, everyone in the study is assured that should they be in the placebo group, they will be offered active drug at the trial’s conclusion, advertised as “promising new medication for depression.” During the study period, usually sixteen weeks—in clinical practice depressed patients receive medication for much longer to sustain the response—although only half the patients receive active medication, everyone receives one of the most potent treatments in medicine: hope. Many patients enter clinical trials for depression medicines feeling hopeless, a common but difficult to quantify symptom of depression, although every seasoned clinician agrees hope is a powerful factor in recovery. The biology of hope has been studied extensively: except in the most depressed individuals (people totally incapable of feeling positive feelings) which constitute only a small percentage of those in antidepressant clinical trials, the anticipation of feeling better stimulates the dopamine-containing brain circuits associated with positive feelings.
Placebo is very different from no treatment. Epidemiological studies of Clinical Depression reveal that only 50% of untreated patients will recover fully, and if and when they do, average recovery time is 6-18 months. Of the others, the majority enter a chronically depressed state while the remaining 10% often suffer a downward course complicated by substance abuse or even death. Given that successful treatment either shortens the length or lessens the severity of depressive episodes, no reasonable clinician would tell a clinically depressed individual to come back in a year to see how he or she is faring!
So, in addition to hope, what else happens to the placebo group in a clinical trial? They receive lots of attention by highly-trained and sophisticated clinicians, who, although unaware of whether or not the patient is receiving active medication, are vested in delivering quality care. They treat every patient with the same consideration and empathy, guaranteeing that the patient feels important, listened to and well-cared for.
In addition to filling out symptom checklists and self-report questionnaires, clinical trial patients put their thoughts and feelings into words each week when they interact with evaluators, an activity that mobilizes a lot of brain activity and can be therapeutic in and of itself. Unlike passive depressed patients waiting to feel better, individuals in clinical trials have already adopted a proactive stance, which self-selects a population more likely to respond to treatment for depression. In order to receive medication, outpatients must attend regularly-scheduled appointments for physical examinations and laboratories studies, adding structure and motivation to their behavior, also therapeutic factors in recovery from depression. Although difficult to quantify, every clinician understands how mobilization puts patients consciously or unconsciously, in a healing mode. The patient feels he is doing something about his illness, as opposed to waiting to feel better, a low probability strategy for recovery.
In the FDA’s eyes, a “positive response to treatment” means only a 50% reduction in symptoms, not full remission, hardly a robust measure of true recovery. Also, In order to qualify for a clinical study, patients taking other antidepressants undergo several weeks of washout from other antidepressants so, in theory, they begin the trial with no antidepressant on board; the typical study aims for what is termed “monotherapy,” that is treatment with one antidepressant medication only. Also, patients with co-occurring substance use disorders, psychosis, or major medical disorders, a significant percentage of “real world” depressed patients are disqualified from clinical trials, hardly a representative of the true patient population of depressed individuals who are stressed and depressed about their health conditions and use alcohol and other substance to self-medicate their symptoms. The first thing a “real world” psychopharmacologist will address and try to eliminate or reduce in a new patient is the confounding use of alcohol or other substances that exacerbate depression.
The number of clinical trials for antidepressant medications increased dramatically in the latter part of the twentieth century, coincident with the predominant theory that depression was caused by a chemical imbalance in the functioning of the three major biogenic amines neurotransmitters—serotonin, nor-epinephrine, and dopamine. As both patients’ hopes increased, mirrored by an increase in clinical researchers’ hope and clinical skills, so did the placebo response, which accounted for upwards of half of the clinical response depending on the severity of the depression and inclusion/exclusion criteria of the study. What this really shows is that psychiatric care has gotten better.
Those claiming that medication treatments for depression are no better than “sugar pills” cite meta-analyses of studies of medication treatments for depression, that is pooled data from multiple pre- and post-approval clinical studies. Although pooled data increases the number of patients under investigation, it also muddles the issue by lumping together patients with varying severity of illness, including those with less serious symptoms who would be expected to respond positively to the hope engendered by being involved in a promising treatment. Would that there were, but there is no convincing data that placebo effectively treats sever, treatment-refractory depression.
Having treated depression for years, I can attest that hope, caring and empathy are essential to the effective psychiatric treatment of depression. It makes perfect sense that as psychiatric care has care has improved, so has the placebo response. There is no ethical way to remove the placebo element of psychiatric care from scientific study. As savvy and experienced clinicians know: “We do far more than dispense medicine. We empathize. We listen. We advise. We give structure. We care. And above all, we give hope.”
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