Angell’s Review of Psychiatry

Marcia Angell has written a two-part article for The New York Review of Books: “The Epidemic of Mental Illness: Why?” and “The Illusions of Psychiatry.” It is a favorable review of 3 recent books:

• The Emperor’s New Drugs: Exploding the Antidepressant Myth by Irving Kirsch
• Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America by Robert Whitaker
• Unhinged: The Trouble With Psychiatry—A Doctor’s Revelations About a Profession in Crisis by Daniel Carlat

and an unfavorable review of the most recent version of the Diagnostic and Statistical Manual of Mental Disorders, DSM-IV-TR. It paints a disturbing picture of psychiatry. It raises a number of serious concerns but it borders on psychiatry-bashing, a sport that I deplored in a previous post.

Angell has good credentials. She is an MD trained in internal medicine and pathology, a former editor of The New England Journal of Medicine, and is currently a Senior Lecturer at Harvard Medical School. When she speaks, she usually has something interesting to say. In a 1998 editorial she and Jerome Kassirer wrote

It is time for the scientific community to stop giving alternative medicine a free ride… There cannot be two kinds of medicine — conventional and alternative. There is only medicine that has been adequately tested and medicine that has not, medicine that works and medicine that may or may not work. Once a treatment has been tested rigorously, it no longer matters whether it was considered alternative at the outset. If it is found to be reasonably safe and effective, it will be accepted.

She has previously criticized the U.S. healthcare system and the pharmaceutical industry in her books Science on Trial: The Clash of Medical Evidence and the Law in the Breast Implant Case and The Truth About the Drug Companies: How They Deceive Us and What to Do About It.

Is There an Epidemic? We are seeing an apparent epidemic of mental illness. 46% of adults are diagnosed with mental illness at some point in their lives. Mental illness is now the leading cause of disability in children, with a 35-fold increase over the last two decades. The tally of those who are so disabled by mental disorders that they qualify for Supplemental Security Income (SSI) or Social Security Disability Insurance (SSDI) increased nearly two and a half times between 1987 and 2007—from one in 184 Americans to one in 76.

Is the incidence of mental illness really increasing? Or are we just getting better at diagnosing it? Or have we expanded the criteria for mental illness to where almost everyone can be classified as mentally ill?  It’s not clear.

My skeptical psychiatric consultant, Dr. William Hoffman, comments:

I suspect that the studies overestimate the lifetime prevalence of depression, anxiety, ADHD, etc. either because the diagnostic criteria are sufficiently vague or because normal individuals are incorrectly diagnosed with mental illness (Aragones et al., 2006).  The problem stems, in part, because depression, anxiety disorders and ADHD (this is a subset, but accounts for most of the problem) overlap with sadness, anxiety and inattentiveness that is not pathological. As there is no independent diagnostic test for these disorders, their prevalence depends critically on where the severity line is drawn in the diagnostic criteria.  Tighten the depression criteria and there are fewer depressed people.  Additionally, in clinical practice, diagnostic criteria may simply not be used (Zimmerman and Galione, 2010).

There are several forces that drive looser diagnostic criteria (Mulder, 2008):

1. Pharmaceutical companies certainly benefit from more inclusive criteria, higher prevalence rates and more prescriptions written. An indication for depression is a gold mine for a pharma company; witness the stampede to get depression indications for antipsychotics. Industry influence can be felt in the design of clinical trials, industry supported education of providers (remember, most antidepressants are prescribed by primary care providers) and direct marketing of the drugs.
2. Looser diagnostic criteria can give the illusion that the clinician is helping more people. Coupled with the (almost certainly erroneous) belief that pharmacotherapy is at worst harmless, this leads to prescriptive practices treat people who do not even meet the permissive DSM-IV criteria (“Dr. Hoffman, why would you deny this patient the possibility that Superdrug might help them? Can’t you see that she’s suffering?”).
3. Permissive criteria also indirectly foster the clinical impression of efficacy. Normative sadness is by definition a time limited phenomenon and, if a sad person is treated with an antidepressant, they certainly cease being sad sometime after drug initiation. Clinicians don’t have as much experience with sad people who weren’t treated with drugs and got better sometime after the decision to withhold pharmacotherapy.

It’s reasonable to hypothesize that permissive diagnostic criteria are responsible for the high rate of failed trials of antidepressants and of the meta-analytic finding that ‘mild’ depression responds to antidepressants no better than to placebo. There are other possible (not mutually exclusive) explanations for these findings (diagnostic heterogeneity, e.g.), but criterion creep probably accounts for a lot of the problem.

How much are pharmaceutical companies to blame? The three authors agree that the pharmaceutical industry has unduly influenced our thinking about diagnosis and treatment. Studies have shown that psychiatrists receive more money from pharmaceutical companies than physicians in any other specialty. In his book, Carlat explains that psychiatrists are an easy target because

Our diagnoses are subjective and expandable, and we have few rational reasons for choosing one treatment over another.

It is illegal for pharmaceutical companies to encourage off-label prescription in their marketing efforts. Several firms have been charged with such offenses in recent years. Angell thinks the laws should cover not just companies, but physicians. She says:

I believe doctors should be prohibited from prescribing psychoactive drugs off-label.

I disagree. Sometimes off-label indications are justified by published evidence before formal approval is obtained. A blanket prohibition on off-label prescribing would slow the incorporation of new knowledge into clinical practice and would be an unwarranted interference with physician autonomy and clinical judgment.

Financial considerations affect individual providers and patients as well as pharmaceutical companies.

Like most other psychiatrists, Carlat treats his patients only with drugs, not talk therapy, and he is candid about the advantages of doing so. If he sees three patients an hour for psychopharmacology, he calculates, he earns about $180 per hour from insurers. In contrast, he would be able to see only one patient an hour for talk therapy, for which insurers would pay him less than $100.

Children are increasingly being given psychoactive drugs that have not been studied in children. Children from low-income families are four times as likely to be on these drugs. SSI income is a strong incentive for labeling them with a qualifying diagnosis.

Are These Diseases Caused by Chemical Imbalance? None of the three authors subscribes to the popular belief that mental illness is caused by a chemical imbalance in the brain.  Indeed, the evidence for it is very shaky.  All we really know for sure is that the chemistry of the brain changes in patients on medication.

My psychiatric consultant Dr. Hoffman agrees that the chemistry imbalance hypothesis is simplistic, misleading, and essentially wrong. However, he argues that this is not a reason to abandon psychoactive medications:

This is not to say that major depression, anxiety disorders and ADHD don’t exist or that no one should be treated with psychotropics for these disorders. Severely depressed people, e.g. those with melancholia, do not improve in a short time, are markedly unresponsive to normal rewards, have group differences in fMRI responses and are much more likely to respond to pharmacotherapy and much less likely to respond to placebo (Heinzel et al., 2009; Horn et al., 2010).  Are patients with melancholia qualitatively different from more mildly unhappy people? That is, does the mechanism by which they are unhappy differ from more usual sadness? Do they have a ‘chemical imbalance’? Let’s look at a more straightforward example.

Schizophrenia is a brain disease. ECA (Epidemiologic Catchment Area) estimates of the prevalence of schizophrenia have not changed. The prevalence of schizophrenia is the same (about 1%) in every human culture and ethnic group. The phenotype of schizophrenia is markedly different from normality and does not overlap much with normal behavior. Schizophrenics as a group have many biologically replicable differences from non-psychotic individuals, although the pathognomonic diagnostic test eludes us still. This qualitative and quantitative difference is reflected in the lower rate of failed clinical trials of antipsychotics and the very low rate of placebo response. Is schizophrenia due to a ‘chemical imbalance’?

Nope. But then, neither is any other neuropsychiatric disorder.

Schizophrenia is one of the most intensely studied neuropsychiatric disorders. No credible neuroscientist doubts that the schizophrenic syndrome arises from genetically influenced brain abnormalities present at birth that interact with subsequent brain development and environmental contributors in a manner that increases the risk of undergoing a psychotic transition sometime in adolescence or early adulthood. Dopamine D2 family antagonists are the only (even partially) effective treatment for some of the symptoms. Despite three decades of looking, there does not seem to be a large primary abnormality in the dopaminergic system in schizophrenics’ brains. Contemporary conceptions of schizophrenic pathology concern abnormalities in brain circuitry (Swerdlow, 2011).  DA modulates the function of some of those circuits and, through this mechanism, DA blockade exerts its influence. Greater DAergic stimulation (like by cocaine) makes schizophrenic symptoms worse and DA blockade makes it a bit better, but the actual state of affairs is quite complex and not due to a simple chemical imbalance.  Depression fits this simplistic model even more poorly, particularly because depression (perhaps of lesser severity) will respond to psychosocial interventions while schizophrenia does not.

Borderline personality disorder, another syndrome that is relatively reliably (don’t know yet about validity) defined responds poorly to drugs and best to specific psychosocial interventions (Gunderson, 2011; Leichsenring et al., 2011). Does response to non-pharmacologic interventions mean that the disorder under consideration is not a brain disease? Does this mean that the individual is somehow more responsible for their disorder than someone with, say Parkinson’s disease? Certainly not. The affective, behavioral and cognitive dysregulation in borderlines is based on genetic and developmental variance from the norm. No one would choose borderline personality disorder as a lifestyle.  It’s just that that disorder, like milder depression, occurs in a brain that is able to respond to techniques that get the patient to practice behaviors that preclude their more troubling symptoms.

This is a source of some confusion and is reflected in some of the authors’ work in the review. Just because the chemical imbalance model is too simplistic (or just plain silly) as an explanation of a disorder does not suggest that the disorder doesn’t exist or imply that (and this is never explicitly stated, only implied) the disorder is not really dependent on brain function in the same way as, say, Parkinson’s Disease. To the extent that the disorder can be reliably diagnosed and has adequate validity (one could readily argue that some DSM-IV disorders lack validity), it must, of necessity, reflect variant brain function.

So why does the model persist? William Hoffman again:

There are many reasons why the chemical imbalance model persists despite no real evidential support of its primary form. Busy clinicians like simplicity. It frees them from uncertainty and provides a guide to purportedly healing actions. A common complaint from psych residents about presentations of the neurobiology of psychiatric disorders is, “But how does this neuroanatomical circuit stuff tell me what to do?” And it doesn’t always tell clinicians what to do, although sometimes it might tell them what to avoid. If one can go through the depression checklist, determine that the person meets criteria, prescribe the first antidepressant on the algorithm (or the miracle drug discussed at the drug dinner last night) and then move on to the next person, one can avoid the anxiety of saying, “Ms. Smith, it sounds like you’ve had a tough time lately. A lot of people react with feelings of sadness in this situation. But most people also pull out of it without having to use antidepressants. I’d like to prescribe an activity schedule that will get you out of the house and doing some of the things that you enjoy. I’m glad you identified a friend who’d be willing to be a short term coach and get you out even when you don’t feel like it. I’d also like you to see Dr. X, who can teach you some new mental techniques that have been shown to help with your kind of sadness. You’ll see him twice a week at first and I’d like you to meet with our activity therapist to review your activity schedule. I’ll see you in a couple weeks to see if you’re able to benefit from this plan.” That’s a complex plan and, because it involves extra visits, it might be more expensive than saying, “Here are some samples of Sliced Bread and a prescription for when those run out. Antidepressants take about three weeks to start working, so I’ll see you for 15 minutes in three weeks.” Pharma is able to exploit clinicians’ desire to help patients and their anxiety in the face of scientific indeterminacy with drugs (Newer! Better! More powerful! [More expensive]) and a plan for their use.

How do psychiatrists arrive at a diagnosis?

[Carlat’s] work consists of asking patients a series of questions about their symptoms to see whether they match up with any of the disorders in the DSM. This matching exercise, he writes, provides “the illusion that we understand our patients when all we are doing is assigning them labels.” Often patients meet criteria for more than one diagnosis, because there is overlap in symptoms.

How do psychiatrists decide which drug to prescribe? Carlat says:

Guided purely by symptoms, we try different drugs, with no real conception of what we are trying to fix, or of how the drugs are working. I am perpetually astonished that we are so effective for so many patients.

Are psychoactive drugs merely placebos? Kirsch has been on something of a crusade to prove that hypothesis. His interpretation of the data on anti-depressants differs from Erick Turner’s interpretation of the same data because of a different understanding of effect size., as I explained in a previous post.

Studies showing that psychoactive drugs are more effective than placebo do not show a very large difference, and it has been speculated that the side effects of these drugs reveal to the patient that he is not getting a placebo, thereby enhancing the placebo effect of the drug. Studies using an “active” placebo that causes side effects seem to support this hypothesis. But a more definitive way to test it would be to do an “exit poll” asking subjects whether they thought they had been assigned to the placebo group or the drug group. In acupuncture studies, subjects who believed they were in the true acupuncture group improved more than those who believed they were in the control group — no matter which group they were actually in! As far as I know, no similar studies have been done for psychoactive medications.

Are these drugs harmful? Whitaker argues that psychoactive drugs may be responsible for turning episodic illness into chronic illness. He says antipsychotic drugs shrink the brain. By altering brain chemistry, they may cause disease. For instance, anti-depressants can cause episodes of mania resulting in a new diagnosis of bipolar disorder. He thinks we are seeing an iatrogenic epidemic of brain dysfunction. It can be difficult to get off the drugs because the brain has adapted to their presence. He particularly demonizes Zyprexa. His arguments are not convincingly supported by evidence, but they do suggest directions for research.

Is the DSM based on science? It appears to be strongly influenced by opinion. It is disturbing that the number of diagnoses keeps increasing, from 182 to 365.

Even Allen Frances, chairman of the DSM-IV task force, is highly critical of the expansion of diagnoses in the DSM-V. In the June 26, 2009, issue of Psychiatric Times, he wrote that the DSM-V will be a “bonanza for the pharmaceutical industry but at a huge cost to the new false positive patients caught in the excessively wide DSM-V net.”

As Angell says,

It looks as though it will be harder and harder to be normal.

The DSM is a noble but flawed effort to standardize psychiatric diagnosis and make it more rational. I’m afraid we are stuck with it. It won’t go away, but we can hope to make it better and more scientific. Despite its flaws, it’s arguably better than going back to pre-DSM days.

Are non-drug options preferable? Angell argues that:

At the very least, we need to stop thinking of psychoactive drugs as the best, and often the only, treatment for mental illness or emotional distress. Both psychotherapy and exercise have been shown to be as effective as drugs for depression, and their effects are longer-lasting.

Yes, but. Non-drug options are not effective for the most severe cases. Psychotherapy can be next to impossible in severely impaired patients, and drug therapy must be added to enable them to respond and cooperate with psychotherapy. And how successful has anyone ever been in getting a severely depressed patient to go out and exercise? Sometimes they can’t even get out of bed.

Conclusion

Angell calls the books she reviews “powerful indictments of the way psychiatry is now practiced.” Indictments have their place, but we mustn’t ignore all the things modern psychiatry gets right. It has (mostly) rejected Freud and is making a valiant effort to become more evidence-based. It has prevented suicides, alleviated incapacitating symptoms, and helped patients enjoy a reasonably normal life at home instead of in a locked ward. Instead of throwing out the baby with the bathwater, how can we employ common sense and rigorous science to improve psychiatric care? Neither Angell nor the books she reviews offer any concrete proposals for improvement. Angell says one thing I can heartily agree with:

Our reliance on psychoactive drugs, seemingly for all of life’s discontents, tends to close off other options… we need to do better.

Hear, hear!

Acknowledgement: Thanks to Dr. William Hoffman for his input. He is a psychiatrist at the Portland VA Medical Center and the Oregon Health & Science University.

Disclaimer: Dr. Hoffman’s opinions expressed herein are his alone and not the opinions of the Department of Veterans Affairs, OHSU, or his cat.

Reference List

Aragones E, Pinol JL, Labad A (The overdiagnosis of depression in non-depressed patients in primary care. Fam Pract 23:363-368.2006).

Gunderson JG (Clinical practice. Borderline personality disorder. N Engl J Med 364:2037-2042.2011).

Heinzel A, Grimm S, Beck J, Schuepbach D, Hell D, Boesiger P, Boeker H, Northoff G (Segregated neural representation of psychological and somatic-vegetative symptoms in severe major depression. Neurosci Lett 456:49-53.2009).

Horn DI, Yu C, Steiner J, Buchmann J, Kaufmann J, Osoba A, Eckert U, Zierhut KC, Schiltz K, He H, Biswal B, Bogerts B, Walter M (Glutamatergic and resting-state functional connectivity correlates of severity in major depression – the role of pregenual anterior cingulate cortex and anterior insula. Front Syst Neurosci 4.2010).

Leichsenring F, Leibing E, Kruse J, New AS, Leweke F (Borderline personality disorder. Lancet 377:74-84.2011).

Mulder RT (An epidemic of depression or the medicalization of distress? Perspect Biol Med 51:238-250.2008).

Swerdlow NR (Are we studying and treating schizophrenia correctly? Schizophr Res 130:1-10.2011).

Zimmerman M, Galione J (Psychiatrists’ and nonpsychiatrist physicians’ reported use of the DSM-IV criteria for major depressive disorder. J Clin Psychiatry 71:235-238.2010).