Cognitive Therapy in Schizophrenia: Worth Another Look

February 15, 2011

While writing my recent post on the placebo effect in schizophrenia (and while reviewing some of the comments I received on this post), I started to think about what aspects of the patients’ experience are most susceptible to change, which might account for the “placebo effect” seen in clinical studies of antipsychotics.  As one commenter correctly pointed out, the placebo effect should not be viewed as a mysterious consequence of ingesting some inert drug, but rather a reflection of the patient’s inherent ability to heal.  Unfortunately we know very little about the mechanisms involved, and we are devoting even less effort to understanding how to capitalize (no pun intended) on this process in the long-term management of psychotic disorders.

I realized, however, that I didn’t acknowledge the fact that psychotherapy does have a place in the treatment of schizophrenia.  Psychosocial treatment approaches, for instance, are routinely employed, with varying degrees of success, and some groups have used cognitive behavioral therapy techniques as well.  Cognitive therapy, in a nutshell, is based on the assumption that early experiences and social environment can give rise to “schemas” about the self, other people, and the world.  These beliefs then lead to cognitive distortions, negative styles of thinking, and misinterpretations of events in the world (or in one’s own mind).  Cognitive therapy aims to question or challenge these distortions and misinterpretations to engender a healthier, more functional view of oneself and one’s ability to master his surroundings.

At first glance, cognitive therapy seems like it would be ineffective in a psychotic patient, who may not be able to appreciate the discrepancy between his subjective experiences and objective reality.  Nevertheless, it has shown some promise, and a classic paper in this field is the 1994 article “Cognitive Behaviour Therapy of Schizophrenia” by Kingdon, Turkington, and John, in the British Journal of Psychiatry.  It is a fascinating, and eye-opening, read.

A particularly striking aspect of the paper (and keep in mind that I received my psychiatric training within the last 10 years, firmly in the atypical antipsychotic era) is that it says nothing about eliminating psychotic symptoms.  The current literature, in contrast, starts with the assumption that hallucinations, delusions, and cognitive deficits of schizophrenia are biochemical entities (which they are, of course, like any other mental phenomenon), but they are deviant and/or undesirable, and biological interventions (i.e., drugs) abolish or “correct” them.  The Kingdon article assumes that schizophrenic thought content lies on a continuum with “normal” cognition, and in fact some of the same cognitive processes are employed, albeit improperly or deficiently.  The authors claim that “abnormal beliefs” can be more or less “amenable to reason” (as with any cognitive distortion in CBT) and a key element of therapy is to “identify meaning in delusional material and then assess alternative explanations.”  In other words, it emphasizes the patient’s subjective experience, rather than the symptoms witnessed by the clinician.

Another surprising feature of the Kingdon article is its implicit acknowledgment that certain delusions or hallucinations may be entirely acceptable.  Schizophrenic patients, they claim, often do not have the ability to “meta-think”– i.e., to think about thinking– so they frequently are not aware that their unusual sensory or perceptual experiences differ from normal thought.  As a result, they cannot usually be “argued out of” a belief, even with the most skilled cognitive behavioral approach, and we must accept that they’ll find their own personal meaning for their experience.  “It may be,” the authors write, “that the reassurance of finding a meaningful explanation, however improbable, in a distressing and perplexing situation is sufficient to explain why the delusion is reached for and clung to, so energetically and with such certainty.”

Newer applications of CBT-based techniques, reviewed in an excellent 2009 article by Tai and Turkington in Schizophrenia Bulletin, have taken advantage of this viewpoint and start with the belief that “it is the individual’s personal meaning, understanding, and coping with symptoms that are the focus of treatment” – not the mere presence or absence of hallucinations or delusions.  In particular, mindfulness-based approaches, acceptance and commitment therapy (ACT), and compassionate mind training (CMT), are therapeutic techniques that involve awareness of one’s experience, acceptance of internal events, and minimization of shame and self-criticism that can arise from paranoid or persecutory thoughts, respectively.

Schizophrenia is probably not a single disease; in fact it is likely to comprise many different cognitive, developmental, physiological, and externally mediated disruptions, all of which lie on a spectrum with the “normal” state.  (The Kingdon article, in fact, goes to great lengths to point out how even non-psychotic individuals can experience “psychotic” beliefs in the form of superstitious thought, overvalued ideas, or psychosis induced by sleep deprivation or hallucinogenic drugs.)  To be sure, some psychotic symptoms in some patients will respond best to a dopamine antagonist, but it is imperative that we employ other tools at our disposal to help patients overcome them, amend them, or just accept them.  Unfortunately, too few psychiatrists in my generation have learned those tools—all we have is the antipsychotic hammer, and “schizophrenia” is the proverbial, monolithic nail.

The Placebo Effect: It Just Gets Better and Better

February 13, 2011

The placebo response is the bane of clinical research.  Placebos, by definition, are inert, inactive compounds that should have absolutely no effect on a patient’s symptoms, although they very frequently do.  Researchers compare new drugs to placebos so that any difference in outcome between drug and placebo can be attributed to the drug rather than to any unrelated factor.

In psychiatry, placebo effects are usually quite robust.  Trials of antidepressants, antianxiety medications, mood stabilizers, and other drugs typically show large placebo response rates.  A new paper by Bruce Kinon and his colleagues in this month’s Current Opinion in Psychiatry, however, reports that placebos are also show some improvement in schizophrenia.  Moreover, placebos seem to have become more effective over the last 20 years!

Now, if there’s any mental illness in which you would not expect to see a placebo response, its schizophrenia.  Other psychiatric disorders, one might argue, involve cognitions, beliefs, expectations, feelings, etc.—all of which could conceivably improve when a patient believes an intervention (yes, even a placebo pill) might make him feel better.  But schizophrenia, by definition, is characterized by a distorted sense of reality, impaired thought processes, an inability to grasp the differences between the external world and the contents of one’s mind, and, frequently, the presence of bizarre sensory phenomena that can only come from the aberrant firing of the schizophrenic’s neurons.  How could these symptoms, which almost surely arise from neurochemistry gone awry, respond to a sugar pill?

Yet respond they do.  And not only do subjects in clinical trials get better with placebo, but the placebo response has been steadily improving over the last 20 years!  Kinon and his colleagues summarized placebo response rates from various antipsychotic trials since 1993 and found a very clear and gradual improvement in scores over the last 15-20 years.

Very mysterious stuff.  Why would patients respond better to placebo today than in years past?  Well, as it turns out (and is explored in more detail in this article), the answer may lie not in the fact that schizophrenics are being magically cured by a placebo, but rather that they have greater expectations for improvement now than in the past (although this is hard to believe for schizophrenia), or that clinical researchers have greater incentives for including patients in trials and therefore inadequately screen their subjects.

In support of the latter argument, Kinon and his colleagues showed that in a recent antidepressant trial (in which some arbitrary minimum depression score was required for subjects to be included), researchers routinely rated their subjects as more depressed than the subjects rated themselves at the beginning of the trial—the “screening phase.”  Naturally, then, subjects showed greater improvement at the end of the trial, regardless of whether they received an antidepressant or placebo.

A more cynical argument for why antipsychotic drugs don’t “separate from placebo” is because they really aren’t that much better than placebo (for an excellent series of posts deconstructing the trials that led to FDA approval of Seroquel, and showing how results may have been “spun” in Seroquel’s favor, check out 1BoringOldMan).

This is an important topic that deserves much more attention.  Obviously, researchers and pharmaceutical companies want their drugs to look as good as possible, and want placebo responses to be nil (or worse than nil).  In fact, Kinon and his colleagues are all employees of Eli Lilly, manufacturer of Zyprexa and other drugs they’d like to bring to market, so they have a clear interest in this phenomenon.

Maybe researchers do “pad” their studies to include as many patients as they can, including some whose symptoms are not severe.  Maybe new antipsychotics aren’t as effective as we’d like to believe them to be.  Or maybe schizophrenics really do respond to a “placebo effect” the same way a depressed person might feel better simply by thinking they’re taking a drug that will help.  Each of these is a plausible explanation.

For me, however, a much bigger question arises: what exactly are we doing when we evaluate a schizophrenic patient and prescribe an antipsychotic?  When I see a patient whom I think may be psychotic, do I (unconsciously) ask questions that lead me to that diagnosis?  Do I look for symptoms that may not exist?  Does it make sense for me to prescribe an antipsychotic when a placebo might do just as well?  (See my previous post on the “conscious” placebo effect.)  If a patient “responds” to a drug, why am I (and the patient) so quick to attribute it to the effect of the medication?

I’m glad that pharmaceutical companies are paying attention to this issue and developing ways to tackle these questions.  Unfortunately, because their underlying goal is to make a drug that looks as different from placebo as possible (to satisfy the shareholders, you know) I question whether their solutions will be ideal.  As with everything in medicine, though, it’s the clinician’s responsibility to evaluate the studies critically—and to evaluate their own patients’ responses to treatment in an unbiased fashion—and not to give credit where credit isn’t due.

“That’s OK, I Didn’t Need That Brain Anyway”

February 10, 2011

Long-term treatment with antipsychotic medication apparently causes a decrease in brain volume, according to a new report by Nancy Andreasen’s group at the University of Iowa in this month’s Archives of General Psychiatry. In the study, over 200 schizophrenic patients, treated with antipsychotics, underwent MRI scans of their brains at various intervals over a 5-14 year period. The results showed that the “intensity” of antipsychotic treatment (i.e., doses and lengths of treatment) correlated with the reduction in brain tissue.

Instead of just looking at an overall “snapshot” of the brain, researchers calculated the volumes of several brain regions (from the whole-brain MRI scans) and found, on average, subtle decreases in both gray matter and white matter volumes, as well as enlargement of the ventricles (the “spaces” in the normal brain). The changes were more pronounced with longer time periods of treatment and, in particular, when higher doses of antipsychotics were used for extended periods of time.

As expected, this finding has generated a great deal of interest— if not concern– and more than a touch of “I-told-you-so” from certain camps (see “Antipsychotics Shrink the Brain” by Robert Whitaker). Indeed, at first blush, it is quite shocking to think that the first-line treatment for such a devastating brain disease might cause damage to the very organ we are trying to treat.

But is it really “damage”? All joking aside, I think the title of this post needs to be taken seriously. Does the observed loss in brain tissue loss mean that a person is incapacitated in any way? That he can no longer think, feel, see, taste, or make plans for the future? Moreover, despite the headlines, the tissue loss was not incredibly dramatic. In other words, we’re not talking about a healthy, robust brain turning into a moth-eaten mass of Swiss cheese. In fact, by my read of the data, the largest individual change in frontal gray matter volume was from about 330 cm3 to 290 cm3 over a 10-year period (yes, that’s >10%, but who knows what else was happening in that patient?). Other changes were much smaller, and many patients actually showed increases in brain volumes.

There were slight correlations with disease severity (more symptomatic disease was associated with a greater decrease in brain volume), and different classes of antipsychotics affected some regions of the brain differently than others. Interestingly, there seemed to be no independent effect of substance abuse on brain volume changes, despite the oft-heard warning that drugs and alcohol “kill brain cells.”

So what does this all mean? Obviously, some will say that this provides evidence that antipsychotics are toxic to brain cells. But there’s no clear evidence that neurons are actually dying; in some studies in monkeys taking antipsychotic medication, the number of neurons remains constant, but they increase in density because support cells (called glia) decrease in number– resulting in the macroscopic appearance of a “smaller brain.”

Moreover, it is quite possible that the disease process itself already leads to a decrease in brain volume (actually, we know this already) and effective treatment helps to further “prune” dysfunctional areas of the brain. In fact, an editorial accompanying the article claims that “strategic reductions in brain volume” might actually be therapeutic, and reminds us that gray matter volume decreases significantly during human adolescence, a process thought to underlie the organization and refinement of brain cells, and elimination of redundancy. (No wonder you have to tell your teenage son six times to clean his room.)

The best way to tackle this question, of course, is to take two groups of schizophrenics, treat one “as usual” with antipsychotics and the other with no medication at all, and perform brain scans at regular intervals. For ethical reasons, we can’t do this (it’s unethical not to treat a psychotic patient with an antipsychotic– although some would argue differently). Another way is to take advantage of the fact that many non-schizophrenic patients are now taking antipsychotics for OTHER diagnoses– bipolar disorder, depression, anxiety, insomnia, PTSD (just to name a few)– and we could compare those on antipsychotics to those on other drugs. If we see brain tissue loss across a wide spectrum of diagnoses, it suggests that this effect may be a direct result of antipsychotic treatment, even though the mechanism remains unknown.

Regardless of what’s actually happening in the brains of treated schizophrenics– and whether it’s “good” or “bad,” or whether it resembles the brain loss observed in birds living near Chernobyl— two things must be kept in mind. First, the patient’s well-being is of utmost importance; it would be inappropriate to withhold antipsychotic treatment from a patient who is clearly tormented and disabled from his paranoia, his delusional preoccupations, and his absolute lack of insight, particularly when we know that such medications do, in most cases, result in dramatic improvement. At the same time, we must also consider the other side of the coin, namely that if antipsychotics might cause an unexplained loss in brain tissue—or any other anatomic defect elsewhere, for that matter—we must seriously consider our rationale for these drugs. In particular, brain development in children is an ongoing process, not complete until late adolescence or early adulthood.

Hopefully this finding will stimulate research to determine how antipsychotics affect brain cells over time. Perhaps then we can find ways to preserve brain structure – or, at least, essential brain structure—while still treating the symptoms of mental illness. In other words, avoiding harm, while still doing good.

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