Anatomy of an Epidemic (28 page)

As early as 1965, before lithium had made its triumphant entry into American psychiatry, German psychiatrists were puzzling over the change they were seeing in their manic-depressive patients. Patients treated with antidepressants were relapsing frequently, the drugs “transforming the illness from an episodic course with free intervals to a chronic course with continuous illness,” they wrote. The German physicians also noted that in some patients, “the drugs produced a destabilization in which, for the first time, hypomania was followed by continual cycling between hypomania and depression.”
³⁸

This was obviously alarming, for the good outcomes in manic-depressive patients arose from the fact that they spent a large part of their lives in symptom-free intervals between episodes, during which time they functioned well. Antidepressants were destroying those asymptomatic interludes, or at least dramatically shortening them. Prior to the drug era, Kraepelin and others reported that only about one-third of manic patients suffered three or more episodes in their lives. Yet studies of bipolar patients in the 1960s and 1970s told of two-thirds who were becoming chronically ill. “The administration of tricyclics may account for artificially high relapse rate estimates,” Fred Goodwin wrote in 1979. “Induction of mania, break down of otherwise long episodes into multiple ones … induction of rapid cycling … are some of the mechanisms by which the administration of tricyclics may contribute to an increase in the number of episodes.”
³⁹

Once again, it was becoming apparent that psychiatric medications were worsening the course of a mental illness. In 1983, Athanasious Koukopoulos, director of a mood disorders clinic in Rome, said that he and his colleagues were observing the same thing in their Italian patients. “The general impression of clinicians today is that the course of recurrences of manic-depressive illness has substantially changed in the last 20 years,” he wrote. “The recurrences of many patients have become more frequent. One sees more manias and hypomanias … more rapid cyclers, and more chronic depressions.” Whereas in the pre-drug era rapid cyclers were unknown, 16 percent of Koukopoulos’s manic-depressive patients were now in this predicament, and they were suffering an astonishing 6.5
mood episodes annually, up from less than one episode a year prior to being treated with an antidepressant. “It certainly seems paradoxical,” he admitted, “that a treatment that is therapeutic for depression can worsen the further course of the disease.”
⁴⁰

In spite of such information, antidepressants continued to be prescribed to bipolar patients, and even today, 60 to 80 percent are exposed to an SSRI or some other antidepressant. As a result, investigators have continued to document the harm done. In 2000, Nassir Ghaemi reported that in a study of thirty-eight bipolar patients treated with an antidepressant, 55 percent developed mania (or hypomania) and 23 percent turned into rapid cyclers. This antidepressant-treated group also spent “significantly more time depressed” than a second group of bipolar patients who weren’t exposed to this class of medication.
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“There are significant risks of mania and long-term worsening with antidepressants,” Ghaemi wrote a few years later, repeating a message that had been uttered many times before.
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At the University of Louisville, Rif El-Mallakh similarly concluded that antidepressants may “destabilize the illness, leading to an increase in the number of both manic and depressive episodes.” The drugs, he added, “increase the likelihood of a mixed state,” in which feelings of depression and mania occur simultaneously.
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In 2003, Koukopoulos chimed in again, reporting that antidepressant-induced rapid cycling fully abates in only one-third of patients over the long term (even after the offending anti depressant is withdrawn), and that 40 percent of patients continue to “cycle rapidly with unmodified severity” for years on end.
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Soon, in 2005, El-Mallakh pointed out yet another problem: Antidepressants could induce a “chronic, dysphoric, irritable state” in bipolar patients, meaning that they were almost continually depressed and miserable.
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Finally, in 2008, in a large NIMH study called the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), “the major predictor of worse outcome was antidepressant use, which about 60 percent of patients received,” Ghaemi noted.
⁴⁶
The antidepressant users were nearly four times more likely than the non-exposed patients to develop rapid cycling, and twice as likely to have multiple manic or depressive episodes.
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“This
study,” wrote Ghaemi, in an editorial that appeared in the
American Journal of Psychiatry
, “may be one more nail in the coffin of antidepressant use in bipolar disorder.”

During the past ten years, several large studies have documented just how constantly symptomatic bipolar patients are today. In a long-term follow-up of 146 bipolar I patients who enrolled in an NIMH study in 1978–81, Lewis Judd found that they were depressed 32 percent of the time, manic or hypomanic 9 percent of the time, and suffering from mixed symptoms 6 percent of the time.
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The bipolar II patients in that study arguably fared even worse: They were depressed 50 percent of the time. “The nature of this deceptively ‘milder’ form of manic-depressive illness is so chronic as to seem to fill the entire life,” Judd wrote.
⁴⁹
Russell Joffe, at the New Jersey Medical School, reported in 2004 that 33 percent of the bipolar I patients and 22 percent of the bipolar II patients he studied were rapid cyclers, and both groups were symptomatic nearly half of the time.
⁵⁰
Meanwhile, Robert Post announced that nearly two-thirds of the 258 bipolar patients he studied had four or more episodes per year.
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All of these studies showed the same bottom-line result: “It is now well established that bipolar disorders are chronic, with a course characterized by frequent affective episode recurrence,” Judd said.
⁵²

In a 2000 paper published in the
Psychiatric Quarterly
, a Harvard Medical School psychiatrist, Carlos Zarate, and a psychiatrist who worked for Eli Lilly, Mauricio Tohen, opened up a new line of concern: Bipolar patients today aren’t just much more symptomatic than in the past, they also don’t function as well. “In the era prior to pharmacotherapy, poor outcome in mania was considered a relatively rare occurrence,” Zarate and Tohen wrote. “However, modern outcome studies have found that a majority of bipolar patients
evidence high rates of functional impairment.” What, they wondered, could explain “these differences”?
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The remarkable decline in the functional outcomes of bipolar patients is easy to document. In the pre-lithium era, 85 percent of mania patients would return to work or to their “pre-morbid” social role (as a housewife, for example). As Winokur wrote in 1969, most patients had “no difficulty resuming their usual occupations.” But then bipolar patients began cycling through emergency rooms more frequently, employment rates began to decline, and soon investigators were reporting that fewer than half of all bipolar patients were employed or otherwise “functionally recovered.” In 1995, Michael Gitlin at UCLA reported that only 28 percent of his bipolar patients had a “good occupational outcome” at the end of five years.
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Three years later, psychiatrists at the University of Cincinnati announced that only 24 percent of their bipolar patients were “functionally recovered” at the end of one year.
⁵⁵
David Kupfer at the University of Pittsburgh School of Medicine, in a study of 2,839 bipolar patients, discovered that even though 60 percent had attended college and 30 percent had graduated, two-thirds were unemployed.
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“In summary,” wrote Ross Baldessarini in a 2007 review article, “functional status is far more impaired in type I bipolar patients than previously believed, [and] remarkably, there is some evidence that functional outcome in type II bipolar patients may be even worse than in type I.”
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The antidepressants, by increasing the frequency of episodes that bipolar patients suffer, naturally reduce their ability to return to work. But, as has become evident in recent years, the problem runs much deeper than that. One of the hallmarks of manic-depressive illness, dating back to Kraepelin, was that once people recovered from their episodes of mania and depression, they were as smart as they had been before they became ill. As Zarate and Tohen noted in their 2000 paper, “studies conducted prior to 1975 found no consistent findings in cognitive deficits in bipolar patients.” But lithium was known to slow thinking, and suddenly researchers began reassessing this belief. In 1993, NIMH investigators compared cognitive function in bipolar and schizophrenia
patients, and they concluded that while the bipolar patients showed signs of impairment, the deficits were “more severe and extensive in schizophrenia.”
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This was something of a glass-half-full finding. You could interpret it to mean that cognitive impairment was not that bad in bipolar patients, or, if you remembered the pre-lithium days, you might wonder why these patients were suddenly showing signs of mental decline. But this was just the beginning salvo of a tragic story. Once lithium monotherapy fell from favor, psychiatrists began to turn to “drug cocktails” to treat their patients, and soon investigators had this to report: “Cognitive impairments [that] exist in schizophrenia and affective disorders … cannot be qualitatively distinguished with sufficient reliability.”
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The degree of impairment in these two illnesses was suddenly converging, and in 2001, Faith Dickerson at the Sheppard Pratt Health System in Baltimore provided a more detailed picture of that convergence. She ran seventy-four medicated schizophrenia patients and twenty-six medicated bipolar patients through a series of tests that assessed forty-one cognitive and social-functioning variables, and found that the bipolar patients were as impaired as the schizophrenia patients on thirty-six of the forty-one measures. There was “a similar pattern of cognitive functioning in patients with bipolar disorder as compared to those with schizophrenia,” she wrote. “On most measures of social functioning, our patients with bipolar disorder were not significantly different from those in the schizophrenia group.”
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After that, reports of significant cognitive decline in bipolar patients seemed to pour in from psychiatric researchers around the globe—English, Swedish, German, Australian, and Spanish investigators all told of it. The Australians reported in 2007 that even when bipolar patients are only mildly symptomatic, they are “neuropsychologically scarred”—impaired in their decision-making skills, their verbal fluency, and their ability to remember things.
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Meanwhile, Spanish investigators, after noting that cognitive function in their bipolar and schizophrenia patients “did not differ over time in any test,” concluded that both groups suffered from dysfunction in the “prefrontal cortex and temporolimbic structures.” They also observed that “the more medications the patients received,
the greater the psychosocial functioning impairment.”
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Finally, English researchers who looked at the daily lives of bipolar patients found that more than two-thirds “rarely or never engaged in social activities with friends,” their social lives nearly as impoverished as those diagnosed with schizophrenia.
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This was an astonishing convergence in long-term outcomes between the two diagnostic groups, and while the psychiatrists in the United States and abroad who documented it mostly tried, in their discussion of the phenomenon, to ignore the medication elephant in the room, several did confess that it was
possible
that psychiatric drugs were to blame. Conventional antipsychotics, said Zarate in one of his papers, “may have a negative impact on the overall course of the illness.”
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Later, he and Tohen wrote that “medication induced changes may be yet another factor in explaining the discrepancies in recovery rates between earlier and more recent studies.” The antidepressants, they noted, might cause a “worsening of the course of illness,” while the antipsychotics might lead to more “depressive episodes” and “lower functional recovery rates.” Cognitive impairment was a primary reason that medicated schizophrenia patients fared so poorly over the long term, they said, and “it has been suggested that drug side effects may in part explain the cognitive deficits in bipolar disorder patients.”
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Baldessarini, in his 2007 review, also acknowledged that “neuropharmacological-neuro-toxic factors” might be causing “cognitive deficits in bipolar disorder patients.” Finally, Kupfer threw one more concern into the mix. He detailed all the physical illnesses that now struck bipolar patients—cardiovascular problems, diabetes, obesity, thyroid dysfunction, etc.—and wondered whether “treatment factors such as toxicity from medications” could be causing these devastating ailments, or at least contributing to them.
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All of these writers put their concerns into a conditional context, stating that the drugs
might
be causing this mental and physical deterioration in their patients. But it’s easy to see that their hesitancy was scientifically unwarranted. Schizophrenia and manic-depressive illness had been diagnostically born as distinct in kind precisely because those with schizophrenia deteriorated cognitively over time, into dementia, while the manic-depressive group did not.
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The convergence in outcomes developed once both groups were treated with similar drug cocktails (which usually included an antipsychotic). “The field is witnessing a convergence of pharmacological approaches to the treatment of schizophrenia and bipolar disorder,” wrote Stephen Stahl, author of
Antipsychotics and Mood Stabilizers
, in 2005. It was adopting “similar blended treatments for these two disease states.”
⁶⁷
Psychiatric drugs, of course, perturb various neurotransmitter pathways in the brain, and thus once schizophrenia and bipolar patients are on similar drug cocktails, they suffer from similar abnormalities in brain function. The convergence of outcomes in the two groups reflects an iatrogenic process at work: The two groups, apart from whatever “natural” problems they may have, both end up suffering from what could be dubbed “polypharmacy psychiatric drug illness.”