Polypharmacy/Bipolar illness

Robert Whitaker


A. Bipolar Illness Before the Psychopharmacology Era

Prior to 1955, bipolar illness was a rare disorder. There were only 12,750 people  hospitalized with that disorder in 1955. In addition,  there were only about 2,400 “first admissions” for bipolar illness yearly in the country’s mental hospitals.

Outcomes were relatively good too. Seventy-five percent or so of the first-admission patients would recover within 12 months.  Over the long-term, only about 15% of all first-admission patients would become chronically ill, and 70% to 85% of the patients would have good outcomes, which meant they worked and had active social lives.


B. Gateways to a Bipolar Diagnosis

Today, bipolar illness is said to affect one in every 40 adults in the United States. A rare disorder has become a very common diagnosis. There are several reasons for this. First, many drugs–both illicit and legal–can stir manic episodes, and thus usage of those drugs leads many to a bipolar diagnosis. Second, the diagnostic boundaries of bipolar illness have been greatly broadened.


Substance abuse

1. Substance abuse in first-episode bipolar 1 disorder. Baethge, C. American Journal of Psychiatry 162 (2005):1008-10.

One-third of patients diagnosed with bipolar I disorder had used marijuana or some other illegal drug prior to their first manic or psychotic episode.

2. Association between illicit drug and alcohol use and first manic episode. Frank, E. Pharmacology, Biochemistry and Behavior 86 (2007):395-400.

One-third of patients diagnosed with bipolar I disorder had used marijuana prior to first manic episode.

3. The effects of antecedent substance abuse on the development of first-episode psychotic mania. Strakowski, S. Journal of Psychiatric Research 30 (1996):59-68.

Substance abuse (of illicit drugs) may “initiate progressively more severe affective responses, culminating in manic or depressive episodes, that then become self-perpetuating.”

4. Overdiagnosis of bipolar disorder among substance use disorder inpatients with mood instability . Goldberg, J. Journal of Clinical Psychiatry 69 (2008):1751-7.

Two-thirds of patients diagnosed with bipolar I or bipolar II disorder at a Connecticut hospital experienced their first bout of “mood instability” after they had abused illicit drugs.

5. Does cannabis use predict the first incidence of mood and anxiety disorders in the adult population? Van Laar, M. Addiction 102 (2007):1251-60.

Marijuana use is “associated with a fivefold increase in the risk of a first diagnosis of bipolar disorder.” One-third of new bipolar cases in the Netherlands result from it.


Antidepressant Use

6. Age effects on antidepressant-induced manic conversion. Martin, A. Archives of Pediatric Adolescent Medicine 158 (2004): 773-80.

In a review of 87,290 patients diagnosed with depression or anxiety between 1997 and 2001, those treated with antidepressants converted to bipolar illness at the rate of 7.7% per year, which was three times the rate for those not exposed to the drugs.

7 . Risk for bipolar illness in patients initially hospitalized for unipolar depression. Goldberg, J. American Journal of Psychiatry 158 (2001):1265-70.

Today, 20% to 40% of all patients initially diagnosed with unipolar depression and treated with antidepressants eventually convert to bipolar illness.

Broadened Definition

8. The prevalence and disability of bipolar spectrum disorders in the US population Judd, L. Journal of Affective Disorders 73 (2003):123-31.

Researchers argue that many people suffer “subthreshold” symptoms of depression and mania and thus can be diagnosed with “bipolar spectrum disorder.” With this expanded definition, 6.4% of American adults are said to suffer from bipolar symptoms.

9. Toward a re-definition of subthreshold bipolarity . Angst, J. Journal of Affective Disorders 73 (2003):133-46.

Using a “broad definition” of bipolar illness, researchers conclude that 11% of adults suffer from the “spectrum of bipolar disorders proper,” and “another 13% represent the softest expression of bipolarity intermediate between bipolar disorder and normality.”


C. Antidepressants Worsen Long-Term Bipolar Outcomes

10. Rapid cyclers, temperament, and antidepressants. Kukopulos, A. Comprehensive Psychiatry 24 (1983):249-58.

Anthansious Koukopoulos, director of a mood disorders clinic, observes in 1983 that his medicated bipolar patients are faring worse than they did 20 years earlier. “The recurrences of many patients have become more frequent. One sees more manias and hypomanias . . . more rapid cyclers, and more chronic depressions.”

11 . Diagnosing bipolar disorder and the effect of antidepressants. Ghaemi, N. Journal of Clinical Psychiatry 61 (2000):804-9.

In a study of 38 bipolar patients treated with an antidepressant, 55% developed mania and 23% turned into rapid cyclers. The antidepressant-treated group also spent “significantly more time depressed” than bipolar patients not given the medication.

12. Antidepressants in bipolar disorder. Ghaemi, N. Bipolar Disorders 5 (2003 (421-33).

Researchers find that “there are significant risks of mania and long-term worsening with antidepressants.”

13. Use of antidepressants to treat depression in bipolar disorder. El-Mallakh, R. Psychiatric Services 53 (2002):580-4.

Use of antidepressants may “destabilize the illness, leading to an increase in the number of both manic and depressive episodes” and “increase the likelihood of a mixed state,” in which feelings of depression and mania occur simultaneously.

14. Duration and stability of the rapid-cycling course . Koukopoulos, A. Journal of Affective Disorders 72 (2003):75-85.

Once antidepressants induce rapid cycling, it abates in only one-third of the patients over the long term, even after the offending antidepressant is withdrawn. Forty percent of patients who have worsened in this way continue to “cycle rapidly with unmodified severity” for years on end.

15. Antidepressant-associated chronic irritable dysphoria (acid) in bipolar disorder. El-Mallakh, R. Journal of Affective Disorders 84 (2005):267-72.

Antidepressants can induce a “chornic, dysphoric, irritable state” in bipolar patients.

16. The prospective course of rapid-cycling bipolar disorder. Schneck, C. American Journal of Psychiatry 165 (2008):37-7.

In a large NIMH study, “the major predictor of worse outcome was antidepressant use.” These patients 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.


D. The Deterioration of Bipolar Outcomes in the Modern Era

In the pre-drug era, bipolar patients were usually asymptomatic between episodes; 85% returned to their usual occupations; and they showed no signs of long-term cognitive decline. Today, bipolar patients are much more symptomatic; only about one-third return to their usual occupations; and they become cognitively impaired over the long term.

17. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Judd, L. Archives of General Psychiatry 59 (2002):530-7.

NIMH researchers report that bipolar I patients are depressed 32% of the time, manic or hypomanic 9% of the time, and have mixed symptoms 6% of the time.

18. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Judd, L. Archives of General Psychiatry 60 (2003):261-9.

Bipolar II patients are symptomatic 53% of the time, with depressive symptoms predominating. “The nature of this deceptively ‘milder’ form of manic-depressive illness is so chronic as to seem to fill the entire life,” reported the NIMH researchers.

19. 12-month outcome of patients with bipolar disorder following hospitalization for a manic or mixed episode. Keck, P. American Journal of Psychiatry 155 (1998):646-52.

University of Cincinnati psychiatrists find that only 24% of their bipolar patients are “functionally recovered” at the end of one year.

20. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. Kupfer, D. Journal of Clinical Psychiatry 63 (2002):120-5.

In a study of 2,839 bipolar patients, University of Pittsburgh researchers found that even though 60% had attended college and 30% had graduated, only one-third were employed.

21. Outpatients with schizophrenia and bipolar I disorder. Dickerson, F. Psychiatry Research 102 (2001):21-27.

Over the long-term, medicated bipolar patients become nearly as cognitively and functionally impaired as medicated schizophrenia patients.

22. Functional impairment and cognition in bipolar disorder . Zarate, C. Psychiatric Quarterly 71 (2000):309-29.

Researchers note that “in the era prior to pharmacotherapy, poor outcome in mania was considered a relatively rare occurrence . . . however, modern outcome studies have found that a majority of bipolar patients evidence high rates of functional impairment.” In their discussion of this deterioration in outcomes, they concluded that “medication-induced changes” may be at least partly responsible. Antidepressants may cause a “worsening of the course of illness,” while the antipsychotics may lead to more “depressive episodes” and “lower functional recovery rates.” Drug side effects, they added, may “explain the cognitive deficits in bipolar disorder patients.”

23. Disability and its treatment in bipolar disorders. Huxley, N. Bipolar Disorders 9 (2007):183-96.

Harvard researchers observe that “prognosis for bipolar disorder was once considered relatively favorable, but contemporary findings suggest that disability and poor outcomes are prevalent.” They note that “neuropharmacological-neurotoxic factors” might be causing “cognitive deficits in bipolar disorder patients.”

24. The increasing medical burden in bipolar disorder. Kupfer, D. JAMA 293293 (2005): 2528-30.

Bipolar patients today suffer from a host of physical illnesses–cardiovascular problems, obesity, thyroid dysfunction, etc.–which, researchers admit, may be due to “toxicity from medications.”

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