Bipolar Disorder: Particle or Wave? DSM Categories or Spectrum Dimensions?

RISKS OF TREATMENTS, COMPARED

The Table compares the short- and long-term risks (significant implications, not just side effects) of these agents, focusing on mood stabilizers that have at least some data supporting antidepressant efficacy.

Every mood stabilizer can, at least rarely, cause death. Most have several other significant long-term risks. By comparison, antidepressants carry less direct risk of death, unless one counts the hotly debated risk of increasing suicidality. Instead, a variety of destabilizing effects have been associated with antidepressants, although the data are scant and debated (for a review, see Phelps²⁶).

Of even greater concern, at least theoretically, is the potential for the antidepressants to worsen an underlying BD—a process generally referred to as “kindling.” Readers are likely well aware that this is a model, a framework for thought, not a research-tested concept. Nonetheless, it is an important concept to consider. Yet kindling concern is rarely raised when discussing the use of antidepressants for BD, perhaps because the data by which to evaluate this risk are almost nonexistent.

For example, Grunze²⁷ criticized the American reticence to use antidepressants in BD, but his review does not mention kindling as a potential risk. By comparison, El-Mallakh and Karippot²⁸ concluded a review on antidepressant use in BD: “Long-term use may destabilize the illness, leading to an increase in the number of both manic and depressed episodes; induce rapid cycling (at least 4 episodes a year); and increase the likelihood of a mixed state.”

A case report of an apparent antidepressant- induced mood instability in a patient with unipolar disorder following 7 years of euthymic response to an antidepressant raises broader concerns,²⁹ akin to the “acid syndrome” (antidepressant-associated chronic irritable dysphoria.)³⁰ Using nationwide register studies, Kessing and Andersen³¹ have demonstrated that the average risk of recurrence increases with the number of episodes in depressive and bipolar affective disorders.

But can precipitating mania or hypomania with an antidepressant kindle an underlying bipolarity so as to make the patient’s long-term course worse than it otherwise would have been? We must ask ourselves this question, even though at present we have no systematic studies of such long-term effects, and such research would be tremendously difficult to conduct. For now and likely for the foreseeable future (perhaps until we have a biomarker to follow over time), this leaves us reliant on case reports and clinical suspicions—a very weak basis for complex treatment decisions.

Therefore, a full appraisal of the risks of antidepressants is not possible at present. A biomarker of antidepressant exacerbation that could be used to project risk would be extremely helpful. Already there is a potential candidate, since inheriting 2 short versions of the serotonin transporter gene may substantially increase this risk (not all studies have supported the connection, but 2 are strongly positive^32,33). In the meantime, differences in opinion regarding how much risk antidepressants pose in patients with BD might be a significant factor explaining why some BD specialists are inclined to avoid them as much as possible, whereas others feel they are being underused. Could some— much?—of the debate about the socalled bipolar spectrum boil down to our different perception of antidepressant risks?

Perhaps we could address that question through attitudinal research. Ironically, psychiatrists’ understanding of bipolarity may not be the most important determinant of just which patients will receive antidepressants—because we are not the most frequent antidepressant prescribers.

PRIMARY CARE PROVIDERS

Rather than psychiatrists or even psychotherapists, primary care providers (PCPs) are clearly the front line of depression treatment in the United States. In a further irony, while psychiatrists are increasingly considering a spectrum approach to bipolar diagnosis, PCPs are being encouraged by colleagues,³⁴ psychiatrists,³⁵ and the pharmaceutical industry³⁶ to use a categoric tool, the Mood Disorders Questionnaire (MDQ).

Although most physicians knew this once, many have forgotten that accurate use (the “predictive value”) of a test like the MDQ depends heavily on clinicians’ pretest hunch (ie, the prior probability of BD).³⁷ Yet developing a discriminating hunch comes from understanding bipolar presentations, from BD I mania through hypomania to the 11 soft signs that form the criteria for bipolar spectrum disorder and the Bipolarity Index, as previously discussed. Such training is rare for PCPs, although an online primer has been available and refined over the past 5 years.³⁷ PCPs are besieged by various efforts to educate them on many topics, and thus the extent to which even continuing medical education can reach them is limited. When we have their ear, as when discussing a consultation, we can teach them to systematically assess 4 areas they already query, in addition to the fifth dimension of bipolarity they will see reflected in the MDQ (hypomania):

• Family history (several versions of the MDQ also assess this, albeit minimally).
• Age at onset of first depression.
• Course of illness (many recurrences vs few, length of episodes, rapid onset/offset).
• Response to previous antidepressants: agitation, insomnia, irritability.

To summarize for them the spectrum perspective in concrete, applicable terms, we could suggest (after reviewing with them the full differential) that the more bipolar soft signs one detects, the earlier one should consider switching from an antidepressant-based strategy to a mood-stabilizer–based strategy. However, we must admit that there is no agreed-on or empirically established cutoff point to guide this decision, and indeed there may not be such a point of natural cleavage: bipolar disorder may not be a species, as in ornithology, despite the implications of the DSM.

CONCLUSION

Despite the advantages of a spectrum view, particularly in matching clinical experience, the DSM’s, categoric approach, with its greater internal structure and validated diagnoses, is also a valuable part of our clinical thinking. We can adopt an approach long used in physics, where 2 apparently exclusive ways of viewing the electromagnetic spectrum are used simultaneously: light is a wave and a particle.

For psychiatrists, this means using the DSMand the spectrum views in complementary fashion, like bifocals in a pair of glasses—carrying both lenses with us, switching back and forth to find the one that best brings an individual patient into focus. Our patients have illnesses that are both waves—varying continuously over a spectrum—and particles—with discrete characteristics that can help us identify who is likely to do well with an antidepressant and who merits caution. As in physics, complementarity helps manage uncertainty. This dual-lens perspective might allow the focus of our debate to shift toward further identifying characteristics that predict adverse reactions to antidepressants (away from debates about the breadth of bipolarity). So far these factors include 11 soft signs.¹¹

Many of our primary care colleagues, however, are struggling to identify any nonmanic version of BD, such as BD II. For them, the MDQ as a screening tool is probably better than no screening tool at all. However, there will be significant misclassification unless they are quickly educated on bipolar phenomenology, which must be used to anchor their interpretation of the MDQ results. Other PCPs are ready to move beyond a categoric view; they need a cautious de-emphasis of the MDQ, with increased emphasis on recognizing intermediate bipolar spectrum variations.

This discussion will be continued in a second article to be published in a future issue of Psychiatric Times.

Dr Phelps has been practicing psychiatry for more than 15 years and specializes in treating bipolar disorder. He recently published Why Am I Still Depressed? Recognizing and Managing the Ups and Downs of Bipolar II and Soft Bipolar Disorder.

Dr Phelps states that he has received grants and honoraria from GlaxoSmithKline, Astra- Zeneca, and Abbott Laboratories.

Drugs Mentioned in This Article

Divalproex sodium (Depakote)
Fluoxetine (Prozac)
Lamotrigine (Lamictal)
Lithium (Eskalith, Lithobid)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Risperidone (Risperdal)

References

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Evidence-based References

Cassano GB, Rucci P, Frank E, et al. The mood spectrum in unipolar and bipolar disorder: arguments for a unitary approach. Am J Psychiatry. 2004;161: 1264-1269.
Ghaemi SN, Ko JY, Goodwin FK. “Cade’s disease” and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry. 2002;47:125-134.