The construct of bipolar spectrum disorder remains a work in progress. Its precise boundaries are still a matter of considerable debate. Some psychiatrists are convinced that it is widely overdiagnosed. It is possible that depending on the clinician and the clinical setting both views are correct.
CASE VIGNETTEMs T, a 22-year-old, presents to you with her third episode of major depression. Her referring doctor-a very competent family physician-tells you that Ms T "has been tried on everything, and nothing seems to help her." Indeed, the patient has taken 5 different antidepressants in the past 4 years and in each case she "felt like crawling out of her skin." Although the referring physician described the patient as having developed a "tolerance" to various antidepressants, this phenomenon was not ameliorated by increasing the antidepressant dosage, as might be expected with true pharmacological tolerance. Rather, the patient would often feel even worse. The doctor insists that she did a careful evaluation for bipolar disorder and found that "there's no personal or family history of any mania. Ms T just gets depressed."
In your office, the patient appears quite irritable, sometimes answering in a loud voice, "I've been through these questions before! I'm sick of them!" Nevertheless, she is also psychomotorically retarded and shows a long lag phase between question and response. Over the past 3 months, the patient has gained about 16 lb, mainly as a result of "stuffing [herself] with potato chips and chocolate." She sleeps around 12 hours per day but still feels lethargic, "like all the blood has been drained out of me."
Results of physical examination and laboratory testing, including thyroid function, have been within normal limits. Ms T's first major depressive episode occurred at age 16 and presented with similar features, as did her second bout at age 20. During the second episode, the patient developed the idea that "God must think I deserve this," and she could not be dissuaded of this belief by her clergyperson. At that time, she was treated with a low dose of risperidone (Risperdal) and emerged from the depression within a month. Her previous depressive episodes also lasted about a month.
During the present episode, the patient states, "Maybe I'm just a rotten person, so I deserve to rot." The patient denies having any episodes that are consistent with mania, as per the referring physician. There is no clear evidence of frank hypomanic episodes fitting all DSM-IV criteria. The patient's mother, who accompanies her, confirms this. However, the patient adds, "Just before I crashed this time, I was, like, going a mile a minute for a day or two. I cleaned my room all night long and spent half my savings account in one day." The patient's family history is apparently negative for frank bipolar disorder or psychiatric treatment, but her mother and a maternal aunt suffer from "bad mood swings" and heavy alcohol use. Response to trials of fluoxetine (Prozac, Sarafem), sertraline (Zoloft), paroxetine (Paxil), trazodone (Desyrel), and duloxetine (Cymbalta) led to the patient feeling "wired" and "like biting people's heads off"-but not to any frank "switching" into mania or hypomania (using DSM-IV criteria).
As the consulting psychiatrist, what do you recommend to the family physician, the patient, and her mother?
Bipolar boundaries, bipolar depression
As noted many times over the years, the construct of "bipolar spectrum disorder" remains a work in progress.1-4 Few of us doubt it exists-but its precise boundaries are still a matter of considerable debate. Similarly, whereas many of us-this writer included-believe that bipolar disorder is frequently missed, some psychiatrists are convinced that it is widely overdiagnosed. It is possible that-depending on the clinician and the clinical setting-both views are correct. But in my 15-year experience as a psychopharmacology consultant, the outpatients sent to me with so-called treatment-resistant depression almost always wind up with a diagnosis of (missed) bipolar spectrum disorder.
Most of them, like Ms T, have been on numerous antidepressant trials with little or no benefit. Most of them describe their experience with antidepressants in the same dysphoric terms used by Ms T. Most have never had a frank manic episode or even a full-fledged DSM-IV-classified hypomanic episode. Many of them report, like Ms T, periods of unusually elevated mood or energy lasting perhaps a day or two that is sometimes followed swiftly by a depressive "crash." Indeed, with the phenotypic requirement that a hypomanic episode last at least 4 days, DSM-IV criteria may exclude some patients with the genotype for bipolarity. When clinicians look beyond the overly strict DSM-IV criteria for bipolar disorder, we find that as many as 5% to 7% of the general public may have some form of bipolar spectrum disorder.2
What about patients who present with a major depressive episode and have a strong history of bipolar disorder in their family but who have no discernable history of mania, hypomania, or even brief periods of elevated mood? These patients represent a difficult dilemma for psychiatrists. If, unbeknown to us, these patients are genotypically bipolar, we may risk pushing them into a manic episode if we treat them with antidepressants alone.3 On the other hand, one could argue that overtreatment with mood stabilizers would result if we gave all of these patients lithium (Eskalith) or divalproex (Depakote).
Although in DSM-IV there are no formal distinctions between a "major depressive episode" in the context of unipolar versus bipolar mood disorders, both research and clinical experience suggest otherwise: notwithstanding a great deal of variability, bipolar depression often does "look different." With the aim of helping the clinician recognize the hallmarks of a bipolar depressive bout, I have developed a mnemonic device that brings together several clinical, pharmacological, and familial "fingerprints" of bipolarity.5-12 The WHIPLASHED mnemonic (Table) has not yet been field-tested for its predictive or prescriptive validity-it simply represents a compendium of my own clinical experience and my synthesis of the research literature.
Worse or "wired" when taking antidepressants. The patient often complains of feeling "antsy," unable to sleep, or more agitated on conventional antidepressants. Numerous failed antidepressant trials; apparent "tolerance" to antidepressants not overcome with increased dosage (pseudotolerance); and antidepressant-induced "switching" into mania or cycle acceleration may be reported.
Hypomania, hyperthymic temperament,* or mood swings by history. Periods of elevated mood or energy often do not fit formal DSM-IV criteria for hypomania; eg, some may last only a day or two. Mood lability in younger patients may be even more dramatic and poorly demarcated.
Irritable, hostile, or showing mixed features during the presenting depression. Some patients may show one or more hypomanic features (eg, racing thoughts) even while depressed.
Psychomotor retardation appears to be more common in bipolar I depression than in unipolar major depression; however, several studies note that psychomotor agitation is more common in bipolar II than in unipolar major depression.
Loaded family history, either for mood swings, frank bipolar disorder, or affective illness in general. A family history of comorbid mood disorder and alcoholism may also point toward bipolarity.
Abrupt onset and/or termination of depressive bouts, or relatively brief depressive episodes (less than 2 to 3 months). Some patients will also report a brief burst of increased energy or subthreshold hypomanic symptoms immediately before the onset of depression.
Seasonal or postpartum pattern of depression. "Winter-type" seasonal affective disorder (depressed in fall/winter, hypomanic in spring) and postpartum psychosis both have clinical and epidemiological links with bipolar disorder.
Hyperphagia and hypersomnia-sometimes termed atypical features-appear to be more common in bipolar than in unipolar depression. Paradoxically, hypersomnia may coexist with psychomotor agitation in bipolar II patients ("sleepy speeders").
Early age at depression onset (younger than 25 years). Major depression first appearing during adolescence, especially with psychotic features, may herald subsequent bipolarity.
Delusions, hallucinations, or other psychotic features appear to be more common in bipolar than in unipolar depression.
Arguably, the least secure of the WHIPLASHED components is its association of bipolar depression with psychomotor retardation.As Dr Nassir Ghaemi has pointed out to me, the literature is somewhat contradictory on the issue of psychomotor change. On the one hand, consistent with many older textbooks, there are convincing data that patients who are depressed with bipo- lar Idemonstrate more psychomotor retardation than do patients with unipolar major depression. This holds true even when one controls for melancholic features.10 On the other hand, several studies comparing depressed patients with bipolar IIwith patients who have unipolar depression have found higher rates of psychomotor activation in the bipolar II group-this, despite the presence of hypersomnia. This seeming paradox may point to the high prevalence of mixed features in depressed patients with bipolar II.11 Perhaps the term "sleepy speeder" might apply to such bipolar II presentations.
Notwithstanding these uncertainties, my working hypothesis is that those patients who meet 5 or more of the WHIPLASHED criteria will, on structured diagnostic interviewing, prove to have some form of bipolar disorder. Clinicians are free to use this screening instrument in their practice, and I welcome feedback on its utility. However, use of this mnemonic is only a first step in what must be a comprehensive and ongoing diagnostic process.
Perhaps some day we will be able to send our patients for a bipolar blood test. Indeed, there is already preliminary evidence that variation in the serotonin transporter gene may predict the likelihood of manic switching on antidepressants.13 In the meantime, I believe that use of the WHIPLASHED mnemonic, in concert with screening instruments such as Falk's DIGFAST mnemonic,14 the Bipolar Spectrum Diagnostic Scale,15 and the Mood Disorder Questionnaire16 will aid the clinician in spotting subtle forms of bipolar disorder. Primary care physicians may find these instruments especially useful, but I believe they are suitable for general psychiatric practice as well.
But what about the patient?
Oh, yes-what about our patient, Ms T? Given her presentation, family history, and previous response to antidepressants, I would probably diagnose Bipolar Disorder Not Otherwise Specified, possibly with psychotic and/or mixed features. I would most likely recommend treatment with lithium, divalproex, or lamotrigine (Lamictal), perhaps in combination with one of the atypical antipsychotics. Each of these agents has its pros and cons, depending on the preponderance of symptoms, medical concerns, and patient preference.
In addition, quetiapine (Seroquel) is looking promising for treatment of bipolar depression, but more data are needed.17 From my perspective, Ms T sounds like someone whose mood has been "WHIPLASHED."
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