Mood-stabilizing drugs slipped into the vocabulary of psychiatrists during the last 15 years without a proper discussion of their definition. Consequently, these medications have been used in ways that have no empirical justification. The original idea behind the term mood stabilizer was the apparent ability of lithium to offer antimanic qualities as well as some measure of antidepressant action. The American Psychiatric Association's Practice Guideline for Treatment of Patients With Bipolar Disorder (1994) defines mood stabilizers as "medications with both antimanic and antidepressive actions." From time to time, research has been contradictory about the efficacy of lithium as an antidepressant (Keck and McElroy, 1996). However, the concept was clear. This is not the case with the various anticonvulsant medications that have been labeled mood stabilizers. Despite widespread use, it is not obvious what is meant by a mood stabilizer and how anticonvulsants fit that description.
There is little if any clear-cut evidence that valproate (Depakote, Depakene), carbamazepine (Tegretol) (Kalin, 1996-1997) or gabapentin (Neurontin) are effective antidepressant agents. Yet as soon as they were shown to have efficacy in acute mania, they were quickly labeled mood stabilizers rather than antimanic agents.
This is not a matter of small significance, since it is not unusual for bipolar patients with a predominantly depressive history to be exclusively put on mood stabilizers with the expectation that the depression will be treated, and that rapid cycling due to the use of traditional antidepressants will be avoided. I'm not referring to the prophylactic use of mood-stabilizing agents when it is expected that antidepressants will later be necessary so that protection against a potential manic episode seems judicious. Frequently, mood stabilizers are used as the sole antidepressant. Indeed, an expert consensus treatment protocol recommends mood stabilizers alone as a first-line approach in treating milder major depressive episodes in bipolar I disorder and as a second-line approach in bipolar II disorder (Frances et al., 1996).
Some experts such as Bowden (1996) and Keck and McElroy (1996) are so concerned about the possibility of rapid cycling that they go still further, considering the use of antidepressants as a last resort in treating bipolar depression only after multiple mood stabilizers have been tried first. While the concern about antidepressants causing rapid cycling is based on an indisputable clinical possibility, these experts have no illusions about the effectiveness (or indisputable evidence for the effectiveness) of anticonvulsant medications as treatment for acute bipolar depression. Both valproate and carbamazepine did little better than placebo in the studies they cited, but if I understand them correctly, they considered bringing relief from the torment of depression as quickly as possible a less important priority than not iatrogenically causing mood instability.
According to Gary S. Sachs, M.D., the definition of the term mood stabilizerdoes not require antidepressant or antimanic efficacy, per se, merely that the medication "decrease vulnerability to subsequent episodes of mania or depression" and not exacerbate the current episode or maintenance phase of treatment (1996). The use of anticonvulsant medicines as mood stabilizers has become even more relevant since the expansion of the bipolar disorder (BD) diagnosis to include bipolar II patients (American Psychiatric Association, 1994). Bipolar II is a reasonable addition to the nosology of mood disorders, sometimes allowing earlier recognition and an appropriate alertness to the softer signs of the illness. However, it also has contributed to an excessive looseness in diagnosing BD. On more than one occasion, I have had patients hospitalized for severe depression and, after a three- or four-day stay, they have returned on a mood-stabilizing agent and nothing else. They have been told that they have bipolar disorder and that their anticonvulsant medication treats the basic problem.
Here is an example.
Ariel, a 16-year-old girl, had a history of repeated severe suicidal depressions punctuated by periods of a few hours, sometimes a day or two (definitely not four days as specified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition for hypomania), in which she felt a bit giddy as well as more social, energetic and creative. There was no family history of manic-depressive illness. She did not feel that her "up" times were a problem. Indeed, she was able to perform at a high level academically and felt more connected to her friends and parents. There was no pressured speech, flight of ideas or a sense that her mind was racing. There was no distractibility; impulsivity; irresponsible spending, driving or sexual behavior; or loss of judgment. Insomnia was not present, and there was no history of a decreased need for sleep. Although there was an improvement in self-esteem, it was not inflated or grandiose. Ariel's parents and friends, as well as Ariel herself, considered her good moods entirely normal and delighted in them.
The arguments for and against using a loose definition of BD hinge on the risk/benefit ratio of active treatment. On the benefit side, at least theoretically, is the kindling model for bipolar disorder. It is hoped that the prevention of frequent manic episodes may prevent rapid cycling that often develops later in the illness. But this is theory, not fact. Even when the diagnosis is clearly bipolar, there's no empirical documentation and no longitudinal studies that demonstrate long-term administration of medications will prevent rapid cycling later in the illness. Despite this lack of proof, when a bipolar diagnosis is unequivocal, treatment is a no-brainer. We treat vigorously with the hope there will be this eventual benefit because good acute control is desirable anyway.
When the diagnosis is based on looser criteria, it is a more complicated issue. There are at least two prospective studies demonstrating that patients with major depressive disorder and a definite family history of BD have a very high risk for transformation to bipolar I disorder (Akiskal et al., 1983; Strober and Carlson, 1982). Clearly in this situation, it is advisable to monitor patients with serious depression closely for early signs, even more so when there are soft signs of hypomania. But if there is no family history, a case can be made to hold back on treating the patient's not diagnostically definable highs.
From this vantage point, if a patient such as Ariel does not have symptoms that she, her family and friends, or any layperson, would consider symptoms, what are we treating? If we believe that we are somehow correcting a fundamental chemical imbalance, there would be a rationale. But we don't know what the chemical imbalance(s) is (are) in bipolar disorder. We don't really know what mood stabilizers do for the illness. Even our guesses hint at diverse possibilities. Thus, valproate seems to have an effect on ?-aminobutyric acid (GABA) receptors, and gabapentin may increase brain levels of GABA. In contrast, the proposed mechanism of action for carbamazepine and lamotrigine (Lamictal) is voltage-dependent inhibition of sodium currents. The latest speculations about lithium are that it is affecting G-proteins, that it exerts a push/pull effect on the neurotransmitter glutamate (Dixon and Hokin, 1998; Lenox et al., 1998), or that it alters sodium transport in nerve and muscle cells and effects a shift toward intraneuronal metabolism of catecholamines (Physicians' Desk Reference, 1999).
Diverse research hypotheses are a good thing, but they are not the same as hard knowledge. How can we argue that we are treating at a fundamental, etiological level of the illness when we don't know what the chemical problem is, when our best guesses about how various mood stabilizers work are that they work differently from each other, and when we don't know how these proposed mechanisms might or might not be related? Moreover, we don't have clear proof that we will prevent the eventual development of the DSM-IV illness; even in the treatment of the DSM-IV illness, we don't yet know if we are altering its long-term course. All we do know is that we have good-not great-medications that help control symptoms.
Hagop S. Akiskal, MD, makes the strongest argument for a liberal view of a very broad bipolar spectrum of abnormalities. He believes DSM-IV is far too limiting and would include a bipolar III and a variety of conditions under the bipolar umbrella (Akiskal, 1996; Akiskal and Mallya, 1987). This position is not absurd in the sense that when we eventually understand the genetics and biology of manic-depressive illness, we may discover fundamental relationships. However, DSM-IV is not a true collection of illnesses defined by etiologies. It is a collection of disorders about which committees decide certain symptoms should be clustered with the hope that someday, true etiological understanding will correlate with these clusters or future clusters as the evidence indicates. The issue here is using medications that may only be working on symptoms (and possibly or probably not etiology or pathogenesis) in patients who do not have symptoms as defined by themselves or reasonable laypeople. In Ariel's case, she was suffering from depression and was given a treatment that has not been shown to be effective for depression.
On the risk side of the equation, the danger of unnecessary medication is obvious with carbamazepine because of the possibility of aplastic anemia and agranulocytosis. While this is rare (six patients per 1 million population per year for agranulocytosis and two patients per 1 million population per year for aplastic anemia), if carbamazepine is used by enough psychiatrists over enough years for unjustifiable purposes, there will be deaths that might not have occurred. In the case of valproate, hair loss, weight gain, fatigue and, most recently, the threat of polycystic ovaries, favors caution in a patient such as Ariel. Tiredness and, sometimes, hypersomnia are not uncommon even at therapeutic levels and contribute to treatment noncompliance. A huge number of patients whom I have followed after inpatient stays with an equivocal diagnosis are sleeping 14 hours a day. Of course, it does not help that locally the standard regimen resulting from these hospitalizations seems to also include Zyprexa (olanzapine).
Ariel did have "mood swings." She would be in a perfectly good mood and then suddenly, with relatively minor provocation, switch to sadness, irritability or an outburst of anger. This was the other major justification for placement on a "mood stabilizer." There's only one problem with this. The use of the term mood swingsin bipolar disorder has usually referred not to labile affect, but to relatively long stretches of depression or mania lasting weeks or months-although occasionally days-which would then swing to the opposite.
While it is true that mixed episodes are not rare and may be characterized by very rapid shifts in mood over the course of a day, mixed episodes may also consist of a vague blending of both euphoric and dysphoric themes. In any case, until recently, the term, mood swings, did not refer to volatile moods.
Apparently, however, without a discussion in the literature of this changed definition, mood swings have come to mean labile affect. Similarly, rapid cycling-defined in the DSM-IV as four or more switches in a year-not infrequently appears in clinical summaries when what is being described are labile moods.
At first, I thought the problem was our local inpatient unit and a mistaken reading of DSM-IV by one doctor in particular. If that were the case, there would be no reason for this article. It soon became apparent that similar diagnoses were being made at three other inpatient units that I have contact with, including two prominent academic centers. I have questioned several nurses on these wards and learned that most misbehaving, impulsive teen-agers (once characterized as rebellious) are now being diagnosed as bipolar. At an outpatient alcohol rehabilitation center, a counselor told me the same thing was happening there. Erratic moods and behavior were being called mood swings, and thus had become bipolar symptoms. Moreover, the new use of the term mood swings had been embraced by the other psychiatrists in town who were doing strictly outpatient work. Social workers and psychologists were asking, as never before, for medication evaluations for bipolar disorder on the basis of mood swings, and many patients were self-referring themselves for mood swings, having read about them on the Internet.
The typical story I heard when I questioned a patient with mood swings was something like the following: "I'd be in a perfectly good mood at a party but then would feel like going home. When my boyfriend gave me a hard time, I'd let him have it." Or, "I would be doing fine shopping at the supermarket. Suddenly, someone would cut in front of me in line, and I'd go ballistic." Or, "I'd be getting along with my parents at home. Then my father would say something, and I'd go stomping off to my room." Sometimes, there would be no external event at all, but the patient would notice a dramatic shift in mood from when they woke up feeling fine to later in the day when they were feeling down.
Generally, in all of these cases the patients had almost no introspective capacity. They had never attempted on their own, or been encouraged by their psychiatrist, to make sense of the personal meaning of their father's comment, or why their boyfriend made them so angry by refusing to come home from the party and so forth. As far as they were concerned, their behavior was totally incomprehensible and beyond their control. They were relieved to hear that the explanation for their difficulty was a chemical imbalance because, not only would it no longer be their fault, but just as importantly, it could now be fixed.
Undoubtedly, over time, some of the impulsive and/or moody adolescents now being diagnosed bipolar II on the basis of their mood swings will later prove to be suffering from manic-depressive illness. This may turn out to be true of Ariel.
Kramlinger and Post (1996) described clear-cut bipolar patients who were followed on a ward and rated for mood every two hours during the course of a day. They found a group of five patients who went up and down throughout the day and wondered whether these represented "ultra-ultra rapid cycles or ultradian cycling." However, this interesting observation is a far cry from the routine labeling of volatile patients as bipolar.
There is another contributing issue to what I believe is the overdiagnosis of BD. In addition to "mood swings" being used as the basis for diagnosis, irritability has gained new status. It has always been appreciated that irritability, rather than euphoria, can be part of a manic episode. But one would assume that irritability by itself would not be the basis for diagnosing bipolar disorder in an unhappy teen-ager or depressed individual, especially since irritability is found much more commonly in depression than in mania. However, I am discovering that many psychiatrists are using this criterion quite freely, especially with patients who have labile affect, and are basically making the diagnosis on a hunch.
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