Biology 202
2000 Third Web Report
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Why No "Unipolar Mania" Listing in DSM-IV?

Melissa Wachterman

If you were to flip through the mood disorders section of DSM-IV (Diagnostic Statistics Manual), you would find, among other conditions, listings for Major Depressive Disorder (commonly known as unipolar depression) and Bipolar Depression (a.k.a. manic depression). What seems to me to be notably missing is Unipolar Mania. Why is it that people suffer from bipolar disorder, which is marked by both depressive and manic episodes sequentially, or from unipolar depression, but, at least according to DSM-IV, cannot manifest manic episodes in the complete absence of depression? This seems to suggest that there is something about mania that links it inextricably to depression. While this will be one issue that this paper seeks to address, the very notion that mania exists only in the confines of bipolar disorder can be challenged.

Perhaps unipolar mania does, in fact, exist, yet is not considered a pathological condition that has to be diagnosed and treated. After all, we must remember that the classification of behavior as "normal" or "abnormal" reflects societal values and definitions of normality. This is reflected in the cross-cultural differences in what is categorized as pathological. For example, imagine that you proclaimed that you were seeing visions of elaborately clothed spirits who were speaking to you about the future of humanity. You might be touted as the spiritual guru of your village if you were in certain tribal societies in Africa, or you might be labeled as schizophrenic and sent to a psychiatric ward if you resided in Brooklyn, New York or Topeka, Kansas. The labeling of behavior as normal or abnormal depends on certain criteria, and subjective judgments definitely factor into the process. Some might say that abnormal behavior is defined as behavior that is not prevalent amongst the majority of the population, and while this may be true of the conditions we consider pathological, it is clearly not sufficient. After all, people who have IQ's above 150 are statistically in the minority; however, our society does not slap a psychiatric diagnosis on them, but rather labels them as geniuses. Thus, it appears that a major characteristic of what is labeled as "normal", as opposed to "abnormal" behavior, is the ability to function as a productive member of a given society (1).

With this background in mind, we turn back to the issue of whether unipolar mania exists, and consider first the possibility that it does exist physiologically, but is not labeled as "abnormal" behavior, and therefore, does not show up in the DSM-IV listings of psychiatric disorders. It seems fairly clear that people who experience bouts of clinical depression have difficulty functioning in our society, and thus, it is logical that such a condition is considered to be pathological, and an effort is made to diagnose and treat the disorder. The question is whether this is the case with mania. Perhaps the characteristics that are associated with the manic state are adaptive in our society, and therefore, those who have mania, in the absence of the depressive symptomatology that follows in bipolar disorder, have no reason to be diagnosed with any form of psychopathology. This is a highly debatable issue, with some arguing that mania itself is a debilitating condition (2), while others maintaining that the manic aspect of bipolar disorder actually has many incredibly positive aspects.

Consider first the second position which points out that there are well-documented connections between the manic episodes of bipolar disorder and artistry, creativity, and charisma (3).During the manic part of the bipolar cycle, it appears that the entire tempo of life speeds up. People with bipolar disorder have heightened levels of activity and their thoughts speed up (4) which, in some cases, enables them to be super-productive, creative, and energetic. Therefore, it is possible for some people to catch up on the work and activities that they neglected during the period when they were depressed (5). The following is a quote by Dr. Kay Jamison, a professor or psychiatry at Johns Hopkins University and a leading expert on bipolar disorder, who, herself has the condition:

"I have often asked myself whether, given the choice, I would choose to have manic-depressive illness...Strangely enough, I think I would choose to have it. It's complicated...I honestly believe that as a result of it I have felt more things, more deeply; had more experiences, more intensely...Depressed, I have crawled on my hands and knees in order to get across a room and have done it for month after month. But normal or manic, I have run faster, thought faster, and loved faster than most I know." (6).

This quote suggests that while the depression inherent in bipolar disorder is incredibly debilitating, the manic state is quite the opposite. If Dr. Jamison's account is representative of the common experience of the manic state, it seems possible that there are many "unipolar manics" amongst us. Since, unlike those suffering from bipolar disorder, they do not suffer from depressive symptomatology, they are not categorized as having a psychopathological condition. In fact, if we were to try to identify the profile of someone who was "unipolar manic", according to Jamison's characterization of the state, it would include many of the attributes that are considered most central to success and creativity in our society. It is often pointed out that a disproportionate number of the most well-known creative people in history had manic depression. Examples are: (writers) F. Scott Fitzgerald, Ernest Hemingway, Sylvia Plath; (poets) Walt Whitman, Ralph Waldo Emerson; (composers) Rachmaninoff, Tchaikovsky (7). These are not just isolated icons of the disorder, but rather there seems to be a validated link between bipolar disorder and the creative genius (8). In a broad-based study, researchers at Harvard University found that those suffering from manic-depressive disorder had higher levels of creativity than controls (8). I would like to know what point in the bipolar cycle the subjects in these studies were in when tested, and would hypothesize that the most creativity was found in individuals who were experiencing manic or hypomanic episodes. It is possible that there are many individuals who have a predisposition towards mania which feeds their creativity. Yet because they do not have accompanying depression, their "condition" is not labeled, and they are simply considered creative, bright members of our society.

So far, this discussion has been based on a viewpoint that puts a very positive spin on the manic aspect of bipolar disorder. However, as I said at the outset, there is another perspective that argues that full-blown mania in and of itself is incredibly debilitating. Some of the controversy may result from considering different points in the progression of a manic episode. In the early stages of a manic episode, a person may seem to be more social, active, talkative, self-confident, insightful and creative than usual. But as the episode unfolds, common symptoms include extreme irritability, overreaction to stimuli, difficulty understanding what is going on, poor judgment, blaming others for things that go wrong, and loss of touch with reality, in some cases including hallucinations and delusions (2). One bipolar sufferer described the state of mania in the following way:

"The fast ideas become too fast and there are far too many...overwhelming confusion replaces stop keeping up with it -- memory goes, infectious humor ceases to amuse. Your friends become frightened...everything is now against the are irritable, angry, frightened." (9).

These descriptions of mania indicate that it is not just the depression of bipolar disorder that is pathological. Furthermore, it suggests that if a condition such as "unipolar mania" existed, it too would be classified as a psychiatric disorder. Additional support for the incapacitating nature of mania is that treatment for bipolar disorder involves efforts to intervene not only during depressive episodes, but also during manic episodes. One of the most challenging aspects of drug therapy for manic depression is that the anti-depressants prescribed to treat the depression can catapult sufferers into a manic state (10). If the behavioral effects of isolated mania were in line with "super-functioning" or at least normal functioning in our society, then treatment for bipolar disorder would focus entirely on treating depression, which is not the case. Therefore, while the possibility that unipolar mania exists, but is just not listed in DSM-IV cannot be completely ruled out, it seems unlikely that no one would be debilitated enough to be diagnosed with the condition. Before moving on to examine several possible reasons why depression co-occurs with mania, one final point related to this first area of inquiry should be noted. It is possible that mania does in fact exist in the absence of depression, and is diagnosed as another disorder. In my mind, the most likely candidate is Attention Deficit Hyperactivity Disorder (ADHD). Support for this idea comes from the finding that abnormalities in the prefrontal areas have been found in both patients with bipolar disorder and those with ADHD (11).

What biological characteristics of depression and mania might account for the observation that millions of people suffer from Major Depressive Disorder (unipolar depression) and at least 2 million suffer from Manic-Depression (bipolar depression) (9), but based on current understanding, people do not suffer from a pure form of mania? Before delving into an examination of several possible factors, a distinction between two types of bipolar disorder should be made. People who cycle back and forth between major depressive episodes and manic episodes are diagnosed as having Bipolar I, while those with the same depressive symptoms, but less severe manic symptoms (called hypomania) are considered to have Bipolar II (12).

The first area of research to be examined has to do with the proposed abnormal neurochemical aspects of unipolar and bipolar depression. Research in the 1960's resulted in the development of the "Biological Amine Theory of Depression", which is also known as "The Monoamine Hypothesis". The underlying idea behind this theory is that behavioral depression comes as a result of insufficient activity of a certain class of neurons called the monaminergic neurons. It is thought that deficits of norepinephrine, serotonin, or dopamine, all neurotransmitters that have a similar structure, result in a chemical imbalance in certain regions of the brain, and this leads to depression (13). On the other hand, mania is thought to be the result of an excess of these same neurotransmitters (14). This theory was refined during the late 1980's because of several problematic findings. One big concern that could not be explained by the theory was the therapeutic lag that exists following the initiation of pharmacological treatment for depression. While the biological effects of drugs that prevent the reuptake of serotonin and norepinephrine occur within a day or two, patients generally do not have relief of their depressive symptoms until 2-4 weeks later (14). Therefore, during the 1980's, the biological amine theory was modified based in the idea of postsynaptic receptor desensitization. According to this theory, depression was not due to the low levels of norepinephrine per sae, but rather was the result of the hyper-responsiveness of postsynaptic receptors, caused by a decreased availability of norepinephrine (13). By administering agonist drugs (ones that increase the action of neurotransmitters) that blocked the reuptake of norepinephrine in the synapse, normal levels of norepinephrine become available at the receptors, thereby inducing postsynaptic receptors to downgrade their activity to normal levels (14). The amount of time that it takes for receptors to down-regulate coincides with the time for pharmacological treatment to take effect, and therefore, is one explanation that would account for the lag time.

Given this background about the way that receptors and neurotransmitters interact in the brain, let's apply the neurochemical theory, in an attempt to explain the cycling nature of bipolar disorder. Recall that the main question at hand is why episodes of mania are inextricably linked to spells of depression. Reflecting on the information gathered, I posit that there is an overall dysregulation of mood-related neurotransmitter release in bipolar disorder and that the switch from mania to depression is the result of a compensatory effect that the body undergoes in an attempt to maintain homeostasis. An interesting observation is that in bipolar disorder, a depressive episode often follows a manic episode, rather than the other way around (15) (5). This may suggest that some aspect of how the body responds to the manic state predispose the body towards the onset of depression. Since the depression literature explains that abnormally low levels of mood-related neurotransmitters leads to an up-regulation of postsynaptic receptors, it seems logical that in the case of a manic episode, in which norepinephrine (and possibly other mood-related neurotransmitters) levels are abnormally high, down-regulation of post-synaptic receptors may well occur in an attempt to maintain homeostasis. Recall that it is hypothesized that during a manic episode, what is happening on the neurochemical level is that neurotransmitters, most notably norepinephrine, are released at heightened rates (14). However, there is a limiting factor, namely the amount of neurotransmitter available for release. One of the main times that the body replenishes its stores of neurotransmitters is during sleep (16). Therefore, since bipolar disorder is characterized by a decreased need for sleep or a feeling that one does not need to sleep, there is less time for the body to synthesize neurotransmitters. As a result, there must clearly come a point when the rate of neurotransmitter production cannot keep pace with the rate of neurotransmitter release. This is the culmination of the manic episode, and there is reason to believe that, at this point, a person is predisposed to entering a state of depression. First of all, following the heightened neurotransmitter release rate associated with mania, stores of neurotransmitters are depleted. Secondly, recall that in order to maintain homeostasis, the post-synaptic receptors down-regulated their activity (16). Therefore, even a normal amount of neurotransmitter will not be able to adequately activate post-synaptic receptors. The cumulative effect may, at least in part, account for the shift from mania to depression.

In many ways, my theory of how bouts of mania (or hypomania) are inevitably associated with periods of depression is analogous to what occurs following a drug-induced high. When people expose themselves to exogenous "upper" drugs such as the amphetamine, cocaine, the body undergoes a compensatory response in which receptor down-regulation occurs in an effort to maintain homeostasis. Thus, the body becomes dependent on the drug, and when the body is deprived of the drug, people often experience a major crash with depressive symptoms. This is because the receptor s down-regulated as a result of the exposure to the drug, and now the levels of neurotransmitter, in the absence of the agonistic effects of the drug, are no longer sufficient to maintain a non-depressed mood (16).

No discussion of bipolar disorder would be complete without at least mentioning the central role of lithium in the treatment regiment. While the mechanism by which lithium works remains a virtual enigma, its therapeutic efficacy as a mood stabilizer is well-established. The drug offers relief to 60% of individuals with bipolar disorder (the response rate among those with a form of bipolar disorder called "rapid cycling bipolar disorder" is notably lower at 20-40%) (17). Perhaps as more is learned about the mechanism by which lithium functions to stabilize mood in bipolar disorder, such findings will offer insight into possible reasons why a condition based purely in mania does not seem to exist.

A second area of research to be examined has to do with the role of circadian rhythm dysfunctions in bipolar disorder. This realm of research has focused primarily on "rapid cycling bipolar disorder", which is characterized as four or more manic, hypomanic, or depressive episodes in any 12 month period. In reality, episodes are often much more frequent than the definition requires (17).The term "circadian rhythms" comes from the Latin circa dies which means "about one day" (18). It is now known that circadian rhythms, which influence the timing of the release of hormones implicated in sleep and wakefulness, metabolic rate, and body temperature (18) are regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, and that the SCN modulates the pineal gland's release of the hormone melatonin (11). Melatonin, which is often sold as a cure for insomnia, is the body's shut-down mechanism(11). Light suppresses melatonin secretion, and thus the hormone is usually secreted at night (19). The issue of whether abnormalities in circadian rhythm regulation are involved in the pathogenesis of mood disorders has been examined for at least the last 50 years (19). The interest in this line of inquiry grew out of four clinical observations. The first such observation was that the amount of time that patients sleep undergoes major changes as they cycle between depression (associated with hypersomnia) and mania (associated with extreme and sometimes complete insomnia) (5). The second observation was that 60 percent of depressed patients enter into remission (symptoms cease) after a night or total or partial sleep deprivation (SD), while SD can actually induce a shift into hypomania or mania. This led to the conception that SD, or extended wakefulness is antidepressant/manicogenic (mania-inducing), while sleep is depressogenic (depression-inducing) (19). The third observation is that decreased sleep duration starts prior to the onset of a hypomanic state (19), which suggests that changes in sleep duration are not just symptoms of the disorder, but also play a pathogenic role. The final observation suggesting that abnormal circadian rhythms play a role in the pathogenesis of mood disorders has to do with diurnal variation. Past research has shown that there is continuous improvement in depressed patients' moods as day unfolds, suggesting that extended wakefulness is associated with an antidepressant response. More recent research at the National Institute of Mental Health (NIMH) extended the phenomenon of diurnal variation to bipolar patients with data showing that rapid-cycling patients shift "up" (i.e. from depression to hypomania) during the day and shift "down" (i.e. from hypomania to depression) overnight (19).

Building upon these observations, phase instability, a susceptibility to disturbances in the circadian rhythm, is thought to be one property of bipolar disorder (3). A recent study at the NIMH suggests that there are phase shifts in nocturnal melatonin secretion as bipolar patients cycle between the depressed and hypomanic states. Researchers have collected preliminary data showing that, in rapid-cycling bipolar sufferers, the time of nocturnal melatonin onset is about 90 minutes earlier when they are hypomanic, relative to when they are depressed (19). In some sense, it is as if bipolar patients, particularly rapid-cyclers, have an endogenous form of jet lag, and internally move back and forth over several time zones as they cycle between hypomania and depression. It is important to point out that the most recent theories hypothesize that phase shifts in melatonin secretion are secondary to the primary causes of bipolar disorder, but do have pathogenic effects, playing a role in the progression of a full-blown affective episode (19). It has been proposed that there is a positive feedback loop between sleep and mood in bipolar patients, which accounts for how their circadian rhythms become so off-track. When a patient begins to manifest hypomanic tendencies, he does not want to sleep, and the lack of sleep begins to destabilize his circadian rhythm. This initially slight shift in the circadian rhythm feeds back and makes him more manic, leading him to not want to sleep even more. Along the same lines, when the person is depressed, he will want to sleep more, which will lead him to become more depressed(5). Eventually, over time, the entire circadian rhythm system becomes completely off track, resulting in extreme mood swings between depression and mania (11). A case study published by a major researcher in the field showed that when a strict, lengthened sleep regimen (14 hours of complete darkness) was adhered to, the bipolar patient's sleep became fairly regular and, after a couple of months, mood cycles stopped. The most interesting finding from this case study was that promoting normal sleep appeared to stop not only hypomania, as the sleep-deprivation studies would suggest, but also the depression that used to follow hypomania (5). Obviously larger, double-blind studies are necessary, but the findings suggest that a contributing factor to bipolar disorder is the overall chaos that results from circadian rhythm instability, and thus when normal circadian rhythms are restored through normalizing sleep, the rapid mood shifts may cease to occur.

Understanding the proposed connection between bipolar disorder and circadian rhythm instability offers insight into why mania is not found to exist on its own. The theory is that individuals who suffer from bipolar disorder have a heightened sensitivity to slight changes in circadian rhythms, such that minor shifts that would not disturb a "normal" person, throw the entire system of someone with bipolar disorder from one mood state to another. Circadian rhythms are based in a cyclical process, and it would be surprising if the phase instability that is characteristic of bipolar disorder only became off track in one direction (i.e. only contributed to the escalation of a manic episode). When a system is unstable, it is just as likely that it will be shifted in one direction as the other. There clearly must be a limit as to how far the circadian rhythm can spiral out of control in one direction, and it would seem logical that a counterbalancing shift in the opposite direction might follow. This would further explain why, particularly in the case of rapid-cycling bipolar disorder, the type of bipolar disorder that most strongly implicates circadian dysfunction, there are frequent shifts between hypomanic or manic states and depressed states.

Clearly, there is not a straightforward answer to the question of why a condition characterized by manic episodes, but no accompanying depressive episodes, does not exist in DSM-IV. The possibility that "unipolar mania" does exist, but is not considered pathological cannot be entirely discounted. Yet, based on my reading, it seems that while there are most likely points in the earlier stages of a manic episode that stimulate creativity and productivity, once a manic episode progresses past a certain point, one's ability to function is compromised. Therefore, I believe that if severe cases of "unipolar mania" did exist, they would be considered to be pathological, and thus, "unipolar mania" would be a listing in DSM-IV. Based on this reasoning, I have suggested several possible physiologically-based reasons why mania does not exist in isolation from depression. There are no doubt holes in the biological rationale that I propose, reflective of the fact that I am not aware of any research that has directly addressed this issue to date. I think that research into why a completely "manic" condition does not seem to exist is called for, as it will further inform the understanding of the neurobiology of bipolar disorder.

WWW Sources

1) Schultz, Marc. Psychology 209, Abnormal Psychology. Bryn Mawr College, February, 1999.

2) Bipolar Mood Disorders

3) Extreme Measures

4) Bipolar Disorders Letter , "Minimized Activity Monitors and New Dosing Strategies Aid Treatment"

5) Bipolar Disorders Letter , "Meeting the Challenge of Rapid-Cycling Bipolar Disorder"

6) Kay Jamison on having manic-depression

7) Famous People with Bipolar Disorders

8) Bipolar Disoder and the Creative Genius , Serendip Website

9) Bipolar Disorder , National Institute of Mental Health homepage

10) Pharmacological treatment of Bipolar Disorder

11) What Causes Bipolar Disorders?

12) Bipolar Disorder - Etiology & Treatment

13) The Neurobiology and Chemical Apspects of Manic Depression/Bipolar Disorder

14) Drug Treatment for Mood Disorders: Depression and Bipolar Disorder

15) Chapter 16 - Mood Disorders

16) Sternberg, Wendy. Psychology 217, Biological Psychology. Haverford College, April 1998

17) Educational Material

18) How the Biological Clock Works

19) Circadian Rhythms Factor in Rapid-Cycling Bipolar Disorder

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