The Recognition and Management of Mania

Faculty and Disclosures

1. The Phenomenology and Diagnosis of Mania
2. Prognosis
3. The Management of Acute Mania
4. Maintenance
References
THE PHENOMENOLOGY AND DIAGNOSIS OF MANIA
A manic episode distinguishes bipolar I disorder, a condition estimated to have a lifetime prevalence of 1.6% in the United States.
[1]
In
contrast to the female predominance that characterizes other affective disorders, the sex ratio of bipolar I disorder is nearly even. Onset
occurs most often in the 20s, but childhood and adolescent onsets have been increasingly recognized in the past decade with the
realization that the phenomenology and course at these ages differ from typical presentations in adults.
[2-5]
Numerous medical conditions
can produce manic syndromes,
[6]
and the first occurrence of a manic episode in older individuals should invite a careful screening for
underlying conditions.
Some manic episodes develop with remarkable speed, although gradual onsets spanning weeks to months occur as well. An individual
being treated for depression may abruptly switch into a manic phase and mania may evolve quickly to depression.
The DSM-IV definition of mania lists 8 symptoms and requires euphoria or irritability. Either of these may occur alone or in combination
with the other, and either may be ascertained by the patient's subjective report or by clinical observation.
Patients with mania experience the decreased sleep that is present in many other disorders. The distinguishing quality in mania is the
absence of resultant fatigue. A useful probe is, "Have you found that you need less sleep than usual to feel rested and energetic?"
A decreased need for sleep is typically accompanied by another manic symptom -- increased activity. Whereas individuals with
depression or anxiety disorder who are unable to sleep often remain in bed and brood about their need for sleep, manic patients are
likely to be up and busy at night. Increased activity should be apparent to others in the patient's environment to be included as a manic
symptom.
Manic patients may or may not acknowledge racing thoughts, but the examiner often appreciates a flight of ideas on interview. The
patient typically moves rapidly from one topic to another but, in contrast to the thought disorder of schizophrenia, the connection
between thoughts is usually perceptible. Patients with pressured speech are not simply circumstantial, but speak rapidly and
expressively. In clinical settings, such patients are more likely than other patients to address all present and to be socially intrusive.
Grandiosity may shade from modest overestimation of talent, intelligence, or economic prospects to grandiose delusions in which the
individual has worldwide or cosmic importance. These beliefs are often complicated by persecutory delusions that may then dominate
the clinical picture.
The sense of optimism and invulnerability that accompanies grandiosity often combines with increased activity to fuel reckless behavior.
This feature is responsible for much of the morbidity consequent to manic episodes. Excessive spending is perhaps its most common
form, but patients often also come to regret impulsive sexual liaisons, abrupt travel, ill-advised business decisions, and excessive
alcohol use.
The distinction between bipolar I disorder and bipolar II disorder hinges on the boundary between mania and hypomania. Patients with
mania experience a mood disturbance that is, according to DSM-IV, "sufficiently severe to cause marked impairment in occupational
functioning or unusual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or
there are psychotic features." Those with hypomania do not, by definition, have this level of severity. This may seem an arbitrary
separation of syndromes, but the results of family
[7]
and follow-up studies
[8,9]
support its validity. Bipolar II disorder occurs far more
frequently in the families of bipolar II probands than in the families of bipolar I probands, and patients with only a history of hypomania
are much more likely to develop manic episodes during extended follow-up periods than are those with histories of mania.

The Recognition and Management of Mania: Prognosis
Faculty and Disclosures

1. The Phenomenology and Diagnosis of Mania
2. Prognosis
3. The Management of Acute Mania
4. Maintenance
References
PROGNOSIS
Emil Kraepelin
[10]
emphasized the episodic nature of manic depressive illness when he first described this condition over 100 years ago.
Manic episodes typically resolve in time with or without treatment, but single episodes are exceedingly rare. Also rare are individuals
who experience only manic episodes over time.
[11]
The term "bipolar" is justified because the vast majority of persons who experience
manic episodes also experience depressive phases. In fact, most bipolar patients have far more morbidity from depression than from
mania.
[12]

Studies have not shown course and outcome to differ by current age or sex. However, onset in childhood or adolescence appears to
portend more long-term morbidity than does later onset.
[4]
Patients who switch directly from one pole (mania or depression) to the other
also tend to have longer and more frequent episodes than do patients who experience discrete episodes of mania or depression.
[13]
A
number of studies have found that phase sequencing is prognostically important as well. Patients who switch from depression to mania
experience longer episodes
[14]
and more breakthrough symptoms during prophylactic treatment than do patients with reverse
sequences.
[15]
Finally, although the presence of psychotic features does not seem to affect acute antimanic responses to lithium, it does
appear to predict a more long-term morbidity.
[16]



THE MANAGEMENT OF ACUTE
MANIA
Acutely manic patients rarely seek treatment on their own initiative, and clinicians often first encounter the patient when summoned to
the emergency room, following an involuntary admission, or, indirectly, through calls from concerned family members. The clinician's
first decision may be whether to hospitalize the patient. Outpatient management is occasionally feasible when the physician is familiar
with the patient and there is excellent family support. In most cases, though, hospitalization will be necessary because the risks for
unpredictable, reckless behavior and for treatment noncompliance are both high. Moreover, hospitalization will usually require a locked
psychiatric unit and referral to a psychiatrist.
The 2 components of acute management consist of (1) the rapid control of hyperactivity, sleeplessness, irritability, and psychotic
features with atypical or typical antipsychotics, and (2) the selection of a mood stabilizer. Placebo-controlled trials have shown each of
the atypical antipsychotics currently marketed in the United States to be effective in the treatment of acute mania.
[17]
None has a clear
advantage over the others, although the rapidly dissolving form of olanzapine may be preferable if surreptitious noncompliance is
suspected because this makes the "cheeking" of medication nearly impossible. Doses can be rapidly increased as they are titrated
against the more prominent symptoms.
Many patients with acute mania initially refuse oral medications, therefore making parenteral antipsychotics necessary. An
intramuscular preparation of ziprasidone has become available recently, but each dose must be reconstituted before use. Among the
typical antipsychotics, haloperidol has been the most widely used. Because treatment with high-potency typical antipsychotics
introduces the risk of dystonic reactions, particularly in younger men, prophylaxis with low doses of anticholinergic agents should be
routine at the outset because such reactions could be quite frightening to patients and produce a negative attitude toward medication in
general. Rapidly escalating doses of the high-potency neuroleptics also produce risks for neuroleptic malignant syndrome, and
clinicians should closely monitor vital signs and mental status changes when attempting to control manic symptoms with these agents.
Atypical antipsychotics are preferable when patients accept oral medicine because their acute side effects are less problematic. Their
use in acute mania is also less likely to be followed by depressive symptoms than is the use of typical antipsychotics.
[18,19]

At least 8 randomized, placebo-controlled trials have demonstrated the prophylactic efficacy of lithium in bipolar disorder.
[20]
Evidence is
relatively scant for the other widely used mood stabilizers. One maintenance study yielded support for divalproex,
[21]
and 2 supported the
efficacy of lamotrigine.
[22,23]
In both of the latter studies, lamotrigine offered better protection against recurrent depression than did
lithium, while lithium offered more protection against the emergence of manic episodes.
The introduction of a mood stabilizer should not be delayed beyond the point at which the patient is willing to accept oral medication.
Placebo-controlled trials have shown both lithium
[24,25]
and valproate
[21,26]
monotherapy to be effective in acute mania. Thus the use of
either of the agents in conjunction with atypical antipsychotics is likely to hasten full resolution of manic symptoms.
A patient's first encounter with a given mood stabilizer may produce lasting impressions that influence his or her long-term compliance
with maintenance therapy. Rapid titration schedules have been proposed for divalproex and these do not appear to entail greater side-
effect burdens than do standard titration schedules.
[27]
This is not true of lithium. Instead, lithium should be initiated at daily divided
doses of 1200 mg, or 900 mg for older individuals. Steady-state levels after 4-5 days can be used to predict the dose necessary to
achieve blood levels between 0.6 mEq/L and 1.2 mEq/L. Side effects such as nausea and tremor may correlate with the speed of blood
level increases as well as with absolute levels,
[28]
so dose titration should be slowed when these symptoms emerge. While there is
limited evidence that plasma levels near 1.0 mEq/L are more effective in acute mania than are lower levels, this level should be
approached gradually because significant toxicity may emerge when levels reach 1.4 mEq/L.
Although there is now evidence that the combined use of an atypical antipsychotic with lithium provides better prophylaxis than does
lithium monotherapy,
[29]
the combination is more likely to result in weight gain and unwanted sedation. Unless prior experience has
demonstrated the need for combined treatment in prophylaxis, it is usually advisable to begin the taper and discontinuation of adjunctive
atypical antipsychotics when there is adequate control of manic symptoms and the target dose or blood level of the mood stabilizer has
been reached.


MAINTENANCE
The highly recurrent nature of bipolar disorder gives foremost importance to optimal prophylaxis, and the most frequent
impediment to this is noncompliance. This, in turn, can arise from poor insight, poorly tolerated side effects, or both.
Because patients may fail to spontaneously describe even side effects they find noxious, clinicians should routinely
screen for the likely ones, particularly early in the course of maintenance. Gastrointestinal side effects are often
amenable to alternative preparations of lithium or divalproex, and lithium-induced tremors may improve with modest
doses of propranolol.
[30]
There is a clear, stepwise, relationship between lithium plasma level during maintenance therapy
and side-effect burden. The higher levels offer some improvement in the prevention of mania but not of
depression.
[31]
The clinician must work closely with the patient to empirically determine the plasma level that produces
the optimal balance between prophylaxis and tolerability.
While divided doses are preferable during the initiation of mood stabilizer therapy, many patients will find a single
bedtime dose equally effective and more convenient.
As noted, most patients with bipolar disorder experience the bulk of their long-term morbidity in the form of depressive
symptoms. If depression develops despite compliance with mood stabilizers at adequate doses, many clinicians simply
add an antidepressant. Controversy surrounds this approach because it is widely believed that antidepressants trigger
manic episodes and increase cycling. Placebo-controlled studies have not supported this view and other evidence has
weighed against a causal connection between antidepressant use and subsequent manic episodes.
[32]
However, there is
scant evidence that antidepressants are effective in bipolar depression. The literature contains 2 placebo-controlled
studies of serotonin reuptake inhibitors in bipolar depression. One was supportive
[33]
and one was not.
[34]

Large, placebo-controlled studies have shown lamotrigine to be effective as monotherapy, both in the treatment of acute
bipolar depression and in the prevention of depression during maintenance. It has not been shown to be effective for
acute mania, and only when data from the 2 published studies of prophylaxis were combined did lamotrigine offer
significantly better protection against mania than did placebo.
[35]
Taken together, these results suggest that patients who
experience persistent depressive symptoms despite lithium prophylaxis may benefit from the addition of lamotrigine.
Recent placebo-controlled trials have also shown significant antidepressant effects of olanzapine
[36]
and
quetiapine
[37]
monotherapy in bipolar depression. Because both agents are also effective in acute mania, they may play
a role in prophylaxis as monotherapy or when used with lithium. In comparison to lamotrigine, though, both are likely to
cause more side effects, and weight gain may be a particular problem. However, the lamotrigine target dose must be
approached very gradually to minimize risks for serious rashes, and the sedation produced by olanzapine and
quetiapine may be an added benefit for patients with chronic sleep difficulties.
In summary, a manic episode comprises one phase of bipolar disorder, a highly recurrent condition in which depressive
symptoms often dominate over time. Careful attention should be given to the selection and optimization of a
prophylactic regimen as this will be the most important factor in reducing long-term morbidity.