Thorough evaluation of many persons with depression reveals bipolar traits, and as many as one in five patients with a depressive disorder also develops frank hypomania or mania. Most switches from unipolar to bipolar disorder occur within 5 yr of the onset of depressive manifestations. Predictors of a switch include early onset of depression ( 25 yr old), postpartum depression, frequent episodes of depression, quick brightening of mood with somatic treatments (eg, antidepressants, phototherapy, sleep deprivation, electroconvulsive therapy), and a family history of mood disorders for three consecutive generations.
Between episodes, patients with bipolar disorder exhibit depressive moodiness and sometimes high-energy activity; disruption in developmental and social functioning is more common than in unipolar disorder. In bipolar disorder, episodes are shorter (3 to 6 mo), age of onset is younger, onset of episodes is more abrupt, and cycles (time from onset of one episode to that of the next) are shorter than in unipolar disorder. Cyclicity is particularly accentuated in rapid-cycling forms of bipolar disorder (usually defined as 4 episodes/yr).
In bipolar I disorder, full-fledged manic and major depressive episodes alternate. Bipolar I disorder commonly begins with depression and is characterized by at least one manic or excited period during its course. The depressive phase can be an immediate prelude or aftermath of mania, or depression and mania can be separated by months or years.
In bipolar II disorder, depressive episodes alternate with hypomanias (relatively mild, nonpsychotic periods of usually 1 wk). During the hypomanic period, mood brightens, the need for sleep decreases, and psychomotor activity accelerates beyond the patient's usual level. Often, the switch is induced by circadian factors (eg, going to bed depressed and waking early in the morning in a hypomanic state). Hypersomnia and overeating are characteristic and may recur seasonally (eg, in autumn or winter); insomnia and poor appetite occur during the depressive phase. For some persons, hypomanic periods are adaptive because they are associated with high energy, confidence, and supernormal social functioning. Many patients who experience pleasant elevation of mood, usually at the end of a depression, do not report it unless specifically questioned. Skillful questioning may reveal morbid signs, such as excesses in spending, impulsive sexual escapades, and stimulant drug abuse. Such information is more likely to be provided by relatives.
Patients with major depressive episodes and a family history of bipolar disorders (unofficially called bipolar III) often exhibit subtle hypomanic tendencies; their temperament is termed hyperthymic (ie, driven, ambitious, and achievement-oriented).
Symptoms and Signs
Symptoms of the depressive phase are similar to those of unipolar depression (see above), except that psychomotor retardation, hypersomnia, and, in extreme cases, stupor are more characteristic.
In full-blown manic psychosis, the mood is usually elation, but irritability and frank hostility with cantankerousness are not uncommon. Typically, manic patients are exuberant and flamboyantly or colorfully dressed; they have an authoritative manner with a rapid, unstoppable flow of speech. They tend to believe they are in their best mental state. Their lack of insight and their inordinate capacity for activity can lead to a dangerously explosive psychotic state. Interpersonal friction results and may lead to paranoid delusions that they are being unjustly treated or persecuted.
Accelerated mental activity is experienced as racing thoughts by the patient, is observed as flights of ideas by the physician, and, in its extreme form, is difficult to distinguish from the loose associations of the schizophrenic. Easily distracted, patients may constantly shift from one theme or endeavor to another. Thoughts and activities are expansive and may progress into frank delusional grandiosity (ie, false conviction of personal wealth, power, inventiveness, and genius or temporary assumption of a grandiose identity). Some patients believe they are being assisted by external agents. Auditory and visual hallucinations sometimes occur. The need for sleep is decreased. Manic patients are inexhaustibly, excessively, and impulsively involved in various activities without recognizing the inherent social dangers. In the extreme, psychomotor activity is so frenzied that any understandable link between mood and behavior is lost; this senseless agitation is known as delirious mania, which is the counterpart of depressive stupor. Rarely seen in psychiatric practice today, delirious mania constitutes a medical emergency, because patients may die from sheer physical exhaustion.
Mixed states are blends of depressive and manic (or hypomanic) manifestations and distinguish bipolar disorders from their unipolar counterparts. The most typical examples include momentary switches to tearfulness during the height of mania or racing thoughts during a depressive period. In at least 1/3 of persons with bipolar disorders, the entire attack--or a succession of attacks--occurs as a mixed episode. A common presentation consists of a dysphorically excited mood, crying, curtailed sleep, racing thoughts, grandiosity, psychomotor restlessness, suicidal ideation, persecutory delusions, auditory hallucinations, indecisiveness, and confusion. This presentation is referred to as dysphoric mania, ie, prominent depressive symptoms superimposed on manic psychosis. Dysphoric mania often develops in women and in persons with a depressive temperament. Alcohol and sedative-hypnotic abuse contributes to the development or aggravation of mixed states.
Depressive mixed states, which are not specifically characterized in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, are best regarded as intrusions of hypomanic symptoms or hyperthymic traits into a retarded major depressive episode. Antidepressant drugs may aggravate these states by producing a subacute irritable depressive state that lasts many months. The clinical picture consists of irritability, pressure of speech against a background of retardation, extreme fatigue, guilty ruminations, free-floating anxiety, panic attacks, intractable insomnia, increased libido, histrionic appearance yet genuine expressions of depressive suffering, and, in the extreme, suicidal obsessions and impulses. Patients with a depressive mixed state and those with dysphoric mania are at high risk of suicide and require expert clinical management.
Mortality from cardiovascular causes is modestly increased in patients with bipolar disorder; the increase is not explained by cardiotoxicity from lithium or tricyclic antidepressants and tends to also occur in first-degree biologic relatives who do not have frank affective episodes. The increase is probably related to comorbid hypertension, diabetes, and coronary artery disease, all of which are aggravated by nicotine and alcohol dependence, which are prevalent in patients with bipolar disorder.
Acute management: Classic euphoric mania often presents as a social emergency and is preferably managed on an inpatient basis. Lithium works best in uncomplicated euphoric mania. After baseline laboratory tests (CBC, urinalysis, thyroxine, TSH, serum electrolytes, creatinine, and BUN) are performed, lithium carbonate 300 mg po bid or tid is given, and the dose is increased over 7 to 10 days until a blood level of 0.8 to 1.2 mEq/L is reached. Patients with acute mania have a high tolerance for lithium and preferentially retain it during the first 10 days while excreting Na+. A regular diet is recommended. Teenagers, whose glomerular function is excellent, need higher doses of lithium to achieve the same level; elderly patients need lower doses. Because lithium's onset of action has a 4- to 10-day latency period, haloperidol 5 to 10 mg po or IM (up to 30 mg/day) or another antipsychotic is sometimes also necessary initially; it is given as needed until the manic stage is controlled. For extremely hyperactive psychotic patients with poor food and fluid intake, giving an antipsychotic IM with supportive care for a week before initiating lithium is preferable. Lorazepam or clonazepam 2 to 4 mg tid IM or po given early in acute management can boost the antipsychotic's effects so that its dose can be reduced.
Lithium is a naturally occurring alkali metal. Its proposed therapeutic mechanisms include reducing neuronal Ca++ mobilization via activation of the membrane phosphoinositide signaling system; hyperpolarizing the neuronal membrane; increasing presynaptic deamination of norepinephrine and decreasing its release; blocking -adrenergic receptor-stimulated adenylate cyclase; decreasing dopamine turnover; increasing tryptophan uptake and consequent stabilization of 5-HT synaptic dynamics; inhibiting the synthesis of prostaglandin E1; and slowing biologic rhythms. Although lithium attenuates bipolar mood swings, it has no effect on normal mood. It also appears to have an antiaggressive action, but whether this action occurs in persons without a bipolar disorder is unclear. Lithium does not directly produce sedation or, ordinarily, cognitive impairment; if the latter occurs, lithium-induced hypothyroidism must be ruled out.
Two thirds of patients with uncomplicated bipolar disorder respond to lithium. Predictors of a good response include a euphoric manic picture as part of a primary mood disorder, < 2 episodes a yr, and a personal and family history of response to lithium. Lithium is less effective in patients with mixed states, rapid-cycling forms of bipolar disorder, comorbid anxiety, substance abuse, or a neurologic disorder.
Lithium, usually given as the carbonate, is rapidly and completely absorbed via the GI tract and peaks in serum in 90 min. It is not biotransformed; 95% is excreted via the kidneys, a process enhanced by a Na+ load. Thus, use of diuretics or disorders that lead to Na+ loss pose a risk of toxicity. The elimination half-life is 24 h, which tends to increase with age. Steady state is reached in 4 to 6 days, producing a delay in acute antimanic action. During a manic episode, the patient retains lithium and excretes Na+; oral dosage and the blood level need to be higher during acute treatment than during maintenance prophylaxis. Lithium has a narrow therapeutic index, and lithium blood levels must be strictly monitored.
The most common acute, mild adverse effects of lithium are fine tremor, fasciculation, nausea, diarrhea, polyuria, thirst, polydipsia, and weight gain (partly attributed to drinking high-calorie beverages). These effects are usually transient and often respond to decreasing the dose slightly, dividing the dose (eg, tid), or using slow-release forms. Once dosage is established, the entire dose should be given after the evening meal. This dosing may improve compliance, and the troughs in blood levels are believed to protect the kidneys. A -blocker, such as atenolol 25 mg po daily or bid, can control incapacitating tremor.
Toxic effects are manifested initially by gross tremor, increased deep tendon reflexes, persistent headache, vomiting, and mental confusion and may progress to stupor, seizures, and cardiac arrhythmias. Except for overdose, lithium toxicity is more likely in elderly patients and in patients with decreased creatinine clearance or with Na+ loss, which may result from fever, vomiting, diarrhea, or use of diuretics. NSAIDs other than aspirin may contribute to hyperlithemia. None of these situations is an absolute contraindication to lithium. However, renal function should be assessed at baseline and monitored frequently (measuring 24-h urine volume, urine concentration, and creatinine clearance), and blood lithium should be measured frequently. Doses may have to be decreased, and dietary sodium supplementation given. TSH response to TRH stimulation and other thyroid indexes should be checked when thyroid disease is suspected. In patients with relatively stable mood, blood lithium levels and weight should be measured quarterly, and creatinine and TSH should be measured biannually.
Common chronic adverse effects of lithium are exacerbation of acne and psoriasis, hypothyroidism, and nephrogenic diabetes insipidus (which may respond to dose reduction or temporary interruption of lithium). Patients with a history of parenchymal kidney disease may be at risk of structural damage to the distal tubule.
Acute manic psychosis is being increasingly managed with the atypical antipsychotics risperidone (usually 4 to 8 mg/day po) and olanzapine (usually 5 to 10 mg/day po), because of their minimal risk of extrapyramidal adverse effects.
Anticonvulsants, especially valproate and carbamazepine, are also widely used. Their precise therapeutic action in bipolar disorder is unknown but may involve GABAergic mechanisms and ultimately G-protein signaling systems. Their main advantages over lithium include a wider therapeutic margin and lack of renal toxicity. Valproate (especially as divalproex, which has good GI tolerability) is approved for acute mania. Unlike carbamazepine, divalproex does not suppress the bone marrow, but it may cause liver damage in children. Divalproex may cause weight gain, alopecia, and tremor in adults. Common adverse effects of carbamazepine include sedation, vertigo, ataxia, diplopia, and pruritic rashes. Carbamazepine induces its own catabolism, necessitating frequent increases in dose during the first months of treatment; divalproex does not.
Carbamazepine (up to about 28 mg/kg/day po) is useful for patients with mood-incongruent psychotic features. Divalproex (up to 60 mg/kg/day po) is preferred by many clinicians in the USA as a mood stabilizer for acute management, especially for hostile, irritable manic patients. "Depakotization" (escalation of dose in a few days) may work rapidly.
Although dysphoric mania can be managed with an antipsychotic, divalproex (up to 60 mg/kg/day po) is the treatment of choice, especially when psychotic features are present. The atypical antipsychotic clozapine can greatly benefit patients with refractory mixed-manic disorder but is associated with the risk of agranulocytosis; olanzapine may be an alternative without such risk. Electroconvulsive therapy is reserved for the most fulminant cases of mania and mixed states.
In patients with bipolar II disorder, any effective antidepressant may cause treatment-emergent hypomania, but bupropion and paroxetine appear least likely to cause it. Tranylcypromine is reserved for cases refractory to bupropion or paroxetine. These antidepressants can be used as monotherapy for patients who are relatively stable between episodes and who have infrequent relapses. For most other patients with bipolar II disorder, mood stabilizers are also needed. Lithium has a modest acute antidepressant effect in the depressive phase of bipolar disorder and can be given alone or with any antidepressant, but preferably with one that is least likely to induce cycling. Augmenting doses of lithium are 600 to 1200 mg/day. Antidepressants can also be augmented with divalproex 500 to 1000 mg/day. Some patients respond to a combination of lithium and divalproex.
Maintenance therapy: Treatment of an isolated manic episode should continue for at least 6 mo. Most manias recur as part of a recurrent bipolar disorder. Maintenance therapy with lithium should be initiated after two classic bipolar episodes < 3 yr apart.
Levels should be maintained between 0.3 and 0.8 mEq/L, usually by giving two to five 300-mg capsules/day. Antidepressants should not be used during prophylaxis unless breakthrough depression is severe and, if used, should be given only for 4 to 12 wk. When disruptive psychomotor acceleration or mixed states supervene, thioridazine 50 to 300 mg/day po for 1 to 4 wk can restabilize the patient; olanzapine 5 to 10 mg/day may be a viable alternative.
In the noncompliant, cantankerous manic patient, a depot phenothiazine, such as fluphenazine decanoate 12.5 to 25 mg IM q 3 to 4 wk, is customarily given. In patients with bipolar disorder and mood-incongruent psychotic features beyond the usual boundaries of "pure" mood disorder, intermittent courses of depot antipsychotics are often necessary.
Anticonvulsants may be easier to use than lithium. Carbamazepine 400 to 2000 mg/day po (blood level: 6 to 12 mg/L) is effective. Because of the risk of agranulocytosis, clinical vigilance and periodic CBCs are prudent. Divalproex 400 to 2000 mg/day (blood level: 40 to 140 mg/L) does not cause hematologic abnormalities, but hepatic function should be checked periodically. Because divalproex is less likely to cause mental obtundation, it is often preferred for prophylaxis.
The anticonvulsant lamotrigine (up to 200 mg/day po) is particularly useful for the depressive phase of bipolar disorder and for severe affective storms in some patients with borderline personality. Treatment should begin with 25 mg; the dose is increased gradually to avoid pruritic rashes, which occur early in 5 to 10% of patients. Discontinuation as soon as a rash occurs averts the rare but grave Stevens-Johnson syndrome. Gabapentin appears to have few adverse effects but is reserved for refractory cases as an augmenting drug.
Prevention of rapid cycling: Antidepressants may induce rapid cycling in some patients (eg, patients with bipolar II disorder and a cyclothymic temperament), even when given with lithium. The best strategy is preventive: limiting the use of antidepressants during the depressive phase. For an established case of rapid cycling, the physician must gradually discontinue all cycling antidepressants, stimulants, caffeine, benzodiazepines, and alcohol. Hospitalization may be required. Lithium (or divalproex) may be given with bupropion. Because borderline hypothyroidism also predisposes to rapid cycling (especially in women), augmenting mood stabilizers with hormones (eg, L-thyroxine 100 to 200 g/day po) often helps. Sometimes carbamazepine can also be useful. Some experts combine an anticonvulsant with lithium, trying to keep both drugs at 1/2 to 2/3 their usual dose. Nimodipine (90 mg bid), a calcium channel blocker, may also help in ultrarapid cycling (ie, cycling every few days), but it is not yet an established strategy.
Combining mood stabilizers is often necessary to obtain optimal results. However, avoiding carbamazepine-divalproex and divalproex-lamotrigine combinations is best because of additive toxic effects.
Phototherapy is a relatively new approach for patients with seasonal bipolar or bipolar II disorder (with autumn-winter depression and spring-summer hypomania). It is probably most useful as augmentation.
Precautions during pregnancy: Women who wish to have a baby should have at least 2 yr of maintenance therapy with no episodes before a lithium holiday is prescribed. Lithium is discontinued in the 1st trimester to avoid the risk of Ebstein's anomaly, a heart defect. Carbamazepine and divalproex should also be discontinued in the 1st trimester because they may cause neural tube defects. For a severe relapse during the 1st trimester, electroconvulsive therapy is safer. Mood stabilizers, if absolutely necessary, can be used during the 2nd and 3rd trimesters but should be stopped 1 to 2 wk before delivery and resumed a few days postpartum. Mothers taking mood stabilizers should not nurse because these drugs pass into the milk.
Psychoeducation and psychotherapy: Enlisting the support of a family member is crucial to prevent major episodes. Patients and their significant others are often seen in group therapy, in which they learn about bipolar disorder, its social sequelae, and the central role of mood stabilizing drugs in its treatment. Patients, particularly those with bipolar II disorder, may not comply with mood stabilizer regimens because they report these drugs overcontrol them and make them less alert and creative. The physician can explain that a decrease in creativity is relatively uncommon, because mood stabilizers generally offer the opportunity for a more even performance in interpersonal, scholastic, professional, and artistic pursuits. Skillful dosing is necessary; the physician must be sensitive to the patient's career while ensuring that relapses do not occur.
Individual psychotherapy may help patients better cope with problems of daily living and adjust to their new self-identities. Patients are unconsciously aware that their periodic tendency to lose control is costly, but they resent being controlled by the physician. For this reason, when appropriate, the physician should consider fulfilling some of the patient's requests to modestly reduce the dose of mood stabilizers; the possibly greater risk of relapse is balanced by better compliance and a trusting relationship. Small doses of an antipsychotic (eg, thioridazine 50 to 100 mg) can be provided to be taken for a few nights if impending signs of relapse, such as a decreased need for sleep, occur. Interventions with the patient's spouse or family can help moderate interpersonal crises. Patients should be counseled to avoid stimulant drugs and alcohol, to minimize sleep deprivation, and to recognize early signs of relapse. If a patient tends to be financially extravagant, finances should be turned over to a trusted family member. Those with a tendency to sexual excesses should be given information about the conjugal consequences (divorce) and the infectious risks of promiscuity (particularly AIDS).
Added November 12th, 2001. (For Bob and 7) Sorry for the delay guys. I hope it helps.