Drug Treatment Of Mania

By | February 8, 2015

When assessing the patient, enquiries should be made about their recent compliance with medication, as sudden discontinuation of lithium may have triggered the manic episode. It is usually prudent to cease any antidepressant medication they may have been taking.

A physical examination and tests of the blood and urine should, if possible, precede drug treatment or take place soon after the patient is sedated, in order to elucidate any physical illness, especially infection, and any causes of secondary mania (e.g., drugs), and to determine baseline renal, hepatic, and thyroid function. An ECG should be performed if high doses of medication are to be used.

Acute Tranquillization

Treatment of the severe and agitated patient begins with control by “acute” or “rapid” tranquillization. This requires an antipsychotic such as haloperidol (5-10 mg IM) or olanzapine (5-10 mg IM), either of which may be given intramuscularly, often in combination with a benzodiazepine such as lorazepam (1-2mg IM). The more disturbed patient may be given an antipsychotic intramuscularly at hourly intervals three times, with additional benzodiazepines until they are calm. Larger single intramuscular doses are discouraged because they are excessive in some patients and because their effect may last for several days, obscuring the diagnosis, and making further management difficult; the patient may no longer appear very disturbed but is likely to deteriorate unless treatment is continued. Large doses of antipsychotic drugs have been associated with sudden deaths in disturbed young patients, probably through cardiac dysrhythmias. Formulary guidelines on doses of antipsychotics should not be exceeded without special precautions, including checking ECG and blood electrolytes; additional benzodiazepines should be used in preference. A comparative trial of intramuscular olanzapine (10 mg) vs. lorazepam (2mg) found olanzapine more effective in reducing symptoms of agitation in mania within 2 hour.

Once calmed the patient with mania then requires treatment over a period of 2 to 4 weeks to achieve further gradual improvement.

Treating Mania: Recommendations of Guidelines

Mania is one of the most insightless forms of mental disorder, and for treatment to be very useful it must be not only effective but also acceptable to the patient, easy to use, and not produce unpleasant side effects. Numerous guidelines exist for the management of bipolar disorder, perhaps reflecting the uncertainty that has prevailed about the efficacy and side effects of treatments (Table: International Guidelines for Treatment of Mania). There is now a convergence of views about the treatment of mania between North American, British, European, and Australasian guidelines. These now recommend that severe mania should be treated with an antipsychotic with or without lithium or valproate. Some include starting with valproate alone, using high doses (20-30 mg/kg). Less severe mania should usually be treated initially with mono-therapy with either an antipsychotic, preferably an atypical, or valproate or lithium; carbamazepine is an alternative.

Table: International Guidelines for Treatment of Mania

  • APA, 1994 – “Mood Stabilizer” (lithium, valproate, or carbamazepine): antipsychotic or benzodiazepine only as “adjunct” for psychosis, agitation, and violence
  • APA, 2002 – Severe mania: combination of lithium or valproate plus antipsychotic Mild mania: lithium or valproate or atypical antipsychotic
  • BAP (9) – Psychotic mania: antipsychotic (preferably atypical) Severe mania: antipsychotic (preferably atypical) or valproate Less ill: lithium, valproate, or carbamazepine
  • WFSBP (10) – Lithium or valproate or atypical antipsychotic with or without benzodiazepine or low potency classical antipsychotic
  • Aus-NZ (11) – “Mood stabilizer” (lithium, valproate, carbamazepine, or olanzapine) plus antipsychotic or benzodiazepine (or their combination)

The major change that has occurred since 1994 is that antipsychotics are no longer regarded as useful only for sedation or for psychosis but as being also antimanic. There has also been more reluctance to use the term “mood stabilizer” without specifying the drugs concerned. The notable remaining difference is that the revised American Guidelines of 2002 favor starting with the combination of an antipsychotic with valproate or lithium, whereas other guidelines include options for monotherapy at the start. The consensus emerging from these official guidelines is summarized in Table: Consensus of Guidelines for Treatment of Mania.

Table: Consensus of Guidelines for Treatment of Mania

  • Severe mania – Antipsychotic preferably atypical, with or without valproate, lithium or carbamazepine
  • Mild mania – Antipsychotic, preferably atypical or lithium or valproate

Antipsychotic Drugs

Surveys of clinical practice have shown that antipsychotics are the most commonly used drugs in patients hospitalized with mania, whether in Britain, Scandinavia, other parts of Europe, or North America.

Classical Antipsychotic Drugs

Moderate or severe mania is usually most rapidly controlled by antipsychotic drugs. Phenothiazines (e.g., chlorpromazine) and thioxanthines (e.g., zuclopenthixol) are effective but the butyrophenone, haloperidol, is often particularly useful in a dose of 5-10mg up to three times a day with an anticholinergic drug (to reduce extrapyramidal side effects). Haloperidol tends to produce initial sedation, which wears off after a day or so during continued treatment. If the patient remains very behaviorally disturbed, chlorpromazine may be more useful because, having antihistaminic properties, it is more sedative than haloperidol. However, many manic patients resent being made to feel drowsy and this limits the dose of chlorpromazine that they will accept. Chlorpromazine is hypotensive and should be used cautiously in the elderly.

Extrapyramidal side effects seem less of a problem with larger doses of haloperidol, but may emerge as the dose is reduced or a few days after it is discontinued. Anti-Parkinsonian medication should, therefore, be continued for up to 7 days after haloperidol is stopped.

Rapid improvement in mania occurs for 1 to 3 days after antipsychotic medication is commenced; the manic state tends then to improve more gradually over the next 2 weeks. There is no clear evidence that increasing the dose of haloperidol above 30 mg/day achieves greater improvement.

For manic patients whose failure to improve is due to poor compliance, depot antipsychotic medication including haloperidol or zuclopenthixol decanoates can be used. Zuclopenthixol acetate is a depot formulation, which has a duration of action of up to 3 days, and a more rapid onset of action than the decanoates; it is useful in disturbed patients who persistently refuse oral medication during the first few days of treatment.

Classical antipsychotics produce unpleasant extrapyramidal side effects such as akathisia, dystonia, and Parkinsonism that (although partially preventable by anticholinergic medication) are resented by patients and that limit their adherence to treatment. It is therefore very important to know whether the use of antipsychotics in mania is justified by evidence of efficacy and whether newer antipsychotics with fewer unpleasant acute side effects (atypical antipsychotics) are also effective in mania.

Atypical Antipsychotics

Atypical antipsychotics with proven efficacy in mania include olanzapine (15-20 mg/ day), risperidone (up to 6 mg/day), quetiapine (600 mg/day), aripiprazole, and ziprasidone. Sulpiride and amisulpride are also used. Mild mania may be treated with atypical antipsychotic drugs or an older drug such as haloperidol 5-10 mg daily; valproate is an alternative. Lithium treatment may also be useful, but improvement takes up to 2 weeks to become apparent.

Drug Treatment Of Mania: Assessing the Evidence

Mechanisms of Antimanic Actions of Drugs

It is thought that antipsychotics owe their antimanic effects mainly to blockade of receptors for dopamine, but additionally to some extent to blockade of noradrenaline at alpha-1 receptors (as in the case of haloperidol), and blockade of histamine at H-1 receptors (causing sedation as in the case of chlorpromazine). Some atypical antipsychotics share all these actions as well as being potent blockers of serotonin receptors (e.g., olanzapine, quetiapine, and risperidone), but are selective for subtypes of dopamine receptors, and others block only subtypes of dopamine receptors (amisulpride). It cannot be assumed that drugs effective in schizophrenia will be effective in mania or vice versa.

Lithium reduces presynaptic release of dopamine transmission, as well as blocking D-l receptors. Valproate too is thought to reduce dopamine turnover, perhaps by increasing the function of the inhibitory transmitter gamma-amino-butyric acid (GABA). An antikindling effect may underlie some of the actions of carbamazepine, but the pharmacological mechanism of action in mania is unclear. Thus, dopamine function is reduced through different mechanisms by antipsychotics and by lithium or valproate. It is therefore reasonable to assume that combinations of these drugs may have additive benefits to improve mania.

Treatment of Mania: Monotherapy or Combination Treatment

Side Effects with Combinations of Lithium and Antipsychotics

Lithium can increase extrapyramidal (Parkinsonian) side effects in patients on anti-psychotic drugs, and can itself produce cog-wheel rigidity in a small minority of patients. In contrast to antipsychotic-induced Parkinsonism, this does not improve with anticholinergic drugs. Cerebellar tremor and incoordination are signs of lithium toxicity, as are more severe forms of fine tremor and Parkinsonism.

Combinations of high levels of lithium with high doses of antipsychotics including haloperidol have been associated with severe neurological symptoms, hyperther-mia, impaired consciousness, and irreversible brain damage. The conditions reported resemble both lithium toxicity and neuroleptic malignant syndrome. Antipsy-chotic drugs can increase intracellular lithium levels suggesting a possible mechanism for this interaction. Subsequent series have demonstrated the safety of combining haloperidol (up to 30 mg/day) with lithium at levels of up to 1 meq/L.

In practice, when combining lithium with antipsychotics, the blood levels should generally be maintained below 1 meq/L, staff should be advised to observe and report the development of neurological symptoms, and lithium should be temporarily discontinued if they develop. The combination of antipsychotics and lithium in bipolar patients can also lead to troublesome somnambulism requiring dosage reduction.

Many patients who fail to improve when taking carbamazepine alone do so when lithium is added. This combination may — as with antipsychotics — increase the risk of lithium neurotoxicity.

ECT in Mania

The earlier reports of the use of ECT in mania showed that about two-thirds of the patients responded. More recently, in a retrospective study, 78% of patients treated with ECT had shown marked improvement compared to 62% on lithium. In a double-blind trial, ECT was superior to lithium during the first 8 weeks especially for severe mania and for mixed states. In some countries, clinicians reserve ECT for only the most severe and drug-resistant manic patients, whereas in other countries it is regarded as generally helpful in mania and used often.

The use of lithium during ECT is discussed above; neurotoxic complications have been reported. The use of ECT for patients on lithium has been associated with acute organic brain syndrome or prolonged confusional states, but a small retrospective case-control study did not find a higher frequency of adverse effects of ECT in patients on lithium.

In the United States, lithium is generally withheld prior to electroconvulsive therapy to reduce the risk of arrhythmia. The ECT Handbook advises stopping lithium 36 to 48 hours before ECT and holding it until after the final ECT treatment, to avoid delirium or prolonged seizures. Many clinicians withhold solely the dose of lithium immediately proceeding an ECT session, and some simply continue routine lithium dosing.


Selections from the book: “Handbook of Bipolar Disorder: Diagnosis and Therapeutic Approaches”, 2005.