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Psychiatric Emergencies in Bipolar and Related Disorders: Page 2 of 2

Psychiatric Emergencies in Bipolar and Related Disorders: Page 2 of 2

Published evidence for effectiveness in agitation and/or mania supports risperidone,33 olanzapine,34 ziprasidone,35,36 quetiapine,37 and aripiprazole.38 For rapid treatment, the availability of oral liquid or intramuscular forms is valuable (see Table 3).39,40

Clozapine may be effective in severe, impulsive aggression41; its clinical antiaggressive effects may be partially independent of its antipsychotic effects.42 Furthermore, clozapine is most effective as an antipsychotic in more aggressive patients in contrast to risperidone or olanzapine.43 Clozapine is not generally a feasible first treatment, however, and the dose cannot be rapidly escalated. The addition of clozapine at low to moderate dosages (average of 150 mg/d) is a valuable potential augmentation strategy for patients who do not experience adequate response to ongoing treatment44; however, because of the need for regular hematological and clinical monitoring, the institution of clozapine is not generally feasible in emergency settings.

Anticonvulsants. Anticonvulsants may work by altering the g-aminobutyric acid (GABA)-excitatory amino acid balance in favor of GABA by protecting against overstimulation, and—when aggression is associated with a seizure disorder or with the potential for alcohol or sedative withdrawal— by raising the convulsive threshold. Evidence has shown that valproate is effective as both an acute and long-term treatment, and it can be administered by rapid oral dose escalation or intravenously.

Valproate has been reported to be effective against impulsive aggression and/or hostility in patients with bipolar disorder45 or borderline personality disorder46 and in adolescents with aggression and labile mood.47,48

Anticonvulsants are generally considered to be suitable for subacute or long-term treatment, although rapid stabilization with intravenous valproic acid has been reported in severe agitation49 and catatonia.50 Rapid escalation of the dose of oral valproic acid can also bring about more rapid resolution of manic episodes.51

Other anticonvulsants, including phenytoin in violent prison inmates52 and carbamazepine in patients with head injuries,53 have been reported to be effective in reducing aggression or agitation but do not have an onset of action that is rapid enough to warrant emergency use. Gabapentin54 and lamotri- gine55,56 have been reported to cause disinhibition or behavioral activation in some patients, generally in those who have neurological disorders.

Sedatives. Benzodiazepines, generally considered to be the safest sedatives, may reduce agitation and behavioral problems associated with severe overarousal or anxiety.26 Benzodiazepines that are more lipid-soluble can have a relatively rapid onset of action. However, disinhibition can also occur with these agents, especially in patients who are older or who have an organic disorder,57 or in those who have a history of aggressive behavior.58 There is also cross-dependence between benzodiazepines and ethanol, leading to recommendations that benzodiazepines not be used in patients who abuse ethanol.59 Benzodiazepines may act synergistically in combination with antipsychotic agents, making it possible to use lower doses than would be required in using either agent alone.39,60

Benzodiazepines are potentially useful for acute treatment, alone with relatively mild agitation and in combination with antipsychotics in more severe agitation. Cognitive effects, tolerance, and potential for abuse limit the value of subacute or long-term treatment.

Antinoradrenergic agents. Norepinephrine may be involved in impulsivity or agitation. Drugs that block the binding or release of norepinephrine can be useful, generally as adjunctive treatment. They include clonidine61 and β-noradrenergic antagonists.62 Clonidine can be a useful treatment in opiate withdrawal.63 β-Blocking agents have been used both to reduce neurological adverse effects of antipsychotic drugs and to reduce aggressive behaviors. Nadolol was found to reduce extrapyramidal effects and aggressive behaviors relative to placebo.64 Pindolol was found to reduce aggression, as measured by the Overt Aggression Scale, but did not alter symptoms of psychosis.65

Transition to maintenance treatment. After patients' acute symptoms have improved, there can be several months during which their functional impairment is still substantial.22 When patients with bipolar disorder decompensate, clinicians should be alert to the possibility that they may be in this stage of illness and that a useful agent may have recently been discontinued too early or too rapidly.

Pharmacological agents for subacute and long-term management

Lithium66 and, perhaps to a lesser extent, serotonin enhancers, including SSRIs, 5-hydroxytryptamine (5HT) 1A agonists, and 5HT2 antagonists26,67 are useful for long-term treatment but are not generally part of emergency treatment because of their slower onset of action and the need for more extensive evaluation before beginning treatment. It may be feasible to start such treatment if a patient has already been taking 1 of these agents and the recent discontinuation is believed to have contributed to the current exacerbation of symptoms. Even then, acute symptoms that are severe enough to result in a psychiatric emergency will probably require other treatments.39 In bipolar disorder, psychosis, or other situations in which overstimulation is prominent, serotonin-enhancing drugs may cause activation or mood destabilization.23 Patients with bipolar disorder should, in essentially all cases, be receiving a mood stabilizer before any antidepressive agent is prescribed. It is somewhat disturbing that one study reported that 32% of patients with positive screens for bipolar disorder were taking an antidepressant alone.68

The decision to add a new long-term treatment should be made in consultation with the patient's regular physician (if available), and a definitive follow-up should be scheduled with the prescribing physician, a collaborator, or preferably, the patient's psychiatrist. Unfortunately, follow-up appointments to monitor or continue new treatment are unlikely to be kept by the patient.69

Combined treatment

Combinations of agents with different mechanisms may be more effective than treatment with single agents. The major classes of medications that are used in conjunction with antipsychotics are lithium, anticonvulsants, serotonin-enhancing drugs, and β-noradrenergic antagonists.

Combination therapy may take advantage of regulatory interactions between transmitter systems involved in agitation and impulsivity. For example, increased GABA function might reduce overstimulation.70 GABA interneurons also inhibit the firing of mesolimbic and mesocortical dopaminergic cells.71 Enhancement of GABA function, therefore, might interact synergistically with the dopaminergic receptor blockade in reducing severe agitation, psychosis, or impulsive aggression.71

Antipsychotic treatments have been combined with mood-stabilizing drugs. Lithium was shown to provide a modest benefit when combined with antipsychotic agents.72 Carbamazepine has been used as an adjunct in aggression associated with psychosis or severe agitation, but a critical review of studies that used the drug concluded that the evidence did not support its use, at least in part because of pharmacokinetic interactions.73 Valproate has the best documented results, including augmentation of response to haloperidol and to atypical antipsychotics in placebo-controlled trials.74 These results are consistent with synergistic effects of dopamine blockade and GABA enhancement.71

Sedatives, especially benzodiaze-pines, are commonly combined with antipsychotic medications. A recent study by Allen and associates39 found that physicians generally used conventional antipsychotic agents in combination with benzodiazepines but were more likely to use atypical antipsychotics without benzodiazepines.

Nonpharmacological management

Pharmacological and nonpharmacological strategies have synergistic roles in the management of aggressive behavior. Acute and long-term treatments have overlapping but different needs. Staff members must be consistent in communications, in setting limits on patient behavior, and in maintaining appropriate interpersonal boundaries. Patient outcome is influenced by interpersonal styles of nursing staff, with empathic, consistent styles of intervention having better outcome.75,76

The patient should have privacy and an appropriate level of environmental stimulation. In general, this means protection against excessive or variable stimulation. Acutely agitated patients were found to have better treatment outcome in settings in which individual attention was maximized and group interaction was reduced.76 Severe overstimulation can require seclusion and/or restraint, but caveats include medical complications such as hyperthermia and difficulty in monitoring the patient.27


Pharmacological treatments with rapid action can reduce aggression or impulsivity and normalize arousal by shifting the balance of amino acid neurotransmission away from excitatory transmission and toward inhibitory transmission (GABA), reducing dopaminergic activity, enhancing serotonergic function, and/or reducing or stabilizing noradren- ergic effects. Combinations of these approaches, such as GABA enhancement and dopaminergic blockade, may be optimal.

Optimal treatment also requires an appropriate environment, with protection against overstimulation and harm, consistent communication, and effective but empathic limit setting. The same principles apply across many psychiatric emergencies in bipolar disorder. They include empathy and respect for the patient and for his situation, assurance of safety, rapid assessment of medical and behavioral risk, use of all sources of information, treatment of problems that compromise safety and health, and establishment of a more definitive long-term plan.

Long-term success requires effective pharmacological and nonpharmacological treatment of underlying chronic or recurrent illnesses, combined when needed with behavioral strategies aimed at reducing aggressive or impulsive behaviors.



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