Mood stabilizer

Lithium, several (but not all) anticonvulsants, and most of the atypical antipsychotic medications are approved by the U.S. Food and Drug Administration (FDA) for the treatment of one of more phases of bipolar disorder. These medications are referred to as mood stabilizers, and they are the foundation of treatment for bipolar disorders. However, the skillful treatment of bipolar disorder requires not only the knowledge of how to prescribe one or more of these medications but also the understanding that some medications are preferred for one phase of the illness but not the other or for long-term use but not necessarily acute use. In this chapter, we first review the clinical use of lithium and the anticonvulsants that are definite or probable mood stabilizers. The general properties of atypical anti-psychotics are reviewed in Chapter 4. In this chapter, we expand on the use of these compounds for the treatment of bipolar disorder. Discussion of the treatment of each phase of bipolar disorder concludes the chapter. 

Lithium is a monovalent cation that inhibits several steps in phos-phoinositide metabolism, as well as many second and third messengers, including G proteins and protein kinases. Recent evidence suggests that lithium ultimately stimulates neurite growth, regeneration, and neurogenesis, which is likely related to its therapeutic effect (Coyle et al. 2003 Kim et al. 2004). 

Lithium has been proven effective for acute and prophylactic treatment of both manic and depressive episodes in patients with bipolar illness (American Psychiatric Association 2002). However, patients with rapid-cycling bipolar disorder (i.e., patients who experience four or more mood disorder episodes per year) have been reported to respond less well to lithium treatment (Dunner and Fieve 1974 Prien et al. 1984 Wehr et al. 1988). Lithium is also effective in preventing future depressive episodes in patients with recurrent unipolar depressive disorder (American Psychiatric Association 2002) and as an adjunct to antidepressant therapy in depressed patients whose illness is partially refractory to treatment with antidepressants alone (discussed in Chapter 2). Furthermore, hthium may be useful in maintaining remission of depressive disorders after electroconvulsive therapy (Coppen et al. 1981 Sackeim et al. 2001). Lithium also has been used effectively in some cases of aggression and behavioral dyscontrol. 

Lithium carbonate is completely absorbed by the gastrointestinal tract and reaches peak plasma levels in 1-2 hours. The elimination half-life is approximately 24 hours. Steady-state lithium levels are achieved in approximately 5 days. Therapeutic plasma levels range from 0.5 to 1.2 mEq/L. Lower plasma levels are associated with less troubling side effects, but levels of at least 0.8 mEq/L are often required in the treatment of acute manic episodes. Therefore, when intolerable side effects have not intervened, treatment of acute mania with lithium should not be considered a failure until plasma levels of 1.0-1.2 mEq/L have been reached and have been maintained for 2 weeks. As discussed at the end of this chapter (see Treatment of Mania or Mixed Episodes ), more severely ill patients may require combination treatment. 

Serum concentrations required for prophylaxis are not as well determined. The only controlled trial of patients randomly assigned to a low lithium level (0.4—0.6 mEq/L) compared with a standard- 

The use of lithium in psychiatry has varied historically. In the nineteenth century, lithium salts were employed in the treatment of anxiety, as well as gout and seizures. The importance of lithium s antimanic actions was indirectly discovered, in 1949, with observations that it produced a calming effect in animals. Human testing in agitated or manic patients followed, with encouraging results. However, lithium s use did not gain acceptance in American medicine until 1970, due to safety concerns 

Lithium is the lightest of the solid elements, is widely found in nature, and because of its chemical activity will combine with other ions to form lithium salts (Gennaro 1980). Lithium salts share some, but not all, properties of sodium and potassium. The two therapeutically available forms are lithium carbonate and lithium citrate (see figure 15-A). 

Note that the availability of the following products is subject to change by manufacturers. 

Lithium demonstrates a narrow therapeutic window—the therapeutic dose is very close to the toxic dose. (See also Therapeutic Index in appendix A.) Consequently, lithium is prescribed not only by dose, and stage of symptoms, but by concentration in the blood (see figure 15-B). Side effects are often indicative of blood level but not always. During acute states, daily doses of 1200 mg to 2400 mg of lithium are required, with most patients needing less after stabilization (600 to 1800 mg per day). Also, as the acute episode resolves, many patients will become more intolerant of side effects, necessitating a dosage reduction. The onset of action of lithium occurs in five to fourteen days, although full stabilization may take up to several months. 

Lithium produces a distinct continuum of side effects which range from relatively benign, transient symptoms to toxicity that can be fatal. The most significant side effects fall into the following categories. 

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Other agents are also used for the treatment of manic-depressive disorders based on preliminary clinical results (177). The antiepileptic carbamazepine [298-46-4] has been reported in some clinical studies to be therapeutically beneficial in mild-to-moderate manic depression. Carbamazepine treatment is used especially in bipolar patients intolerant to lithium or nonresponders. A majority of Hthium-resistant, rapidly cycling manic-depressive patients were reported in one study to improve on carbamazepine (178). Carbamazepine blocks noradrenaline reuptake and inhibits noradrenaline exocytosis. The main adverse events are those found commonly with antiepileptics, ie, vigilance problems, nystagmus, ataxia, and anemia, in addition to nausea, diarrhea, or constipation. Carbamazepine can be used in combination with lithium. Several clinical studies report that the calcium channel blocker verapamil [52-53-9] registered for angina pectoris and supraventricular arrhythmias, may also be effective in the treatment of acute mania. Its use as a mood stabilizer may be unrelated to its calcium-blocking properties. Verapamil also decreases the activity of several neurotransmitters. Severe manic depression is often treated with antipsychotics or benzodiazepine anxiolytics. 

There is, however, a unique risk in the bipolar form that antidepressant treatment may trigger a switch into mania. This may occur either as the natural outcome of recovery from depression or as a pharmacological effect of the drug. Particular antidepressants (the selective serotonin reuptake inhibitors) seem less liable to induce the switch into mania than other antidepressants or electroconvulsive therapy. Treatment for mania consists initially of antipsychotic medication, for instance the widely used haloperidol, often combined with other less specific sedative medication such as the benzodiazepines (lorazepam intramuscularly or diazepam orally). The manic state will usually begin to subside within hours and this improvement develops further over the next 2 weeks. If the patient remains disturbed with manic symptoms, additional treatment with a mood stabilizer may help. 

The first mood stabilizer was lithium (its antimanic action being discovered in 1948) more recently the anticonvulsant drugs carbamazepine and valproate have been found to be effective in acute mania. Unfortunately these mood stabilizers are only successful in controlling mania to a limited extent and few patients are well enough to leave hospital at the end of 3 weeks of treatment using these drugs as monotherapy. It is increasingly common for combination treatment to be advocated, in which an antipsychotic dmg is combined with lithium or an anticonvulsant. 

The mood stabilizers were so called because they prevent recurrences of mood swings in people with bipolar disorder. The evidence for this is best with lithium, but is based on smdies carried out more than 20 years ago. However, recent naturalistic surveys tend to find that lithium is far less useful in general clinical practice than in research settings. Many patients discontinue lithium... 

Sajatovic M, Gerhart C, Semple W (1997). Association between mood-stabilizing medication and mental health resource use in the management of acute mania. Psychiatr Serv 48, 1037M1. 

The primary treatment modality for manic episodes is mood-stabilizing agents, often combined with antipsychotic drugs. 

Optimize the dose of mood-stabilizing medication(s) before adding on benzodiazepines if psychotic features are present, add on antipsychotic ECT used for severe or treatment-resistant manic/mixed episodes or psychotic features... 

First, initiate and/or optimize mood-stabilizing medication lithium3 or valproate3 or atypical antipsychotic (e.g., olanzapine, quetiapine, risperidone)... 

Pharmacotherapy is the cornerstone of acute and maintenance treatment of bipolar disorder. Mood-stabilizing drugs are the usual first-choice treatments and include lithium, divalproex, carbamazepine, and lamotrigine. Atypical antipsychotics other than clozapine are also approved for treatment of acute mania. Lithium, lamotrigine, olanzapine, and aripiprazole are approved for maintenance therapy. Drugs used with less research support and without Food and Drug Administration (FDA) approval include topiramate and oxcarbazepine. Benzodiazepines are used adjunctively for mania. 

Mood-stabilizing drugs are considered the primary pharmacotherapy for relapse prevention. Olanzapine and aripiprazole are also approved for maintenance therapy. 

Increasing evidence shows an effect of lithium on suicidal behavior that is superior to other mood-stabilizing drugs.28 Lithium reduces the risk of deliberate self-harm or suicide by about 70%. 

Sprinkle capsule 15, 25 mg Atypical Antipsychotics FDA approved for use in bipolar disorder Aripiprazole Abilify Tablets 5, 10, 15, Dosage should be slowly increased to minimize adverse effects (e.g., 25 mg at bedtime for 1 week, then 25-50 mg/day increments at weekly intervals) 10-30 mg/day once daily acute treatment of mania or mixed episodes due to lack of efficacy used as an adjunctive agent with established mood stabilizers Use as monotherapy or in... 

It is common for lithium to be combined with other mood-stabilizing drugs or antipsychotic drugs, if necessary, in order to achieve more complete remission of symptoms. Studies indicate that monotherapy is often insufficient to reach this goal.17... 

Lithium and other mood-stabilizing drugs require baseline and routine laboratory monitoring to help determine medical appropriateness for initiation of therapy and monitoring of potential adverse effects. Guidelines for such monitoring are outlined in Table 36-6. 

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

Mechanism of Action The mechanism of action of carbamazepine is not well understood. It blocks ion channels and inhibits sustained repetitive neuronal excitation, but whether this explains its effect as a mood-stabilizing drug is not known.32... 

Conventional antipsychotic drugs such as chlorpromazine and haloperidol have long been used in the treatment of acute mania. More recently, atypical antipsychotic drugs including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasi-done have been approved for the treatment of bipolar mania or mixed mood episodes as monotherapy or in combination with mood-stabilizing drugs.25 Aripiprazole and olanzapine are also approved for maintenance therapy. The combination of olanzapine and fluoxetine is approved for treatment of bipolar depression. Quetiapine is approved for treatment of... 

Guidelines agree that when antidepressants must be used, they should be combined with a mood-stabilizing drug to reduce the risk of mood switch to hypomania or mania.17,41 The question of which antidepressant drugs are less likely to cause a mood switch is not resolved. Anecdotal reports suggested bupropion may be less likely to cause this effect, but systematic reviews have not supported this conclusion. Prevailing evidence recommends that tricyclic antidepressants be avoided.41,43... 

Duration of antidepressant therapy is also an unsettled question. It may be possible in some patients to prevent depressive relapse with a mood-stabilizing drug without maintenance antidepressant therapy following acute treatment with an antidepressant. If so, the risk of a mood switch with continued antidepressant therapy would be reduced. 

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