Antipsychotic drugs, lithium used

Lithium was the first agent shown to be useful in the treatment of the manic phase of bipolar disorder that was not also an antipsychotic drug. Lithium... 

Although lithium is not a true antipsychotic drug, it is considered with the antipsychotics because of its use in regulating the severe fluctuations of the manic phase of bipolar disorder (a psychiatric disorder characterized by severe mood swings of extreme hyperactivity to depression). During the manic phase, the person experiences altered thought processes, which can lead to bizarre delusions. The drug diminishes the frequency and intensity of hyperactive (manic) episodes. 

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... 

Introduced in clinical practice in the 1960s, lithium was the first mood stabilizer to be used in China. This was followed by carbamazepine and sodium valproate. For many years, these were the only treatment options available as mood stabilizers. Although lamotrigine was approved for maintenance treatment of bipolar I disorder in 2003 by FDA (Food and Drug Administration) in the USA, this indication has not yet been approved by the Chinese authorities. At present, only one atypical antipsychotic drug, risperidone, has been approved for treating acute mania (February 2005 by SFDA [State Food and Drug Administration]) in China (see Table 6.1). 

Lithium remains the treatment of choice for bipolar patients who experience classic euphoric episodes of mania. Current evidence suggests that those with mixed episodes or rapid cycling episodes respond preferably to anticonvulsants or atypical antipsychotic drugs. In addition to its use as a mood stabilizer, lithium is effective in converting unipolar antidepressant nonresponders to responders. Finally, lithium may also be an effective treatment for patients with clnster headaches. 

Antipsychotic drugs are also indicated for schizoaffective disorders, which share characteristics of both schizophrenia and affective disorders. No fundamental difference between these two diagnoses has been reliably demonstrated. They are part of a continuum with bipolar psychotic disorder. The psychotic aspects of the illness require treatment with antipsychotic drugs, which may be used with other drugs such as antidepressants, lithium, or valproic acid. The manic phase in bipolar affective disorder often requires treatment with antipsychotic agents, although lithium or valproic acid supplemented with high-potency benzodiazepines (eg, lorazepam or clonazepam) may suffice in milder cases. Recent controlled trials support the efficacy of monotherapy with atypical antipsychotics in the acute phase (up to 4 weeks) of mania, and olanzapine and quetiapine has been approved for this indication. 

Until recently, lithium carbonate was the universally preferred treatment for bipolar disorder, especially in the manic phase. With the approval of valproate, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone for this indication, a smaller percentage of bipolar patients now receive lithium. This trend is reinforced by the slow onset of action of lithium, which has often been supplemented with concurrent use of antipsychotic drugs or potent benzodiazepines in severely manic patients. The overall success rate for achieving remission from the manic phase of bipolar disorder can be as high as 80% but lower among patients who require hospitalization. A similar situation applies to maintenance treatment, which is about 60% effective overall but less in severely ill patients. These considerations have led to increased use of combined treatment in severe cases. After mania is controlled, the antipsychotic drug may be stopped and benzodiazepines and lithium continued as maintenance therapy. 

The prevalence of overweight (BMI 20 or more) and obesity (BMI 30 or more) has been evaluated in 89 euthy-mic bipolar patients and 445 age- and sex-matched controls (693). The bipolar women were more overweight and more obese than the controls and the bipolar men were more obese but not more overweight. Obesity was clearly related to antipsychotic drug use and less so to lithium and anticonvulsants (but patients taking lithium alone had an obesity rate 1.5 times that of the general population). 

The tertiary members of these classes (Figure 8-2) are often used for their effects on the eye or the central nervous system. Many antihistaminic (see Chapter 16 Histamine, Serotonin, the Ergot Alkaloids), antipsychotic (see Chapter 29 Antipsychotic Agents Lithium), and antidepressant (see Chapter 30 Antidepressant Agents) drugs have similar structures and, predictably, significant antimuscarinic effects. 

Schizoaffective disorders are characterized by a mixture of schizophrenic symptoms and altered affect in the form of depression or excitement. Antipsychotic drugs alone or combined with lithium are used in the excited as well as in the maintenance phases clozapine may be particularly effective. Various antidepressants are added if depression is present, but none has been adequately studied in this condition. 

Lithium is an alkaline earth element that is used medicinally in the form of salts such as lithium chloride and lithium carbonate. Its main use is in the prevention or attenuation of recurrent episodes of mania and depression in individuals with bipolar mood disorder (manic depression). Lithium also has clearly established antima-nic activity, although its relatively slow onset of action often necessitates the use of ancillary drugs, such as antipsychotic drugs and/or benzodiazepines, at the start of therapy. If lithium alone is ineffective for recurrent bipolar mood disorder, combining it or replacing it with car-bamazepine or valproate may be of value reports with lamotrigine and olanzapine are also encouraging. 

In a study of 1230 patients with initially unexplained cardiomyopathies, lithium was implicated in one case (114). Using a data-based mining Bayesian statistical approach to the WHO database of adverse reactions to examine antipsychotic drugs and heart muscle disorders, a significant association was found between lithium and cardiomyopathy, but not myocarditis (146). The authors acknowledged that further study is needed to determine if the association is causal. 

Occasionally, long-term use of lithium is associated with cogwheel rigidity and a parkinsonian tremor (189). More often than not, concurrent or past treatment with an antipsychotic drug is involved. In a review of SSRI-induced extrapyramidal adverse effects, lithium was listed, but not discussed, as a possible risk factor (190). A review of drug-induced parkinsonism provided references to case reports of lithium s occasionally inducing or exacerbating parkinsonism (191). 

The adverse effects of lithium in elderly patients include cognitive status worsening, tremor, and hypothyroidism. The authors suggested that divalproex is also useful in elderly patients with mania and that concentrations of divalproex in the elderly are similar to those useful for the treatment of mania in younger patients. They noted that carbamazepine should be considered a second-line treatment for mania in the elderly. A partial response would warrant the addition of an atypical antipsychotic drug. For bipolar depression, they recommended lithium in combination with an antidepressant, such as an SSRI. They also noted that lamotrigine may be useful for bipolar depression. Electroconvulsive therapy (ECT) may also be useful, but there have been no comparisons of ECT and pharmacotherapy in elderly patients with bipolar depression. 

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