Lithium combined with antipsychotics

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. 

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. 

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... 

Clonazepam. Case reports and one small double-blind study indicate that oral clonazepam may be useful for psychotic agitation when combined with lithium or an antipsychotic (see also the section Management of an Acute Manic Episode in Chapter 10) ( j,7.0, 175). 

In psychotic manic episodes, lower doses of antipsychotic in combination with lithium may be as effective as higher doses and perhaps diminish the possibility of an NMS recurrence (155). 

Clonazepam. Clonazepam is marketed primarily for petit mal variant, myoclonic, and akinetic seizures. It also has had wide psychiatric application, including the treatment of acute mania or other agitated psychotic conditions, usually in combination with lithium or antipsychotics. The literature on clonazepam s efficacy for acute mania is based on the work of Chouinard (120) and coworkers who compared this agent with placebo or standard treatments for acute mania. As noted earlier, however, another group from Montreal found that comparable doses of lorazepam were more effective than clonazepam for acute mania (119). 

Typical doses of clonazepam have been in the range of 2 to 16 mg/day given on a once or twice per day schedule due to its longer half-life. A major advantage of this anticonvulsant is its relative lack of adverse effects and freedom from laboratory monitoring in comparison with CBZ and VPA. Clonazepam may be more useful when combined with lithium or CBZ rather than as a specific antimanic agent, perhaps supplanting the need for antipsychotics. In this sense, it can be viewed as a behavioral suppressor, rather than a true mood stabilizer (121). 

Various combinations of mood stabilizers and antipsychotics may then be considered, always in a stepwise strategy. Although clozapine may be combined with lithium and/or VPA, we caution against the combined use of clozapine plus CBZ, given the former s propensity to induce agranulocytosis and the latter s ability to suppress bone marrow production. 

Schizoaffective disorder, another condition with an affective component characterized by a mixture of schizophrenic symptoms and depression or excitement, is treated with antipsychotic drugs alone or combined with lithium. Various antidepressants are added if depression is present. 

Renal clearance of lithium is reduced about 25% by diuretics (eg, thiazides), and doses may need to be reduced by a similar amount. A similar reduction in lithium clearance has been noted with several of the newer nonsteroidal anti-inflammatory drugs that block synthesis of prostaglandins. This interaction has not been reported for either aspirin or acetaminophen. All neuroleptics tested to date, with the possible exception of clozapine and the newer atypical antipsychotics, may produce more severe extrapyramidal syndromes when combined with lithium. 

During 2004 a number of clinical trials were reported involving acute and maintenance studies of lithium, mostly either comparing new atypical antipsychotic drugs with lithium in bipolar disorder or in combined treatment studies. Of the relatively few studies of the adverse effects of lithium, most clustered in the areas of cardiovascular effects and issues regarding lithium toxicity. 

Although data have suggested that amfebutamone has approximately the same seizure potential as the tricyclic compounds (SEDA-8, 30) (584), the manufacturers reported an increased risk of seizures in patients taking over 600 mg/day in combination with lithium or antipsychotic drugs (SEDA-10, 20) (585). 

Works well in combination with lithium and/or atypical antipsychotics... 

Olanzapine is an antipsychotic that controls psychotic symptoms throngh antagonism of selected dopamine and serotonin receptors in the central nervons system (CNS). It is indicated in the treatment of schizophrenia (oral) shortterm treatment of acnte mixed or manic episodes with bipolar I disorder (oral) in combination with lithium or valproate, for short-term treatment of acnte episodes associated with bipolar 1 disorder (oral) and treatment of agitation associated with schizophrenia and bipolar I mania (IM). 

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... 

The combination of carbamazepine with lithium, valproate, and antipsychotics is often used for manic episodes in treatment-resistant patients. 

Alternatively, the current antidepressant may be augmented (potentiated) by the addition of another agent (e.g., lithium, T3), or an atypical antipsychotic (e.g., risperidone). Risperidone has been shown to be effective in combination with fluvoxamine, paroxetine, or citalopram in treatment-resistant depression. Olanzapine and fluoxetine have been found to be safe and effective in treatment-resistant depression. 

Aggravation of the extrapyramidal effects of antipsychotic agents have been described and it has been reported that the use of lithium in combination with haloperidol may result in irreversible neurological toxicity. Lithium can increase the hypothyroid effects of antithyroid agents or iodides. 

Neurotoxic reactions have been periodically reported with lithium alone or in combination with antipsychotics, CBZ, verapamil, or methyidopa, with the elderly probably at much greater risk for such events (Table 10-21). Although such drug combinations are often necessary and usually well tolerated, common clinical sense dictates that only the minimally effective doses be prescribed. It is also advised that patients carry or wear some form of identification indicating that they are receiving... 

The question of increased neurotoxic reactions with the combination of lithium and an antipsychotic (especially haloperidol) has been vigorously debated since the report of Cohen and Cohen (346, 347, 348 and 349). Possible explanations have included the following ... 

FIGURE 7—35. Combination treatments for bipolar disorder (bipolar combos). Combination drug treatment is the rule rather than the exception for patients with bipolar disorder. It is best to attempt monotherapy, however, with first-line lithium or valproic acid, with second-line atypical antipsychotics, or with third-line anticonvulsant mood stabilizers. A very common situation in acute treatment of the manic phase of bipolar disorder is to treat with both a mood stabilizer and an atypical antipsychotic (atypical combo). Agitated patients may require intermittent doses of sedating benzodiazepines (benzo assault weapon), whereas patients out of control may require intermittent doses of tranquil-izing neuroleptics (neuroleptic nuclear weapon). For maintenance treatment, patients often require combinations of two mood stabilizers (mood stabilizer combo) or a mood stabilizer with an atypical antipsychotic (atypical combo). For patients who have depressive episodes despite mood stabilizer or atypical combos, antidepressants may be required (antidepressant combo). However, antidepressants may also decompensate patients into overt mania, rapid cycling states, or mixed states of mania and depression. Thus, antidepressant combos are used cautiously. 

The program is straightforward in its call to start drugging children in the absence of any scientific basis In the absence of treatment data, treatment of childhood bipolar illness is modeled on that of adults. Even if the child shows no signs of psychosis, the most toxic adult drugs are recommended For non-psychotic children, in descending order, treatment should be tried with lithium, divalproex, atypical antipsychotic, combining any of these approaches, and other anticonvulsants plus atypical antipsychotics or conventional antipsychotic. ... 

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. 

The risk of extrapyramidal adverse effects may be increased when lithium is combined with antipsychotic drugs. 

Useful In combination with atypical antipsychotics and/or lithium for acute mania... 

Indications and use. Lithium carbonate is effective treatment in > 75% of episodes of acute mania or hypomania. Because its therapeutic action takes 2-3 weeks to develop, lithium is generally used in combination with a benzodiazepine such as lorazepam or diazepam (or with an antipsychotic agent where there are also psychotic features). 

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