Lithium bipolar depression

Treatment of depressive episodes in bipolar disorder patients presents a particular challenge because of the risk of a pharmacologic mood switch to mania, although there is not complete agreement about such risk. Treatment guidelines suggest lithium or lamotrigine as first-line therapy.17,41 Olanzapine has also demonstrated efficacy in treatment of bipolar depression, and quetiapine is under review for approval of treatment of bipolar depression.42 When these fail, efficacy data support use of antidepressants. 

Lithium, divalproex sodium (valproate), aripiprazole, olanzapine, que-tiapine, risperidone, and ziprasidone are currently approved by the FDA for treatment of acute mania in bipolar disorder. Lithium, olanzapine, and lamotrigine are approved for maintenance treatment of bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar depression. 

Use standard therapeutic serum concentration ranges if clinically indicated if partial response or breakthrough episode, adjust dose to achieve higher serum concentrations without causing intolerable adverse effects valproate is preferred over lithium for mixed episodes and rapid cycling lithium and/or lamotrigine is preferred over valproate for bipolar depression. 

Bipolar depression Rapid cycling Poor lithium response Secondary mania Rapid cycling Poor lithium response... 

Although there are continuation and maintenance guidelines for the use of antidepressants for unipolar depression, it is not clear how long a patient with bipolar depression should be treated with these medications. Rates of recurrence of bipolar depression of approximately 60% have been observed in patients taking adequate doses of lithium, alone or in combination with imipramine (APA, 1994b). As the TCAs have not been shown to be efficacious for youth with... 

Patients whose first episodes of mania or bipolar depression occur between ages 30 to 60 years appear to have clearer episodes of mood disorder, have mania characterized by euphoria and irritability (rather than irritability alone), and be less likely to develop substance addiction (though they may engage in substance abuse as part of their acute episodes). Although psychosis occurs frequently and can be severe, in such late-onset cases confusion with other disorders is usually not a problem. Finally, this more classical presentation is generally responsive to lithium (Carlson, 2000). 

The treatment of the major depressive disorders such as unipolar and bipolar depressions was initially considered to be uniform, ffowever, with psychopharmacological advances, it has been demonstrated that the patients with bipolar depression may be partially responsive, at least prophylactically responsive, to lithium therapy, whereas the patients with unipolar depression are not as responsive (Abou-Saleh 1992). In addition, the treatment of depression may contribute through serendipity to the confirmation of a subgroup of patients with a bipolar disorder referred to as bipolar II. These patients, following treatment with antidepressants, will switch over to a hypomanic or fully manic phase resulting from pharmacological mechanisms. Thus, another subgroup of the bipolar disorder may be identified in the future. 

In contrast with studies of the treatment of acute mania, studies of lithium in bipolar depression are less common. Initially, Cade (1949) reported that lithium had no efficacy in the treatment of depression, although this opinion was reversed by the results of several open trials and finally a controlled study by Fieve et al. in 1968. Subsequently, eight placebo-controlled trials have been... 

In contrast with lithium, there are no controlled trials of valproate in the treatment of bipolar depression. Three uncontrolled reports (Hayes 1989 ... 

Beckmann H, St-Laurent J, Goodwin FK The effect of lithium on urinary MHPG in unipolar and bipolar depressed patients. Psychopharmacologia 42 277-282, 1975 Beersma DGM, van den Hoofdakker RH Can non-REM sleep be depressogenic J Affect Disord 24 101-108, 1992... 

Dubovsky SL, Lee C, Christiano J, et al Elevated platelet intracellular calcium concentration in bipolar depression. Biol Psychiatry 29 441-450, 1991a Dubovsky SL, Lee C, Christiano J, et al Lithium lowers platelet intracellular ion concentration in bipolar patients. Lithium 2 167-174, 1991b Dubovsky SL, Murphy J, Thomas M, et al Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients. Am J Psychiatry 149 118-120, 1992a... 

Goodwin FK, Murphy DL, Dunner DL, et al Dthium response in unipolar versus bipolar depression. Am J Psychiatry 129 76-79, 1972 Goodwin GM, DeSouza RJ, Wood AJ, et al TJie enhancement by lithium of the 5-HTlA mediated serotonin syndrome produced by 8-OH-DPAT in the rat evidence for a post-synaptic mechanism. Psychopharmacology 90 488-493, 1986a Goodwin GM, DeSouza RJ, Wood AJ, et al Lithium decreases 5-HTlA and 5-HT2 receptor and alpha-2 adrenoceptor mediated function in mice. Psychopharmacology 90 482-487, 1986b... 

Bipolar depression Lithium, lamotrigine, olanzapine-fluoxetine combination... 

A common mistake is to treat bipolar depression in the same manner that one treats unipolar depression, overlooking the need for a mood stabilizer. In bipolar depression, the first pharmacological intervention should be to start or optimize treatment with a mood stabilizer rather than to start administering an antidepressant medication. In addition, thyroid function should be evaluated, particularly if the patient is taking lithium. Subclinical hypothyroidism, manifested as an increased thyroid-stimulating hormone level and normal triiodothyronine and thyroxine levels, may present as depression in affectively predisposed individuals. In such cases, the addition of thyroid hormones may be beneficial, even if there is no other evidence of hypothyroidism. 

Lithium, lamotrigine, and olanzapine-fluoxetine combination therapy are first-line treatments for bipolar depression. The response... 

Results of crossover studies indicate that lithium is efficacious in treating acute depression in bipolar subjects unequivocally (36%, 29/80) and partially (43%. 34/80). respectively (Xomberg and Pope, 1993 Keck and McElroy, 2002). Various antidepressants have shown variable rates of efficacy in the treatment of acute bipolar depression, i.e. desipramine (50%), maprotiline (67%), imipra-mine (40 60%), tranylcypromine (87%), moclobemide (53%) and fluoxetine (60%) (Keck and McElroy, 2002). Among the anticonvulsants, valproic add and lamotrigine appear to have some potential efficacy in the treatment of acute bipolar depression (Calabrese et al., 1992, 1999 Fatemi et al., 1997). 

Lithium has been found to be superior to placebo, particularly as an acute treatment for the depressed phase of a bipolar disorder (. Jable 7-13). Mendels et al. (195) reviewed and Souza and Goodwin (196) statistically combined the data from many of the same trials. Their results also indicate that the marginal evidence for the acute antidepressant effect of lithium was in the bipolar depressed patient group. 

In bipolar depressed patients, lithium (with or without concurrent antidepressants) is the maintenance treatment of choice, with divalproex (DVPX) or carbamazepine as potential alternatives (see also Chapter 10, Maintenance/Prophylaxis ). Maintenance lithium has also been shown to prevent relapse in recurrent unipolar depression (Table 7-22). 

ECT should be considered for more severe forms of depression (e.g., those associated with melancholic and psychotic features, particularly when the patient exhibits an increased risk for self-injurious behavior) or when there is a past, well-documented history of nonresponse or intolerance to pharmacological intervention. Limited data indicate that bipolar depressed patients may be at risk for a switch to mania when given a standard TCA. A mood stabilizer alone (i.e., lithium, valproate, carbamazepine, lamotrigine), or in combination with an antidepressant, may be the strategy of choice in these patients. Some elderly patients and those with acquired immunodeficiency syndrome may also benefit from low doses of a psychostimulant only (e.g., methylphenidate) (see also Chapter 14, The HIV-Infected Patient ). Fig. 7-1 summarizes the strategy for a patient whose depressive episode is insufficiently responsive to standard therapies. 

Another group of mood-stabilizing drugs that are also anticonvulsant agents have become more widely used than lithium. These include carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by FDA for the treatment of manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for the treatment of bipolar depression. 

There are a few surprising medical uses among the alkali and alkaline earth metals. Lithium combined with chlorine has been used for decades to treat a form of depression called bipolar disorder. Scientists are not exactly sure how lithium affects depression, but they think it may somehow change chemical messages in the brain. Doctors use barium, one of the heaviest alkaline earth metals, to get a better look at the stomach and intestines. They give their patients a drink called barium sulfate that travels to the gut. Bariums 56 electrons absorb X-rays and light up the stomach and intestines to reveal ulcers and other problems. 

The addition of lithium in treating major depressive disorder in patients unresponsive to antidepressant drugs has been discussed, and it has been noted that about 50% of patients respond to lithium augmentation in 2 1 weeks (71), while others have pointed to the absence of controlled data for this treatment in bipolar depression, while nevertheless recommending its use (72). In summary, there are data that support the use of lithium augmentation for treatment-resistant unipolar major depression. However, the data are not robust and are based on only a few hundred patients. Placebo-controlled studies of lithium augmentation for treatment-resistant bipolar depression are lacking (73). 

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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