Lithium treatment-resistant depression

Optimize the dose of mood stabilizing medication(s) before adding on lithium, lamotrigine, or antidepressant (e.g., bupropion or an SSRI) if psychotic features are present, add on an antipsychotic ECT used for severe or treatment-resistant depressive episodes or for psychosis or catatonia... 

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. 

Post RM, Kramlinger KG. The addition of lithium to carbamazepine. Antidepressant efficacy in treatment-resistant depression. Arch Gen Psychiatry 1989 46 794-800. 

Bschor T, Lewitzka U, Sasse J, et al. Lithium augmentation in treatment-resistant depression clinical evidence, serotonergic and endocrine mechanisms. Pharmacopsychiatry. 2003 36(suppl 3) S230—S234. 

In 12 healthy volunteers, there were no clinically significant alterations in blood concentrations of lithium or nefazodone and its metabolites when the drugs were coadministered (587). The addition of lithium for 6 weeks to nefazodone in 14 treatment-resistant patients produced no serious adverse effects and no dropouts (588). Lithium augmentation of nefazodone in 13 treatment-resistant depressed patients was associated with a variety of annoying adverse effects, but none led to treatment withdrawal (589). 

Lithium is also used to augment the action of antidepressants in treatment-resistant depression (see p. 375). 

Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression metaanalysis of placebo-controlled studies. J Clin Psychopharmacol 1999 19 427-34... 

A study in 14 treatment-resistant depressed patients aged between 61 and 82 found that 7 showed eomplete improvement and 3 showed partial improvement, 3 to 21 days after lithium was added to treatment with the tricyclic or related antidepressants. Lithium adverse effects occurred in 6 patients 4 of whom stopped lithium as a result. One of them was successfully restarted at a lower dose. Tremor was the most frequent adverse effect, and reversible neurotoxicity with a stroke-like syndrome was the most severe. The antidepressants used were amitriptyline, doxepin, maprotiline and trazodone. A meta-analysis of 9 studies on the acute treatment of unipolar or bipolar depression indicated that the combined use of a mood stabiliser (lithium in 6 studies) and a tricyclic antidepressant was associated with an increased risk of switches into (hypo)mania, when compared with a mood stabiliser alone. It was suggested that monotherapy with a mood stabiliser should be tried to see if it is effective, before adding an antidepressant. Tricyclics were considered to be second-line antidepressants, with SSRIs the preferred choice. ... 

Laffeiman J, Solomon K, Ruskin P. Lithium augmentation for treatment-resistant depression in the elderly. J Geriatr Psychiatry Neurol (1988) 1,49-52. 

Unipolar depression In an open randomized study in 46 subjects with unipolar depression examined over 3 weeks lithium augmented mirtazapine successfully (n — 13), but carbamazepine was ineffective when added to mirtazapine (n = 10) compared with mirtazapine alone (n = 23) [14 f. Lithium augmentation in treatment-resistant depression remains among the best studied successful interventions [15 f. 

Lithium Lithium augmentation of standard antidepressants has been reported to significantly benefit previously treatment-resistant and psychotic depressions, particularly in bipolar patients ( 371, 372). There is substantial case report literature reporting that many patients have benefited when lithium was added to ongoing TCA therapy. Often these results occurred rapidly, sometimes with low doses of lithium. Although the results of controlled trials have not been as dramatic, they still support this approach, which should be seriously considered for treatment-resistant major depression. 

Post and Kramlinger (386) have also suggested that lithium added to carbamazepine may be useful in treatment-resistant mood-disordered patients. One possible basis for this approach is that carbamazepine, which has a tricyclic ring structure similar to imipramine, may sensitize postsynaptic serotonin receptors in a similar way to standard drugs such as imipramine. A mood stabilizer (e.g., lithium, valproate, carbamazepine) plus antidepressant may benefit some rapid cycling or mixed bipolar patients, attenuating the propensity to switch from mania to depression. 

Lithium may also be used in the depressive phase of a bipolar disorder, alone or to augment other antidepressants, and in combination with VPA or CBZ for more treatment-resistant mania (see also Chapter 7). 

The mood stabilizer lithium was developed as the first treatment for bipolar disorder. It has definitely modified the long-term outcome of bipolar disorder because it not only treats acute episodes of mania, but it is the first psychotropic drug proven to have a prophylactic effect in preventing future episodes of illness. Lithium even treats depression in bipolar patients, although it is not so clear that it is a powerful antidepressant for unipolar depression. Nevertheless, it is used to augment antidepressants for treating resistant cases of unipolar depression. 

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 addition of lithium to other drug therapy has been studied in 92 patients with treatment-resistant major depression taking nortriptyline (97). Non-responders to nortriptyline (n = 35) were randomized to added lithium or placebo there was no significant difference. 

Lithium augmentation of antidepressants is a well-established treatment for resistant depression and is usually well tolerated with all classes of antidepressants, although there have been a few reports of the serotonin syndrome with SSRIs (581). It is possible that shared adverse effects could be magnified by combining lithium with various antidepressants (for example tremor, weight... 

Lithium is one of the most useful adjunctive agents to augment antidepressants for treatment-resistant unipolar depression... 

By the late 1960s, lithium became the drug of choice for treatment of manic depression. Today, lithium is one of the most reliable drugs for lowering the manic high of bipolar depression. Lithium has proved an efficient treatment for mania with a response rate of 60 percent to 80 percent in classic euphoric mania cases. It is also sometimes used in treatment-resistant unipolar depression. Lithium is commonly taken as a salt, lithium carbonate, and is sold under a variety of brand names (Carbolith, Cibalith-S, Duralith, Eskalith , Lithane, Lithizine, Lithobid). Not only is it unique for calming the manic phase of depression, its chemical structure and properties are like no other antidepressant. 

It is indicated in the treatment of depressive episodes associated with bipolar disorder. A combination of an antipsychotic drug and an antidepressant may be useful in some cases, especially in depressed psychotic patients, or in cases of agitated major depression with psychotic features. The first combination antipsychotic/antidepressant (olanza-pine/fluoxetine Symbyax) was recently FDA approved in the United States for treatment of depressive episodes associated with bipolar disorder. However, antidepressants and stimulants are unlikely to reduce apathy and withdrawal in schizophrenia, and they may induce clinical worsening in some cases. Adjunctive addition of lithium or an antimanic anticonvulsant, such as carbamazepine, may add benefit in some psychotic patients with prominent affective, aggressive, or resistant symptoms. 

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. 

Fava M, Rosenbaum JF, McGrath PJ, et al. Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression A double-blind, controlled study. Am J Psychiatry 1994 151 1372-1374. 

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