Lithium augmentation of antidepressants

Lithium augmentation of antidepressants, carbamazepine, lamotrigine, and valproate can improve response, but it may increase the risk of sedation, weight gain, GI complaints, and tremor. 

Hypothalamic-pituitary-adrenal axis function in bipolar disorder has been reviewed, but lithium was mentioned only in passing (617). Two studies (n = 25, n = 24), possibly reporting many of the same patients, showed that lithium augmentation of antidepressant-resistant unipolar depression increased hypothalamic-pituitary-adrenal axis activity, measured by the dexamethasone suppression test, either alone or combined with the corticotropin releasing hormone test (618,619). However, the tests did not distinguish between lithium responders and nonresponders. 

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... 

Morishita S, Arita S. Lithium augmentation of antidepressants in the treatment of protracted depression. Int Med J 2003 10 29-32. 

Austin LS, Arana GW, Melvin JA. Toxicity resulting from lithium augmentation of antidepressant treatment in elderly patients. J CUn Psychiatry (1990) 51,344-5. 

Heninger GR, Charney DS, Sternberg DE Lithium carbonate augmentation of antidepressant treatment an effective prescription for treatment-refractory depression. Arch Gen Psychiatry 40 1335-1342, 1983 Henry JA Overdose and safety with fluvoxamine. Int Clin Psychopharmacol 6 [suppl 3) 41-47, 1991... 

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. 

Joffe R, Levitt A, Bagby M, et al. Predictors of response to lithium and triiodothyronine augmentation of antidepressants in tricyclic non-responders. Br J Psychiatry 1993 163 574-578. 

Of 30 patients with major depressive disorder who had responded to lithium augmentation for antidepressant-resistant depression, 15 were switched to placebo over 1-7 days (454). Two became manic, and it was suggested... 

Nierenberg AA, Papakostas GI, Petersen J, Montoya HD, Worthington JJ, Tedlow J, Alpert JE, Fava M. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol 2003 23 92-5. 

Whether elderly patients taking lithium received proper monitoring was questioned in a case note audit of 91 patients, over 40% of whom had deviations from practice standards. These included absence of pretreatment laboratory tests, infrequent monitoring of serum lithium concentrations, lack of adequate adverse effects documentation, and the use of risky concomitant drugs (403). In a placebo-controlled study, there was poor tolerance of hthium augmentation of antidepressants in 76% (13/17) of elderly (mean age 70 years) patients at a mean serum concentration of 0.63 mmol/1, due to tremor and muscle twitches, cognitive disturbance, tiredness and sedation, and gastrointestinal upsets (404). 

Adding lithium. Coadministration of lithium is a proven method for enhancing the thymoleptic action of antidepressants in patients with depression (Heninger et al. 1983). Lithium has been hypothesized to potentiate antidepressant-induced increases in serotonin neurotransmission by enhancing presynaptic serotonin release in some brain regions (Blier and de Montigny 1992]. The success of lithium augmentation in depression and the hypothesized role of serotonin in OCD has prompted studies of the anti-OC efficacy of this approach. 

Kakigi T, Tanimoto K, Maeda K The effect of various antidepressants on the concentration of somatostatin in the rat brain. Jpn J Psychiatry Neurol 44 145, 1990 Kalasapudi VD, Sheftel G, Divish MM, et al Lithium augments fos protoonocogene expression in PC 12 pheochromocytoma cells imphcations for therapeutic action of lithium. Brain Res 521 47-54, 1990... 

Joffe RT, Singer W, Levitt AJ, et al A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Arch Gen Psychiatry 50 387-393, 1993... 

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 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 most common is augmentation is with the mood stabiliser lithium carbonate. Indeed, lithium may be effective as monotherapy for depression but is not preferred because of its adverse effect profile and need for plasma concentration monitoring. Its prescription in combination with antidepressants that have failed to produce remission is more usual and evidence suggests that up to 50% of patients who have not responded to standard antidepressants can respond after lithium augmentation. Addition of lithium requires careful titration of the plasma concentration up to the therapeutic range, with periodic checks thereafter and monitoring for toxicity (see p. 389). 

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

Lithium augmentation may be used in depression (p. 375). Lithium is given in combination with aTCA, SSRI or novel antidepressant, usually when the symptoms have proved resistant to adequate trials of two or more antidepressants. 

In addition, it exerts beneficial effects in many disorders as an adjuvant to other treatment modalities. Such effects are apparent only if it is administered to an already pharmacologically treated patient. For example, in unresponsive major depressive disorder, the co-administration of lithium to an ongoing antidepressant treatment increases the response rate by up to 50%. In most cases, the response to lithium augmentation is either considerable or not at all ( all-or-none phenomenon). Some (currently not convincing) results have also been reported in unipolar depression, bulimia nervosa, and attention deficit hyperactivity disorder (ADHD). Lithium also exerts antiaggressive effects in conduct disorder, independent of any mood disorder, and can reduce behavioral dyscontrol and self-mutilation in mentally retarded patients. One of the most striking effects of lithium is its antisuicidal effect in patients who suffer from bipolar and unipolar depressive disorder irrespective of comorbid axis I disorder. ... 

Lamotrigine is effective for the maintenance treatment of bipolar I disorder in adults. It has both antidepressant and mood-stabilizing effects, and it may have augmenting properties when combined with lithium or valproate. It has low rates of switching patients to mania. Although it is less effective for acute mania compared to lithium and valproate, it may be beneficial for the maintenance therapy of treatment-resistant bipolar I and II disorders, rapidcycling, and mixed states. It is often used for bipolar II 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. 

Miscellaneous Medications. A variety of other medications have also been used to treat depression. They have mainly been used together with an antidepressant to augment or boost its effectiveness. These augmenting medications include lithium, tri-iodothyronine (T3), buspirone, pindolol, estrogen, and anticonvulsants. 

When the residual depression is mild to moderate, then the risks of using lithium are probably not warranted. A less aggressive approach using a safer but less proven augmenting medication is best. The alternatives include adding T3, buspirone, pindolol, a second antidepressant, a stimulant, estrogen, or an anticonvulsant. 

Bauer, M., Bschor, T, Kunz, D., Berghoefer, A., Strohle, A., and Muller-Oerlinghausen, B. (2000) Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation tteatment of unipolar major depression. Am J Psychiatry 157 1429-1435. 

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