Depression lamotrigine

Depression is a common problem in patients with epilepsy, with approximately 30% having symptoms of major depression at some point.34 Patients with epilepsy should be routinely assessed for signs of depression, and treatment should be initiated if necessary. Certain AEDs may exacerbate depression, for example levetirac-etam and phenytoin. Other AEDs (e.g., lamotrigine, carba-mazepine, and oxcarbazepine) maybe useful in treating depression. Changes in mood can be precipitated by addition or discontinuation of an AED. If treatment for depression is necessary, caution should be exercised in choosing an agent that does not increase seizure frequency and does not interact with AEDs. 

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... 

Lamotrigine is not approved for the acute treatment of depression, and the dose must be started low and slowly titrated up to decrease adverse effects if used for maintenance therapy of bipolar I disorder. A drug interaction and a severe dermatologic rash may occur when lamotrigine is combined with valproate (i.e., lamotrigine doses must be halved from standard dosing titration). 

Lamotrigine is effective for the maintenance treatment of bipolar disorder. It is more effective for depression relapse prevention than for mania relapse. Its primary limitation as an acute treatment is the time required for titration to an effective dosage. In addition to maintenance monotherapy, it is sometimes used in combination with lithium or divalproex, although combination with divalproex increases the risk of rash, and lamotrigine dosage adjustment is required.37... 

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. 

Turning to the pharmacotherapy for mania, for decades lithium was the only effective drug treatment. More recently, a number of antiepileptic drugs including carba maze pine, lamotrigine and valproate have been shown to also act as mood stabilisers and are becoming established for the treatment and prophylaxis of both unipolar mania and bipolar manic depressive disorders. 

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. 

Lamotrigine is approved for the maintenance treatment of bipolar I disorder. It has been used as monotherapy or add-on therapy for refractory 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. 

Lamotngine (Lamictal). Lamotrigine, another anticonvulsant used to treat BPAD, is currently FDA approved for the prevention of both depressive and manic episodes during BPAD maintenance therapy. This represents a shift in the paradigms for BPAD therapy, as medications used to treat acute episodes have also typically been used for antimanic prophylaxis. Lamotrigine is not effective in the acute treatment of mania but has become for many the drug of choice for bipolar depression as well as for prevention of subsequent mood episodes of either polarity. 

In a recent pilot study, 16 out of 22 (72%) adolescents with BD treated with additional lamotrigine during their depressed phase responded to treatment by the end of week 4 this suggests that lamotrigine might be useful in adolescent bipolar depression. (Kusumakar and Yathan, 1997). 

Bowden, C.L., Mitchell, P., and Suppes, T. (1999) Lamotrigine in the treatment of bipolar depression. Eur Neuropsychopharmacol 9 (Suppl 4) S113-S117. 

Kusumakar, V. and Yatham, L.N. (1997) An open study of lamotrigine in refractory bipolar depression. Psychiatry Res 72 145-148. 

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

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

Calabrese JR, Bowden CL, Sachs GS, et al A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Lamictal 605 Study Group. J Clin Psychiatry 64 1013-1024, 2003 Calabrese JR, Keck PE, Macfadden W, et al A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar 1 or 11 depression. Am J Psychiatry 162 1351-1360, 2005 Chen G, Manji HK, Hawver DB, et al Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro. J Neurochem 63 2361-2364, 1994... 

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). 

Calabrese, J.R., Bowden, CX., Sachs, G.S., et al A double-blind placebo-controlled study of lamotrigine monotherapy in patients with bipolar I depression. J. Clin. 

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. 

Lamotrigine has been approved as an adjunctive treatment for partial and generalized seizures. Its mechanism of action is thought to involve inhibition of glutamate release (227, 228). Open-label, case series reports and ongoing double-blind, controlled trials have explored this agent s usefulness in both bipolar mania and depression (229, 230). 

In a double-blind comparison of lamotrigine versus desipramine or placebo, 450 unipolar depressed patients were studied. Lamotrigine was found to be significantly better than placebo, with desipramine falling between lamotrigine and placebo in terms of efficacy. 

These early trials indicate a possible bimodal therapeutic effect with lamotrigine for both the manic and depressed phases. Low starting doses and slow titration are required, however, due to the increased risk of rash (approximately 10%), of which 1% may be more severe and possibly life-threatening ( 233), limiting this agent s use for acute episodes. 

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. 

The depressive phase of manic-depressive disorder often requires concurrent use of an antidepressant drug (see Chapter 30). Tricyclic antidepressant agents have been linked to precipitation of mania, with more rapid cycling of mood swings, although most patients do not show this effect. Selective serotonin reuptake inhibitors are less likely to induce mania but may have limited efficacy. Bupropion has shown some promise but—like tricyclic antidepressants—may induce mania at higher doses. As shown in recent controlled trials, the anticonvulsant lamotrigine is effective for many patients with bipolar depression. For some patients, however, one of the older monoamine oxidase inhibitors may be the antidepressant of choice. Quetiapine and the combination of olanzapine and fluoxetine has been approved for use in bipolar depression. 

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