CNS Spectr. 2010;15(9):599-601
Dr. Ozer is specialist of psychiatry, Dr. Ekinci is research assistant of psychiatry, and Dr. Caykoylu is professor and clinical director in the Department of Psychiatry at Ataturk Education and Research Hospital in Ankara, Turkey.
Faculty Disclosures: Drs. Ozer, Ekinci, and Caykoylu report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Submitted for publication: January 21, 2009; Accepted for publication: August 5, 2009.
Please direct all correspondence to: Ankara Ataturk Egitim ve Arastirma Hastanesi Psikiyatri Klinigi, 06520 Bilkent/Ankara, Turkey. Tel: +90-312-2912525, Fax: +90-312-2912705; E-mail: email@example.com.
To the Editor:
The role of antidepressants in the treatment of the depressed phase of bipolar disorder remains controversial due to risk of induction of hypomania, mixed episodes, and rapid cycling.1,2 In addition, antidepressants may not be as efficacious in the management of the depressed phase of bipolar disorder as they are in the management of major depressive disorder. Many experts believe that the treatment of bipolar depression should include antidepressants in combination with an antimanic drug such as lithium.3 However, few studies are available that guide the next best treatment if a mood stabilizer plus an antidepressant fails to help patients with bipolar depression. The limited available data suggests that patients can be switched to either electroconvulsive therapy4 or monoamine oxidase inhibitors (MAOIs).5,6 Other options include combining mood stabilizers,7 switching to the combination of olanzapine and fluoxetine,8 and switching to quetiapine.9
Recently, lamotrigine has been found to be efficacious in the long-term management of bipolar disorder (especially in delaying depressive recurrence), either as a monotherapy or adjunctive therapy, but its efficacy in the acute treatment of bipolar depression is less clear.10,11 However, to our knowledge, there is no literature available that addresses rapid improvement induced by low-dose lamotrigine augmentation in bipolar II depression. Here, we report two cases of bipolar II depressed patients who did not respond to two different antidepressant trials that lasted for >8 weeks, but subsequently showed rapid improvement after low-dose lamotrigine augmentation.
Mrs. M was a 45-year-old married woman with a primary school education who was admitted to our hospital. She had suffered from bipolar II disorder for the previous 5 years and had experienced three depressive episodes and one hypomanic episode within that time. The first episode of her illness was a depressive episode at 40 years of age. She had been treated with various atypical antipsychotics, mood stabilizers including lithium, and various antidepressants including paroxetine, escitalopram, and sertraline during this period.
Upon examination, she was found to suffer from severe pervasive sadness; anhedonia; hypersomnia; severe psychomotor retardation; feelings of worthlessness; distractibility; occasional passive suicidal ideation; and decreased energy, concentration, appetite, and self-esteem. She remained in bed most of the time, rarely cared for herself, and could not work. She experienced these symptoms on most days and nearly every day during the month prior to admission. This was the fourth depressive episode of her illness. Her 17-item Hamilton Depression Rating Scale (HAM-D17)12 score was 31. An 8-week trial of escitalopram failed to consistently improve her depression. Subsequently, her medication was replaced by venlafaxine, which has a more rapid onset of action and is often used in bipolar depression. Venlafaxine was started at a dose of 75 mg/day and gradually increased to 300 mg/day within 2 weeks. At week 6 of venlafaxine treatment, there was no significant improvement in her depressive symptoms. Her HAM-D total score was 26. Therefore, lithium was added to her medication and gradually increased to 900 mg/day (the mean plasma levels were 0.77). Since the clinical response at week 4 after lithium augmentation was only partial, 25 mg/day lamotrigine was added to this regimen. The patient responded to lamotrigine after 3 days of treatment while on a dose of 25 mg/day. The patient reported increased energy, improvement in hypersomnia, a greater ability to concentrate, and increased appetite.
After 1 week of treatment, there was a significant clinical improvement in her depression. Her HAM-D total score was 8. The individual symptoms that showed rapid improvements (week 1) were depressed mood (HAM-D item 1), feelings of guilt (HAM-D item 2), suicide (HAM-D item 3), work and activities (HAM-D item 7), and anxiety psychic (HAM-D item 10). On day 9 of combination therapy, her depressive symptoms remitted completely with no evidence of adverse effects. The final HAM-D total score was 2. In addition, there were no symptoms suggestive of either a mixed episode or hypomanic state. The patient continued this combination regimen, including venlafaxine 300 mg/day, lithium 900 mg/day, and lamotrigine 25 mg/day, without recurrence of depression or emergence of hypomania or adverse effects for 2 months.
Mrs. G was a 41-year-old married woman with a high school education who was admitted to our inpatient clinic. She had suffered from bipolar II disorder for the previous 7 years and had experienced six depressive episodes and two hypomanic episodes within that time. The first episode of her illness was a depressive episode at 34 years of age. She had been treated with various antipsychotics (including quetiapine, olanzapine, and risperidone), mood stabilizers (including lithium), and antidepressants (including sertraline, venlafaxine, and escitalopram) during this period. She had been regularly maintained on a treatment regimen (including lithium 1,200 mg/day and quetiapine 200 mg/day) for 2 months when she experienced a depressive episode. The mean plasma level of lithium was 0.82. Upon examination, she was found to suffer from severe pervasive sadness, anhedonia, insomnia, moderate psychomotor retardation, feelings of worthlessness, distractibility, recurrent suicidal ideation, somatic symptoms, and somatic anxiety as well as decreased energy, concentration, and appetite. Her HAM-D total score was 34. In light of this, escitalopram was added to the ongoing lithium and quetiapine treatment. An 8-week escitalopram trial failed to consistently improve her depression. Subsequently, her medication was replaced with sertraline. Sertraline was started at a dose of 50 mg/day and gradually increased to 150 mg/day. After 8 weeks of sertraline treatment, there was no significant improvement in her depressive symptoms. Her HAM-D total score was 28. Subsequently, 25 mg/day lamotrigine was added to her treatment regimen. The patient responded to lamotrigine after ~2 days of treatment while on a dose of 25 mg/day. The patient experienced a significant improvement in HAM-D scores for suicide, insomnia, retardation, general somatic symptoms, and anxiety somatic. Within 1 week, the patient’s HAM-D total score dramatically decreased from 28 to 9. In addition, there were no symptoms suggestive of either a mixed episode or hypomanic state. The patient continued this combination regimen, including sertraline 150 mg/day, lamotrigine 25 mg/day, lithium 1,200 mg/day, and quetiapine 200 mg/day, without recurrence of depression or emergence of hypomania or adverse effects for 2 months.
Previous studies have suggested that lamotrigine, used alone or in combination with other psychotropic drugs, is safe and effective in the management of bipolar II depression, but not mania.10,13,14 However, for the acute treatment of bipolar II depression, lithium, lamotrigine, and quetiapine have been recommended as second-line options and there is insufficient information to recommend any medication as a first-line treatment.15
The exact mechanism by which lamotrigine exerts its action has not been completely elucidated, but a number of putative neurochemical effects have been postulated. In forced swim test, increased swimming and decreased immobility indicate antidepressant-like effect. It has been demonstrated that, when combined with veratrine, a Na+ channel opener, the antidepressant-like effect of lamotrigine is reversed, but that the antidepressant-like effect of imipramine, desipramine, and paroxetine is not changed. This finding indicates that the mechanism of action of lamotrigine is different from that of antidepressants.11 It has been suggested that the antidepressant-like effect of lamotrigine is related to the noradrenergic system, likely due to an activation of a1- and a2-postsynaptic adrenoceptors, and serotonergic systems.16,17 Muck-Seler and colleagues18 found that lamotrigine has an effect on platelet MAO-B activity in patients with bipolar depression, and they suggested that its in vivo MAO-B inhibiting effect might have contributed, in part, to its antidepressant activity. On the other hand, there is evidence that bipolar depression is characterized by increased glutamate coupled with increased energy expenditure. Evidence has also suggested that in patients with refractory affective disorder, excitatory amino acids are dysregulated. Lamotrigine appears to reduce glutamine levels associated with treatment remission. This may be another action mechanism of lamotrigine in bipolar depression treatment.19
In the present study, low-dose lamotrigine induced rapid improvement from depressive symptoms in bipolar II disorder; however, the mechanism behind this result is unclear. Its broader action mechanism (with effects on noradrenergic, dopaminergic, serotonergic, and glutamatergic neurotransmission, MAO-B inhibiting effect, and the effects of sodium and calcium channel) may be an explanation for the rapid and sustained improvement induced by its low-dose augmentation in the reported cases. The literature suggests that atypical antipsychotics may induce a rapid improvement in individuals with depression. For example, rapid improvement associated with the augmentation strategy has been described in relation to olanzapine and risperidone in previous studies.20,21 These studies suggest that the augmentation effect of atypical antipsychotics may depend on the antidepressant being in place, a mechanism postulated to explain lithium augmentation of antidepressant drugs in unipolar depression. De Montigny and colleagues,22 describing a case series of eight patients who responded rapidly to lithium introduction after having failed to respond to a tricyclic antidepressant (TCA), suggested that TCA pretreatment sensitized the serotonin receptor to create an antidepressant effect and then lithium increased the efficacy of the central serotonergic system. Similarly, such a model may account for the substantive antidepressant responses reported when low-dose lamotrigine was added to antidepressant medication in patients who did not respond to the combination of an antidepressant and lithium.
On the other hand, Calabrese and colleagues23 demonstrated that lamotrigine monotherapy did not demonstrate efficacy in the acute treatment of bipolar depression in four out of five placebo controlled clinical studies. However, it is important to note that lamotrigine was used as a monotherapy in their study while it was used as an adjunctive therapy in the reported cases. Lamotrigine has mostly been studied as monotherapy in bipolar depression. Recently, van der Loos and colleagues24 compared the acute effects of lamotrigine and placebo as add-on therapy to ongoing treatment with lithium in patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition bipolar I or II disorder and had a major depressive episode while receiving lithium treatment (0.6–1.2 mmol/L). They showed that lamotrigine was effective and safe as add-on treatment to lithium in the acute treatment of bipolar depression. In addition, it has been demonstrated that the combination of lithium and lamotrigine was effective for acute depressive symptoms in about half of treatment-resistant bipolar patients.25 Therefore, this may be another factor that contributes to the rapid improvement related to the addition of low dose lamotrigine in the reported cases.
Some studies have suggested that tachyphylaxis (which refers to the gradual loss of efficacy after repeated antidepressant exposures over time),26 may be influenced by antidepressant class,27 with the greatest proportion occurring during selective serotonin reuptake inhibitor therapy. Moreover, some studies have suggested that tachyphylaxis may occur more frequently in patients with bipolar II depressive episode28,29 and that these patients may be more likely to develop treatment-resistant depression.29,30 Although some authors propose that lamotrigine, used alone or in combination with other psychotropic drugs, is safe and effective in the management of treatment-resistant bipolar II depression,10,13 no study has examined the effect of lamotrigine on tachyphylaxis associated with long-term antidepressant exposure.
Depression in bipolar illness is an important syndrome. It occupies a large fraction of the patients’ lives and is related to significant morbidity and mortality. In spite of its high prevalence, bipolar II depression and its treatment strategies remain poorly understood. This report provides further evidence that lamotrigine used in combination with other psychotropic drugs is safe and effective in the management of bipolar II depression. These cases also highlight the possibility of lamotrigine in low doses acting as a quick antidepressant, even when added to other mood stabilizers. However, the mechanisms behind the rapid improvement induced by lamotrigine in the reported cases remains unclear. Controlled studies are necessary to understand the pharmacologic mechanisms underlying rapid improvement in bipolar II depression following treatment with low-dose lamotrigine.
Omer Akil Ozer, MD
Okan Ekinci, MD
Ali Caykoylu, MD
1. Ghaemi SN, Ko JY, Goodwin FK. “Cade’s disease” and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry. 2002;47:125-134.
2. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163:232-239.
3. Altshuler LL, Suppes T, Black DO, et al. Lower switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with second generation antidepressants. Am J Psychiatry. 2006;163:313-315.
4. Homan S, Lachenbruch PA, Winkur G, et al. An efficacy study of electroconvulsive therapy and antidepressants in the treatment of primary depression. Psychol Med. 1982;12:615-624.
5. Himmelhoch JM, Thase ME, Mallinger AG, et al. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry. 1991;148:910-916.
6. Thase ME, Mallinger AG, McKnight D, et al. Treatment of imipramine-resistant recurrent depression, IV: a double- blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry. 1992;149:195-198.
7. Young LT, Joffe RT, Robb JC, et al. Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Am J Psychiatry. 2000;157:124-126.
8. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1088.
9. Calabrese JR, Keck PE Jr, Macfadden W, et al. (BOLDER Study Group): A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351-1360.
10. Sharma V, Khan M, Corpse C. Role of lamotrigine in the management of treatment-resistant bipolar II depression: a chart review. J Affect Disord. 2008;111(1):100-105.
11. Prica C, Hascoet M, Bourin M. Antidepressant-like effect of lamotrigine is reversed by veratrine: a possible role of sodium channels in bipolar depression. Behav Brain Res. 2008;191(1):49-54.
12. Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.
13. Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006; 163(2):210-216.
14. Schaffer A, Zuker P, Levitt A. Randomized, double-blind pilot trial comparing lamotrigine versus citalopram for the treatment of bipolar depression. J Affect Disord. 2006;96:95-99.
15. Yatham LN, Kennedy SH, O’Donovan C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: update 2007. Bipolar Disord. 2006; 8:721-739.
16. Consoni FT, Vital MA, Andreatini R. Dual monoamine modulation for the antidepressant-like effect of lamotrigine in the modified forced swimming test. Eur Neuropsychopharmacol. 2006;16(6):451-458.
17. Kaster MP, Raupp I, Binfaré RW, et al. Antidepressant-like effect of lamotrigine in the mouse forced swimming test: evidence for the involvement of the noradrenergic system. Eur J Pharmacol. 2007;565:119-124.
18. Muck-Seler D, Sagud M, Mustapic M, et al. The effect of lamotrigine on platelet monoamine oxidase type B activity in patients with bipolar depression. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(5):1195-1198.
19. Frye MA, Watzl J, Banakar S, et al. Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression. Neuropsychopharmacology. 2007;32(12):2490-2499.
20. Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry. 1999; 60:256-259.
21. Parker G. Olanzapine augmentation in the treatment of melancholia: the trajectory of improvement in rapid responders. Int Clin Psychopharmacol. 2002;17:87-89.
22. De Montigny C, Grunberg F, Mayer A, et al. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry. 1981;138:252-256,
23. Calabrese JR, Huffman RF, White RL, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord. 2008;10(2):323-333.
24. van der Loos ML, Mulder PG, Hartong EG, et al. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(2):223-231.
25. Ghaemi SN, Schrauwen E, Klugman J, et al. Long-term lamotrigine plus lithium for bipolar disorder: One year outcome. J Psychiatr Pract. 2006;12(5):300-305.
26. Leykin Y, Amsterdam JD, DeRubeis RJ, et al. Progressive resistance to SSRI therapy but not to cognitive therapy in the treatment of major depression. J Consult Clin Psychol. 2007;75(2):267-276.
27. Posternak MA, Zimmerman M. Dual reuptake inhibitors incur lower rates of tachyphylaxis than selective serotonin reuptake inhibitors: A retrospective study. J Clin Psychiatry. 2005;66:705-707.
28. Sharma V. Loss of response to antidepressants and subsequent refractoriness: diagnostic issues in a retrospective case series. J Affect Disord. 2001;64 (1):99-106.
29. Sharma V, Khan M, Smith A. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord. 2005;84:251-257.
30. Ei-Mallakh, RS, Karippot, A. Antidepressant-associated chronic irritable dysphoria (ACID) in bipolar disorder: a case series. J Affect Disord. 2005;84:267–272.