BRIEF COMMUNICATION
Augmentation of Valproate with Lithium in a Case of Rapid Cycling Affective Disorder* VERINDER SHARMA, M.B. 1 AND EMMANUEL PERSAD, M.B. 2
an antidepressant and as a prophylactic agent for bipolar illness than there is for its antimanic properties (8,9). We present the case of a patient with rapid cycling affective disorder treated with a combination of valproate and lithium carbonate.
Rapid cycling affective disorder is characteristically unresponsive to conventional interventions. In bipolar rapid cycling affective disorder, the manic episodes may be controlled with either neuroleptics or electroconvulsive therapy, but the depressive episodes are highly intractable. This report describes the successful treatment ofa patient with a bipolar rapid cycling affective disorder using a combination of valproic acid and lithium carbonate.
Case Report This 72 years old patient's bipolar illness began at age 21 with an episode of depression. She remained well for the next 17 years, until she had a recurrence of post-partum depression. She has required several admissions to a psychiatric hospital, including an admission in April 1986. For years she was treated with psychotropic drugs, including tricyclic antidepressants and neuroleptics, as well as many trials of electroconvulsive therapy (ECT). As she grew older, the episodes of the illness became much more frequent. Over the past few years the illness has taken a circular course; the patient cycles from one episode to another without any intervening periods of euthymia. Mrs. CD was transferred to the Mood Disorders Unit at our hospital in January 1989 for further assessment and treatment of her illness. Her previous charts were carefully reviewed to study the course of her illness and the medications she had received in order to construct a life chart (as suggested by Post et al) (10). The nursing staff recorded her mood fluctuations twice daily on a scale devised by the authors. This exercise enabled us to draw several conclusions. First, it was clear that antidepressants were contributing to the rapid cycling of the disorder. It therefore was decided that these drugs should not be used at all. Second, it was obvious that she had never undergone an adequate trial with a mood stabilizer because of her'persistent belief that lithium carbonate made her depressed. She had developed hematological problems after a brief trial with carbamazepine. The close monitoring of her condition helped us to study fluctuations in her condition. We found that her manic episodes were characterized by high levels of energy, preoccupation with religion, intrusiveness, grandiosity, and erratic compliance with prescribed medications. During periods of depression, she often complained of a low level of energy, poor concentration, a low mood and daytime somnolence. We decided to try valproic acid. It soon became clear that with this treatment she no longer had periods of hypomania/mania, but continued to suffer from mild to moderate
R
apid cycling affective disorders (RCAD) have the following diagnostic features (1-3): episodes vary from four to 20 per year and last from 48 hours to 12 weeks (clinically, the number of episodes may be less significant than the clearly established course of frequent episodes); episodes occur more frequently in females and are associated with post-partum and post-menopausal onset; episodes can occur in patients with the unipolar form ofthe disorder, but are more frequent in bipolar patients; the disorder may be associated with hypothyroidism; there are no specific biological markers; a mixture of manic and depressive symptoms may coexist, the so-called mixed state; and patients may have a premorbid cyclothymic personality (4). Rapid cycling affective disorder had been regarded as particularly unresponsive to treatment with lithium (2). Such a designation has been questioned and, as Schou (5) points out, these disorders respond poorly to most treatments. Various pharmacotherapeutic strategies have been proposed, such as carbamazepine, valproate and clonazepam, electroconvulsive therapy, thyroid hormones, L-tryptophan, calcium channel blockers, beta-adrenergic blockers and a combination of various medications (6-9). Over the past few years, valproate has been used more often, either alone or in combination with lithium carbonate. There is less evidence that it is effective as
'Manuscript received April 1991, revised August 1991. JDirector, Mood Disorders Unit, London Psychiatric Hospital; Assistant Professor of Psychiatry, University of Western Ontario, London, Ontario. 2Consultant, Mood Disorders Unit, London Psychiatric Hospital; Associate Professor of Psychiatry, University of Western Ontario, London, Ontario. Address reprint requests to: Dr. V. Sharma, Director, Mood Disorders Unit, London Psychiatric Hospital, 850 Highbury Avenue, London, Ontario N6A 4HI
Can. J. Psychiatry Vol. 37, October 1992
584
October, 1992
AUGMENTATION OF
V ALPROATE WITH
depression. During one depressive episode, she missed a few doses of valproic acid and quickly went into a manic phase, for which she required the addition of a small dose of haloperidol. After being in a euthymic state for a few days, she once again plunged into a severe depression. She was then ready to try any drug, including lithium carbonate. Within 24 hours of adding lithium carbonate to valproic acid, she reported a marked improvement in her mood, but continued to have a low level of energy and poor concentration. Lithium carbonate was increased by small increments until a daily dose of 900 mg was reached. She experienced a brief hypomanic episode after her lithium dose was reduced to 600 mg per day. The dosage was reduced because her serum lithium, which had been serially monitored, had risen steadily and she had complained of vomiting, diarrhea and had a coarse tremor in both hands. At the same time, there was little change in her serum valproic acid level. Currently, she is on a combination of lithium carbonate 600 mg and valproic acid 1,250 mg per day. Despite the fact that she has had a few mood fluctuations, she has remained euthymic for the past 15 months following her discharge in 1991.
Discussion This case illustrates the difficulties encountered in treating some patients with rapid cycling bipolar illness. Antidepressants are clearly helpful and are needed by certain patients, while for others they contribute to rapid cycling. The management of depression in such patients should be carried where possible with bimodal agents, either alone or in combination. Lithium carbonate has been known to augment the antidepressant effect of tricyclic drugs (11), monoamine oxidase inhibitors (12) and finally carbamazepine (13). Ours may be the first report to suggest that this drug may have the same effect in augmenting the antidepressant properties of valproate. The serum levels of both lithium carbonate and valproate need to be monitored closely. This patient's serum level of lithium increased with the concomitant use of valproate. Monitoring is especially important for elderly patients because of their greater vulnerability to the adverse effects of drugs (14). Acknowledgements We are grateful to the nursing staff of the Mood Disorders Unit and Ms. Karen Kueneman, research assistant, for their assistancein the preparation of this manuscript.
585
LITHIUM
References I. Alarcon RD. Rapid cycling affective disorders: a clinical review. Compr Psychiatry 1985;26(6): 522-540. 2. Dunner DL, Fieve RR. Clinical factors in lithium prophylaxis failure. Arch Gen Psychiatry 1974; 30: 229-233. 3. Stancer HC, Furlong FW, Ghodse CD. A longitudinal investigation of lithium as a prophylactic agent for recurrent depressions. Can Psychiatr Assoc J 1970; 15(1): 29-40. 4. Persad E. Treatment resistant depression and rapid cycling affective disorder. In: McCann D, Endler N, eds. Depression, new directions in theory, research and practice. Toronto ON: Wall and Emerson Inc., 1990. 5. Schou M. Lithium prophylaxis: myths and realities. Am J Psychiatry 1989; 146: 573-576. 6. Sachs GS. Adjuncts and alternatives to lithium therapy for bipolar illness. J Clin Psychiatry 1989;50(12 Suppl): 31-39. 7. Post RM. Introduction: emerging perspectives on valproate in affective disorders. J Clin Psychiatry 1989; 50(3 Suppl): 3-9. 8. McElroy SL, Keck PE, Pope HG, et al. Valproatein psychiatric disorders: literature review and clinical guideline. J Clin Psychiatry 1989; 50(30 Suppl): 23-29. 9. Pope HG, McElroy SL, Keck PE Jr, et al. Valproate in the treatmentof acutemania.ArchGen Psychiatry 1991;48: 62-68. 10. Post RM, Roy-Byrne PP, Uhde TW.Graphic representationof the life course of illness in patients with affective disorder. Am J Psychiatry 1988; 145(7):844-848. II. Schopf 1. Treatmentof depressionsresistantto tricyclic antidepressants,related drugs or MAO-inhibitors by lithium addition: review of the literature. Pharmacopsychiatry 1989; 22: 174182. 12. Nelson JC, Byck R. Rapid response to lithium in phenelzine non-responders. Br J Psychiatry 1982; 141: 85-86. 13. Kramlinger KG, Post RM. The addition of lithium to carbamazepine. Arch Gen Psychiatry 1989;46(9): 794-800. 14. Lipowski Z1. Delirium in the elderly patient. N Engl J Med 1989; 320: 578-581.
Resume II est typique que le malade atteint d' un trouble affectif a cycle rapide ne repond pas aux traitements conventionnels. Si le trouble est bipolaire, l' administration de neuroleptiques ou I' etectrochoc permettent de controler les crises maniaques; par contre, les crises de depression sont extremement refractaires. Les auteurs decrivent le succes remporte en administrant de l' acide valproique et du carbonate de lithium aun malade atteint d' un trouble affectif acycle rapide bipolaire. Les resultats donnent penser que le carbonate de lithium intensifie l' effet antidepressif de l' acide valproique.
a
Augmentation of Valproate with Lithium in a Case of Rapid Cycling Affective Disorder* VERINDER SHARMA, M.B. 1 AND EMMANUEL PERSAD, M.B. 2
an antidepressant and as a prophylactic agent for bipolar illness than there is for its antimanic properties (8,9). We present the case of a patient with rapid cycling affective disorder treated with a combination of valproate and lithium carbonate.
Rapid cycling affective disorder is characteristically unresponsive to conventional interventions. In bipolar rapid cycling affective disorder, the manic episodes may be controlled with either neuroleptics or electroconvulsive therapy, but the depressive episodes are highly intractable. This report describes the successful treatment ofa patient with a bipolar rapid cycling affective disorder using a combination of valproic acid and lithium carbonate.
Case Report This 72 years old patient's bipolar illness began at age 21 with an episode of depression. She remained well for the next 17 years, until she had a recurrence of post-partum depression. She has required several admissions to a psychiatric hospital, including an admission in April 1986. For years she was treated with psychotropic drugs, including tricyclic antidepressants and neuroleptics, as well as many trials of electroconvulsive therapy (ECT). As she grew older, the episodes of the illness became much more frequent. Over the past few years the illness has taken a circular course; the patient cycles from one episode to another without any intervening periods of euthymia. Mrs. CD was transferred to the Mood Disorders Unit at our hospital in January 1989 for further assessment and treatment of her illness. Her previous charts were carefully reviewed to study the course of her illness and the medications she had received in order to construct a life chart (as suggested by Post et al) (10). The nursing staff recorded her mood fluctuations twice daily on a scale devised by the authors. This exercise enabled us to draw several conclusions. First, it was clear that antidepressants were contributing to the rapid cycling of the disorder. It therefore was decided that these drugs should not be used at all. Second, it was obvious that she had never undergone an adequate trial with a mood stabilizer because of her'persistent belief that lithium carbonate made her depressed. She had developed hematological problems after a brief trial with carbamazepine. The close monitoring of her condition helped us to study fluctuations in her condition. We found that her manic episodes were characterized by high levels of energy, preoccupation with religion, intrusiveness, grandiosity, and erratic compliance with prescribed medications. During periods of depression, she often complained of a low level of energy, poor concentration, a low mood and daytime somnolence. We decided to try valproic acid. It soon became clear that with this treatment she no longer had periods of hypomania/mania, but continued to suffer from mild to moderate
R
apid cycling affective disorders (RCAD) have the following diagnostic features (1-3): episodes vary from four to 20 per year and last from 48 hours to 12 weeks (clinically, the number of episodes may be less significant than the clearly established course of frequent episodes); episodes occur more frequently in females and are associated with post-partum and post-menopausal onset; episodes can occur in patients with the unipolar form ofthe disorder, but are more frequent in bipolar patients; the disorder may be associated with hypothyroidism; there are no specific biological markers; a mixture of manic and depressive symptoms may coexist, the so-called mixed state; and patients may have a premorbid cyclothymic personality (4). Rapid cycling affective disorder had been regarded as particularly unresponsive to treatment with lithium (2). Such a designation has been questioned and, as Schou (5) points out, these disorders respond poorly to most treatments. Various pharmacotherapeutic strategies have been proposed, such as carbamazepine, valproate and clonazepam, electroconvulsive therapy, thyroid hormones, L-tryptophan, calcium channel blockers, beta-adrenergic blockers and a combination of various medications (6-9). Over the past few years, valproate has been used more often, either alone or in combination with lithium carbonate. There is less evidence that it is effective as
'Manuscript received April 1991, revised August 1991. JDirector, Mood Disorders Unit, London Psychiatric Hospital; Assistant Professor of Psychiatry, University of Western Ontario, London, Ontario. 2Consultant, Mood Disorders Unit, London Psychiatric Hospital; Associate Professor of Psychiatry, University of Western Ontario, London, Ontario. Address reprint requests to: Dr. V. Sharma, Director, Mood Disorders Unit, London Psychiatric Hospital, 850 Highbury Avenue, London, Ontario N6A 4HI
Can. J. Psychiatry Vol. 37, October 1992
584
October, 1992
AUGMENTATION OF
V ALPROATE WITH
depression. During one depressive episode, she missed a few doses of valproic acid and quickly went into a manic phase, for which she required the addition of a small dose of haloperidol. After being in a euthymic state for a few days, she once again plunged into a severe depression. She was then ready to try any drug, including lithium carbonate. Within 24 hours of adding lithium carbonate to valproic acid, she reported a marked improvement in her mood, but continued to have a low level of energy and poor concentration. Lithium carbonate was increased by small increments until a daily dose of 900 mg was reached. She experienced a brief hypomanic episode after her lithium dose was reduced to 600 mg per day. The dosage was reduced because her serum lithium, which had been serially monitored, had risen steadily and she had complained of vomiting, diarrhea and had a coarse tremor in both hands. At the same time, there was little change in her serum valproic acid level. Currently, she is on a combination of lithium carbonate 600 mg and valproic acid 1,250 mg per day. Despite the fact that she has had a few mood fluctuations, she has remained euthymic for the past 15 months following her discharge in 1991.
Discussion This case illustrates the difficulties encountered in treating some patients with rapid cycling bipolar illness. Antidepressants are clearly helpful and are needed by certain patients, while for others they contribute to rapid cycling. The management of depression in such patients should be carried where possible with bimodal agents, either alone or in combination. Lithium carbonate has been known to augment the antidepressant effect of tricyclic drugs (11), monoamine oxidase inhibitors (12) and finally carbamazepine (13). Ours may be the first report to suggest that this drug may have the same effect in augmenting the antidepressant properties of valproate. The serum levels of both lithium carbonate and valproate need to be monitored closely. This patient's serum level of lithium increased with the concomitant use of valproate. Monitoring is especially important for elderly patients because of their greater vulnerability to the adverse effects of drugs (14). Acknowledgements We are grateful to the nursing staff of the Mood Disorders Unit and Ms. Karen Kueneman, research assistant, for their assistancein the preparation of this manuscript.
585
LITHIUM
References I. Alarcon RD. Rapid cycling affective disorders: a clinical review. Compr Psychiatry 1985;26(6): 522-540. 2. Dunner DL, Fieve RR. Clinical factors in lithium prophylaxis failure. Arch Gen Psychiatry 1974; 30: 229-233. 3. Stancer HC, Furlong FW, Ghodse CD. A longitudinal investigation of lithium as a prophylactic agent for recurrent depressions. Can Psychiatr Assoc J 1970; 15(1): 29-40. 4. Persad E. Treatment resistant depression and rapid cycling affective disorder. In: McCann D, Endler N, eds. Depression, new directions in theory, research and practice. Toronto ON: Wall and Emerson Inc., 1990. 5. Schou M. Lithium prophylaxis: myths and realities. Am J Psychiatry 1989; 146: 573-576. 6. Sachs GS. Adjuncts and alternatives to lithium therapy for bipolar illness. J Clin Psychiatry 1989;50(12 Suppl): 31-39. 7. Post RM. Introduction: emerging perspectives on valproate in affective disorders. J Clin Psychiatry 1989; 50(3 Suppl): 3-9. 8. McElroy SL, Keck PE, Pope HG, et al. Valproatein psychiatric disorders: literature review and clinical guideline. J Clin Psychiatry 1989; 50(30 Suppl): 23-29. 9. Pope HG, McElroy SL, Keck PE Jr, et al. Valproate in the treatmentof acutemania.ArchGen Psychiatry 1991;48: 62-68. 10. Post RM, Roy-Byrne PP, Uhde TW.Graphic representationof the life course of illness in patients with affective disorder. Am J Psychiatry 1988; 145(7):844-848. II. Schopf 1. Treatmentof depressionsresistantto tricyclic antidepressants,related drugs or MAO-inhibitors by lithium addition: review of the literature. Pharmacopsychiatry 1989; 22: 174182. 12. Nelson JC, Byck R. Rapid response to lithium in phenelzine non-responders. Br J Psychiatry 1982; 141: 85-86. 13. Kramlinger KG, Post RM. The addition of lithium to carbamazepine. Arch Gen Psychiatry 1989;46(9): 794-800. 14. Lipowski Z1. Delirium in the elderly patient. N Engl J Med 1989; 320: 578-581.
Resume II est typique que le malade atteint d' un trouble affectif a cycle rapide ne repond pas aux traitements conventionnels. Si le trouble est bipolaire, l' administration de neuroleptiques ou I' etectrochoc permettent de controler les crises maniaques; par contre, les crises de depression sont extremement refractaires. Les auteurs decrivent le succes remporte en administrant de l' acide valproique et du carbonate de lithium aun malade atteint d' un trouble affectif acycle rapide bipolaire. Les resultats donnent penser que le carbonate de lithium intensifie l' effet antidepressif de l' acide valproique.
a
