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Lithium and calcium channel blockers: Possible neurotoxicity
SIOL ~YC~EArRY
635
1~9~~:635~636
CORRESPONDENCE Letters of 600 words or less, with minimal allowance for tables, figures am1 references, wilt be considered for publication Rules regarding prior publication, conflict of interest, etc., are tke same as for fu'lt ~ n uscripts. All letters are subject to edit~,~g and condensation. Proofs will not be distributed.
Lithium and Calcium Channel Blockers: Possible Neurotoxicity To the Editor: Calcium channel blockers (CCBs) are occasionally used in combination with lithium, not only in the treatment of psychopathology, but also in patients wir~.~ coexistent cardiovascular and psychiatric disorders. However, one must use caution with the s~multaneous administration of these agents, as neurotoxicity may be precipitated by this combination. The following case describes a patient who showed neurotoxicity on lithium and verapamil, but did not display such symptoms with the combination of lithium and nifedipine.
Case Report A 58-ye~-old woman with a history of bipolar type I1 disorder, alcohol abuse, and hypertension had been euthyrnic on lithium, imipramine, and atenolol; however, hospitalization was necessary following several days of hypomania, confusion, and elevated serum drug concentrations of lithium (2. ! mEq/L) and imipramine/desipramine (660 ng/ml). Following initial discontinuation of medicine, lithium was resumed (450 mg/day), and veraparnil (240 mgday) was substituted for atenolol for the control of hypertension and hypomania (Dose and Emrich 1985; Dubovsky ct-"al 1982; Giarmirfi et al ~'~°~,o,+; . . . nu~:m' ..... mad Kozeny 1989). Over the next several days she displayed progressive ataxia and dysarthria despite a constant serum lithium level (0.60 mEq/L). Verapamil was discontinued, and nifedipine was restarted at 40 mgdday. During the ensuing 6 days, her mental status dramatically improved---she was now euth3/mic, articulate, and not ataxic. In an attempt to determine if her symptoms may have been, in part, secondary to a lithium-verapamil interaction, we discontinued the nifedipine and reinstituted verapamil at 240 rag/day. Over the next 5 days, the patient again became dysarthric and ataxic despite a constant lithium dose of 450 mg/day and a
© 1991 Society of Biological Psy,:hiatry
stable lithium ~evel of 0.55--0.70 m_EffL. Her ~ u rologic symptoms resolved entL,'ely over a 24-hr period after substituting nifedipine for vempamil. This patient's hospital~tion was n e c e s ~ because of hypomania, toxic drag o'¢erdose~, and possibly alcohol w i t h ~ w ~ . Her c ~ r s c was complicated by a probable lithium-verapamil-induced neurotoxicity, which masked her gradual clinical improvement. With discontinuation of ve~pamil, this improvement became apparent. Upon reinstitution of verapamil, she once again displayed neur~oxicity. Neurotoxicity, including nausea, weakness., trerrmr, ataxia, and parkinsoma_n symptoms, has been reported with the covcomitant adrnimstration of lithium and CCBs (Price and G i ~ i n i |986; ~ c e and Sh~ley 1987; Valdiserri 1985). It has been postulated that the neuror.oxicity is due to a cumulative reduction in adenyl cyclase activi~ and s~ultaneous com~tition with calcium ions (Rubm 1970). One would expect that the ~ s t r a t i o n of t i t h i ~ and nifedipine w ~ I d result in neurotoxicity in a patient who displayed these symptoms with a li~ium-verapamil combination; however our patient displayed a selective neurotoxicity to lithium and a specific CCB. V e r a p ~ l , as o p ~ s e d to nifedipine, undergoes substantial first-p~s metabolism m the liver (Gilman et all 1985). Although our patient had normal liver function tests, it is possible that she did not metabolize verapamii efficiently d ~ g the first pass, res u i u n ~ in a l v m u v ~ y - ' , ~ ~
ser'dm concenh'~tlon
of verapamil. In addition, verapamil, w~ch acts at different receptors than nifedipine (Snyder and Reynolds, 1985), may be inherently more neurotoxic. This is supported by the fact that verapamiI has an increased effect on the cardiac conduction system. Moreover, in distinction to other CCBs, v e r a p ~ I (and/or its major metabolite, norverapamil) crosses the blood-brain barrier, increasing the risk of neurotoxicity. There is at least one report of delirium secondary to the administration of verapamil (Jacobsen et al 1987); our patient may have become neurotoxic even in the absence of lithituT..
0006-3223/91/$03.50
636
Correspondence
BIOL PSYCHIATRY 1991 '.30:635~636
Regardless of the etiology of this patient's selective toxicity, it is important to remember ,hat the combination of lithium with CCBs, especially verapamil, may result in neurotoxicity. Bruce A. Wright David B. Jarrett Western Psychiatric Institute and Clinic University of Pittsburgh 3811 O'Hara St. Pittsbu~h, PA ! 5213
References Dose, M, Emrich HM {1985): Antimanic properties of verapamil, in Shagass C, et al (eds), Biological Psychiatr), 1985. New York: Elsevier, pp 320-322. Dubovsky SL, Franks RD, Lifschitz ML, Coen P (1982): Effectiveness of verapamil in the treatment of a manic patient. Am J Psychiatr3, ! 39:504-504. Gianmni AJ, Hooser WL, Loiselle RM, et al (1984): An-
timanic effects of v e ~ L Am J Psychiatry 141:16021603. Gilman AG, Goodman LS, Rail TW, Murad F (1985): The Pharmacologic Basis of Dierapeutics, (ed 7L New York: Macmillan, pp 816-821. Hoschl C, Kozeny J (1989): Verap~'nil in affective disorders: A controlled, 6ouble-blind study. Biol Psychialry 25:128-140. Jacobsen MJ, Sack DA, James SP (1987): Delirium induced by verapamil. Am J Psychiatry 144(2):248~ Price WA, Giannini J ( 1986): Neu~oxicity caused by lithium-verapamil synergism. J Clin Pharmacol 26:717719. Price WA, Shalley JE (i'987): Lithium.verapamJl toxicity in the elderly. J Am Geriatr Soc 35:i77-179. Rubin RP (1970)" The role of calcium in the release of neuro-transmirter svbstance and hormones. Pharmocol Rev 22:389-428. Snyder SH, Reynolds IJ (1985): Calciu• antagonists drugs: Receptor interactions that clarify therapeutic effects. N Engl J Med 313:995-1002. Valdiserri EV (1985): A possible interaction between lithium and ~ti~.~em: Case ~lx~. J Cl/n,Ps3vh/atry 46:540541.
635
1~9~~:635~636
CORRESPONDENCE Letters of 600 words or less, with minimal allowance for tables, figures am1 references, wilt be considered for publication Rules regarding prior publication, conflict of interest, etc., are tke same as for fu'lt ~ n uscripts. All letters are subject to edit~,~g and condensation. Proofs will not be distributed.
Lithium and Calcium Channel Blockers: Possible Neurotoxicity To the Editor: Calcium channel blockers (CCBs) are occasionally used in combination with lithium, not only in the treatment of psychopathology, but also in patients wir~.~ coexistent cardiovascular and psychiatric disorders. However, one must use caution with the s~multaneous administration of these agents, as neurotoxicity may be precipitated by this combination. The following case describes a patient who showed neurotoxicity on lithium and verapamil, but did not display such symptoms with the combination of lithium and nifedipine.
Case Report A 58-ye~-old woman with a history of bipolar type I1 disorder, alcohol abuse, and hypertension had been euthyrnic on lithium, imipramine, and atenolol; however, hospitalization was necessary following several days of hypomania, confusion, and elevated serum drug concentrations of lithium (2. ! mEq/L) and imipramine/desipramine (660 ng/ml). Following initial discontinuation of medicine, lithium was resumed (450 mg/day), and veraparnil (240 mgday) was substituted for atenolol for the control of hypertension and hypomania (Dose and Emrich 1985; Dubovsky ct-"al 1982; Giarmirfi et al ~'~°~,o,+; . . . nu~:m' ..... mad Kozeny 1989). Over the next several days she displayed progressive ataxia and dysarthria despite a constant serum lithium level (0.60 mEq/L). Verapamil was discontinued, and nifedipine was restarted at 40 mgdday. During the ensuing 6 days, her mental status dramatically improved---she was now euth3/mic, articulate, and not ataxic. In an attempt to determine if her symptoms may have been, in part, secondary to a lithium-verapamil interaction, we discontinued the nifedipine and reinstituted verapamil at 240 rag/day. Over the next 5 days, the patient again became dysarthric and ataxic despite a constant lithium dose of 450 mg/day and a
© 1991 Society of Biological Psy,:hiatry
stable lithium ~evel of 0.55--0.70 m_EffL. Her ~ u rologic symptoms resolved entL,'ely over a 24-hr period after substituting nifedipine for vempamil. This patient's hospital~tion was n e c e s ~ because of hypomania, toxic drag o'¢erdose~, and possibly alcohol w i t h ~ w ~ . Her c ~ r s c was complicated by a probable lithium-verapamil-induced neurotoxicity, which masked her gradual clinical improvement. With discontinuation of ve~pamil, this improvement became apparent. Upon reinstitution of verapamil, she once again displayed neur~oxicity. Neurotoxicity, including nausea, weakness., trerrmr, ataxia, and parkinsoma_n symptoms, has been reported with the covcomitant adrnimstration of lithium and CCBs (Price and G i ~ i n i |986; ~ c e and Sh~ley 1987; Valdiserri 1985). It has been postulated that the neuror.oxicity is due to a cumulative reduction in adenyl cyclase activi~ and s~ultaneous com~tition with calcium ions (Rubm 1970). One would expect that the ~ s t r a t i o n of t i t h i ~ and nifedipine w ~ I d result in neurotoxicity in a patient who displayed these symptoms with a li~ium-verapamil combination; however our patient displayed a selective neurotoxicity to lithium and a specific CCB. V e r a p ~ l , as o p ~ s e d to nifedipine, undergoes substantial first-p~s metabolism m the liver (Gilman et all 1985). Although our patient had normal liver function tests, it is possible that she did not metabolize verapamii efficiently d ~ g the first pass, res u i u n ~ in a l v m u v ~ y - ' , ~ ~
ser'dm concenh'~tlon
of verapamil. In addition, verapamil, w~ch acts at different receptors than nifedipine (Snyder and Reynolds, 1985), may be inherently more neurotoxic. This is supported by the fact that verapamiI has an increased effect on the cardiac conduction system. Moreover, in distinction to other CCBs, v e r a p ~ I (and/or its major metabolite, norverapamil) crosses the blood-brain barrier, increasing the risk of neurotoxicity. There is at least one report of delirium secondary to the administration of verapamil (Jacobsen et al 1987); our patient may have become neurotoxic even in the absence of lithituT..
0006-3223/91/$03.50
636
Correspondence
BIOL PSYCHIATRY 1991 '.30:635~636
Regardless of the etiology of this patient's selective toxicity, it is important to remember ,hat the combination of lithium with CCBs, especially verapamil, may result in neurotoxicity. Bruce A. Wright David B. Jarrett Western Psychiatric Institute and Clinic University of Pittsburgh 3811 O'Hara St. Pittsbu~h, PA ! 5213
References Dose, M, Emrich HM {1985): Antimanic properties of verapamil, in Shagass C, et al (eds), Biological Psychiatr), 1985. New York: Elsevier, pp 320-322. Dubovsky SL, Franks RD, Lifschitz ML, Coen P (1982): Effectiveness of verapamil in the treatment of a manic patient. Am J Psychiatr3, ! 39:504-504. Gianmni AJ, Hooser WL, Loiselle RM, et al (1984): An-
timanic effects of v e ~ L Am J Psychiatry 141:16021603. Gilman AG, Goodman LS, Rail TW, Murad F (1985): The Pharmacologic Basis of Dierapeutics, (ed 7L New York: Macmillan, pp 816-821. Hoschl C, Kozeny J (1989): Verap~'nil in affective disorders: A controlled, 6ouble-blind study. Biol Psychialry 25:128-140. Jacobsen MJ, Sack DA, James SP (1987): Delirium induced by verapamil. Am J Psychiatry 144(2):248~ Price WA, Giannini J ( 1986): Neu~oxicity caused by lithium-verapamil synergism. J Clin Pharmacol 26:717719. Price WA, Shalley JE (i'987): Lithium.verapamJl toxicity in the elderly. J Am Geriatr Soc 35:i77-179. Rubin RP (1970)" The role of calcium in the release of neuro-transmirter svbstance and hormones. Pharmocol Rev 22:389-428. Snyder SH, Reynolds IJ (1985): Calciu• antagonists drugs: Receptor interactions that clarify therapeutic effects. N Engl J Med 313:995-1002. Valdiserri EV (1985): A possible interaction between lithium and ~ti~.~em: Case ~lx~. J Cl/n,Ps3vh/atry 46:540541.