BIOL PSYCHIATRY 1992;32:369-374
369
Carbamazepine Addition in Tricyclic AntidepressantResistant Unipolar Depression Jos6 M. De la Fuente and Julien Mendlewicz
Introduction Patients with treatment-resistant depression constitute a minority but they consume a great portion of the clinician's time. The incidence is estimated to be over 10% to 30% of total depressive disorders (Nierenberg et al 1990). The literature is scanty and there is no systematic research on how to treat these affective-disordered patients who fail to respond to adequate antidepressant trials (therapeutic doses of medication given for a sufficient length of time). However, there are several strategies that most clinicians have used, sometimes empirically, to solve the problem. These strategies are increasing the dosage of the antidepressant agent, changing to another antidepressant of the same group, changing the family of drugs, cotreating with lithium or L-tryptophan, administering two antidepressants from different chemical groups, and so on. So far, there is no general consensus about the ideal therapeutic attitude for resistant depression. Carbamazepine has been used in the management of pain syndromes such as trigeminal neuralgia, and as an anticonvulsant drug since the 1960s (for review, see Elphick 1989). Subsequent evidence of its beneficial effect not only on epilepsy but also on the psychological condition of epileptic patients (independently of the improvement in the seizure disorder) has made this drug a very important tool in the management of affective and behavioral disorders. Carbamazepine has been prescribed frequently in clinical psychiatry since the early 1970s. Takezaki and Hanaoka first reported its usefulness in 1971 as an antimanic agent. Their experience was followed by a large number of case-reports and of patient's series confirming these findings (Dalby 1971; Kobayashi~ et al 1988). Most clinical trials have focused on its now-demonstrated efficacy as a prophylactic agent in manic depression. There are very few trials aimed at acute treatment of depression. Post et al (1986) found some acute antidepressant ,efficacy when they prescribed carbamazepine only, for an average of 45 days; the effects became apparent after only 1-2 weeks. In an open trial of carbamazepine in chronically depressed patients, Prasad (1985) reported that 11 out of 12 patients showed improvement. However, the available data suggest that carbamazepine is not very effective in the acute treatment of depression (for review, see Ballenger 1988). Here we report the case of a patient with major depression resistant to tricyclic med-
From the Department of Psychiatry, H6pital Erasme, Bmbsels, Belgium. Address reprint requests to Jos~ M. De la Fuente, Departmentof Psychiatry, HOpitaiErasme, Route de Lennik 808, B.1070 Brussels, Belgium. Received May 18, 1991; revised March 3, 1992. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
F-OFF ..........
35
J.M. De la Fuente and J. Mendlewicz
BIOL PSYCHIATRY 1992;32:369-374
370
RDD 3
l-ON ..........
MDD4
I OFF
I
ON
MDD 5
HADS
30 25 20 15 10
|
o
|
i CLOHI
a,OHl ° CBZ
P ALL
(~.,OHl, CX
Figure 1
ication who was successfully treated by the addition of carbamazepine to clomipramine. The pharmacological design was an off-on/off-on design spontaneously produced by the patient's interrupting the dn~g-combination therapy.
Case Report Ms. GV, a 7 l-year-old woman was admitted to our inpatient psychiatric unit in October 1989. The Research Diagnostic Criteria (Spit,~er et al 1978) diagnosis at admission was a major depressive disorder of primary, endogenous s~lbtype, mainly anxious, without psychotic features, unipolar and recurrent. The patient did not exhibit any cognitive impairment. The Mini Mental State Examination (Folstein et al 1975) was of 30/30 at admission and at discharge. Depression scores at admission were 31 and 32 on the Hamilton Depression Rating Scale (HRDS.24) .and the Montgomery and Asberg Depression Scale (MADS), respectively. (See Figure l.) Previously, our patient had expelienced two other depressive episodes since the age of 59. In the past she had received melitracene/flupenthixol, nortryptiline, amitryptiline, and various anxiolytic treatments, with no significant improvement. She never received lithium nor any other prophylactic medication. The former hospitalization (second depressive episode) was motivated by a serious suicidal attempt (self-poisoning) in July 1989. At that time, she received amitryptiline
Carbamazepine in Tricyclic Resistance
BIOL PSYCHIATRY 1992;32:369--374
371
(200 mg per day), which produced sufficient symptom remission to allow discharge from the hospital in September 1989. At the time of admission, she had been taking 200 mg of amitryptiline for 3 months, but suffered a severe depressive relapse for approximately 15 days prior to admission. We first proceeded to progressively withdraw all psychotropic medication within a period of 10 days. After a physical check-up and an electroencephalographic sleep recording lasting 2 consecutive nights (after 1 habituation night) thal~,showed a shortened REM-latency (43 and 13 min) and no evidence of seizure activity, we initiated clomipramine treatment with increasing doses. Dosage was adjusted during a 4-week period until the therapeutic plasma range was reached (160-192 ng/ml of clomipramine plus desmethylclomipramine corresponding to a dosis of 100 mg of clomipramine PO per day). We maintained this drug for 8 weeks, with only moderate improvement in the patient's depressive symptoms. However, the improvement was judged sufficient for her to leave the hospital with the same medication schedule. At this time depression scores were 25 on the HRDS and 21 on the MADS. Plasma clomipramine and its major metabolite levels continued to be controlled periodically and were maintained at between 160 and 200 ng/ml. Thirteen weeks after the beginning of the clomipramine therapy the patient e~perienced a clear acute relapse in mood (MDD 4 in Figure 1; HRDS, 33; and MADS, 32). At this time we proposed a cotreatment strategy, adding lithium carbonate to clomipramine. However, our patient refused to take lithium because of the possible nephrotoxicity, so we proposed carbamazepine as concomitant medication instead, which she accepted. Carbamazepine was started at a single oral dose of 200 mg/day and increased over 2 weeks to the final dose of 600 mg per day. Carbamazepine levels were monitored and plasma levels of 6 to 9.8 ttg/ml (clearly within the theoretical "therapeutic" range) were obtained after these 2 weeks without any apparent adverse effect. Plasma levels of clomipramine plus desmet~ylclomipramine fell to 70 ng/ml (for the same dose of 100 mg of clomipramine PO per day), probably because of the hepatic enzyme-inducing properties of carbamazepine. However, we did not increase the dosage of the tricyclic agent in agreement with the data reported by Baldessarini et al (1988) concerning cotreatment with tricyclic antidepressants and anticonvulsivant drugs in epileptic patients, and because a method for detecting the tricyclic hydroxy derivates was not available in our department. The patient's mood and most depressive symptoms improved rapidly, 36-48 hr after administration of the first dose of carbamazepine. This early improvement concerned both the depressive and the anxiety-type symptoms. Seven days later the patient was entirely recovered. Our patient remained euthymic for I whole year with this same combination. No adverse effects were observed. Thirteen months after the beginning of the effective treatment and against our advice, the patient interrupted her medications because "she felt well enough to stop them." Ten days after the discontinuation, she suffered another acute depressive relapse. The depression scores this time were 34 on the HDRS and 32 on the MADS. We reintroduced clomipramine alone (100 mg per day reached over a 2-week period with plasma levels of 170-200 ng/ml). This treatment was then continued for 4 weeks, again with only a very moderate improvement (HRD~, 25; MADS, 26). During the 6th week of the present relapse, carbamazepine was once more added to
372
BIOL PSYCHIATRY 1992:32:369-374
J.M. De la Fuente and J. Mendlewicz
clomipramine. An initial dose of 200 mg was progressively increased until a final dose of 600 mg per day was reached over a 2-week period. Plasma levels 8 weeks after the introduction of clomipramine (second week after the initiation of carbamazepine) were 50 ng/ml for clomipramine plus desmethylclomipramine and 4,1 p.g/ml for carbamazepine. As in our first combined trial, all the depressive as well as the anxiety-type symptoms improved rapidly within 36-48 hr and the patient was entirely recovered within 8 days. Our patient has remained euthymic on the same medication schedule for almost 8 months now.
Discussion The case reported here concerns four consecutive episodes of unipolar depression resistant to tricyclic treatment alone. This patient was then successfully treated with the addition of carbamazepine to clomipramine. After the patient discontinued her treatment and relapsed (fifth acute depressive episode), a new clinical remission was again obtained rapidly after adding carbamazepine to a 6-week treatment with clomipramine. Carbamazepine has already been reported to be an effective prophylactic agent in bipolar and unipolar depression, alone or in combination with lithium (Takezaki and Hanaoka 1971; Dalbi 1971). It has also been reported to have some efficacy when given alone in acute depression (Post et al 1986). In our opinion, the antidepressant effect in this patient is not merely a delayed effect of clomipramine alone, nor is it due to the putative antidepressant effect of carbamazepine only, but rather to its combination with the tricyclic drug. Indeed, Post et al (1986) reported that their depressive patients who responded to carbamazepine monotherapy showed improvement in a time course similar to that observed with classical antidepressant drugs, whereas our patient showed a dramatic switch of mood already 36-48 hr after we added carbamazepine. Moreover, the rapid mood switch resembles the switches observed when lithium is added to a tricyclic agent in the treatment of resistant depression (De Montigny et al 1981, 1983). On the other hand, the longer duration of the three first episodes contrasting with the rapidity of the two lasts switches of mood (when we added carbamazepine to the clomipramine) advocate against the occurrence of a spontaneous remission. Finally, the fact that the patient spontaneously stopped this combination and relapsed gave us the opportunity to confirm our initial hypothesis through a naturalistic off-on/off-on pharmacological model. As in the case of lithium, the neurobiological explanation for the present therapeutic effect of carbamazepine remains unclear. When lithium is added to tricyclic compounds (TCA) it has been postulated that its augmentation effect is mediated through an enhancement of the serotoninergic presynaptic function (release of serotonin [5-HT]) on TCA-hypersensitized postsynaptic 5-HT receptors (De Montigny et al 1981, 1983). Neuroendocrine challenge tests in humans have recently suggested that carbamazepine may also increase presynaptic 5-HT neurotransmission (Elphick et al 1990). There might be at least three mechanisms by which the serotoninergic presynaptic function could be enhanced by carbamazepine.
Carbamazepine in Tricyclic Resistance
BIOL PSYCHIATRY 1992;32:369--.374
373
1. As with lithium, carbamazepine m~,y increase total and free plasma tryptophan levels in humans (Pratt et al 1984) and is known to enhance brain levels of 5-HT and 5-Hydroxyindoleacetic acht in mice (Pratt et al 1985). 2. On the other hand, Eiphick et al (1990) observed that the carbamazepine enhancement of the 5-HT brain function i~ humans was not concomitant to any increase of total tryptophan plasma levels and so was probably independent of this effect. Unfortunately they did not measure the free fraction of this amino acid. 3. Finally, there is mounting evidence for a direct ~ction of carbamazepine on adenosine receptors. Marangos et al (1983, 1987) found a potent inhibitory effect of carbamazepine on adenosine receptor binding that is competitive. They postulated an antagonist effect of carbamazepine on the adenosine receptor. As we know that adenosine has presynaptic modula*.oryeffects on most ~'teurotransmitters (decreasing their release) including serotonin (Fredholm and Dunwiddie 1988) it seems logical to postulate a presynaptic serotoninergic enhancement of carbamazepine via the inhibition of the serotonin release-inhibitor adenosine. Thus, it seems acceptable that an enhancement of presynaptic brain 5-HT function on TCA-hypersensitized postsynaptic serotonin receptors may constitute a common neuropharmacologic effect for lithium and carbamazepine in tricyclic-addition strategies. To our knowledge this is the first observation reporting the success of adding carbamazepine to a tricyclic antidepressant (clomipramine) in the treatment of a tricyclicresistant recurrent unipolar major depression. Systematic controlled studies are needed to confirm and extend this prel:rninary observation in a sample of patients with resistant depression.
References Baldessarini RJ, Teicher MH, Cassidy JW, Stein MH (1988): Anticonvulsant cotreatment may increase toxic metabolites of antidepressants and other psychotropic drugs. J Clin Psychopharmacol 8:381-382. Ballenger JC (1988): The clinical use of carbamazepine in affective disorders. J Clin Psychiatry 49(Suppl): 13-19. Dalby MA (1971): Anti-epileptic and psychotropic effect of Carbamazepine in the treatment of psychomotor epilepsy. Epilepsia 12:325-334. De Montigny C, Grunberg F, Mayer A, Deschenes JP (1981): Lithium induces rapid relief of depression in tricyclic antidepressant drug nonresponders. Br J Psychiatry 138:252-256. De Montigny C, Cournoyer G, Morissette R, Langlois R, Caill6 G (1983): Lithium carbonate addition in tricyclic antidepressant-resistant unipelar depression. Arch Gen Psychiatry 40:13271334. Elphick M (1989): Clinical issues in the use of carbamazepine in psychiatry: A review. Psychol Med 19:591-604. Elphick M, Yang JD, Cowen PJ (1990): Effects of carbamazepine on dopamine~ and serotoninmediated neuroendocrine responses. Arch Gen Psychiatry 47:135-140. Folstein M, Folstein S, McHughTR (! 975): Mini mental state examination. J Psychiatr Res 12:189198. Fredholm BB, Dunwiddie TV (1988): How does adenosine inhibit transmitter release? TIPS 9:130134. KobayashiA, KishimotoA, InagakiT (1988): Treatmentof periodic depression with carbamazepine. Acta Psychiatr Scand 77:364-367.
374
BIOL PSYCHIATRY 1992;32:369-374
J.M. De la Fuente and J. Mendlewicz
Marangos PJ, Post RM, Patel J, Zander K, Parma A, Weiss S (1983): Specific and potent interactions of carbamazepine with brain adenosine receptors. Eur J Pharmacol 93:175-182. Marangos PJ, Patel .!, Smith KD, Post RM (1987): Epilepsia 28:387-394. Meltzer HY (1987): Psychopharmacology: A Third Generation of Progress. New York: Raven Press. Nierenberg AA, Amsterdam JD (1990): Treatment-resistant depression: Definition and treatment approaches. J Clin Psychiatry 51(6 Suppl): 39-47. Post RM, Uhde TW, Roy-Byrne PP, Joffe RT (1986): Antidepressant effects of carbamazepine. Am J Psychiatry 143:29-34. Prasad AJ (1985): Efficacy of carbamazepine as an antidepressant in chronic resistant depressives. J Indian Med Assoc 83:235-237. Pratt JA, Jenner P, Reynolds EH, Shorvon SD (1984): Anticonvulsant drugs produce different effects on plasma tryptophan concentrations in epileptic patients. In: Progress in Tryptophan and Serotonin Research (Schlossberger HG, Kochen W, Linzen B and Steinhart H Eds): 479--482. Walter de Gruyter Berlin. Pratt JA, Jenner P, Marsden CD (1985a): Comparison of the effects of benzodiazepines and other anticonvulsant drugs on synthesis and utilization of 5-HT in mouse brain. Neuropharmacology 24:59-68. Spitzer RL, Endicott J, Robins E (1978): Research diagnostic criteria: Rationale and reliability. Arch Gen Psvchiat~, ~5:773 -782. Takezaki H, Hanaoka M (1971): The use of carbamazepine in the control of manic-depressive psychosis and other manic, depressive states. Seishin igaku 13:173-183.
369
Carbamazepine Addition in Tricyclic AntidepressantResistant Unipolar Depression Jos6 M. De la Fuente and Julien Mendlewicz
Introduction Patients with treatment-resistant depression constitute a minority but they consume a great portion of the clinician's time. The incidence is estimated to be over 10% to 30% of total depressive disorders (Nierenberg et al 1990). The literature is scanty and there is no systematic research on how to treat these affective-disordered patients who fail to respond to adequate antidepressant trials (therapeutic doses of medication given for a sufficient length of time). However, there are several strategies that most clinicians have used, sometimes empirically, to solve the problem. These strategies are increasing the dosage of the antidepressant agent, changing to another antidepressant of the same group, changing the family of drugs, cotreating with lithium or L-tryptophan, administering two antidepressants from different chemical groups, and so on. So far, there is no general consensus about the ideal therapeutic attitude for resistant depression. Carbamazepine has been used in the management of pain syndromes such as trigeminal neuralgia, and as an anticonvulsant drug since the 1960s (for review, see Elphick 1989). Subsequent evidence of its beneficial effect not only on epilepsy but also on the psychological condition of epileptic patients (independently of the improvement in the seizure disorder) has made this drug a very important tool in the management of affective and behavioral disorders. Carbamazepine has been prescribed frequently in clinical psychiatry since the early 1970s. Takezaki and Hanaoka first reported its usefulness in 1971 as an antimanic agent. Their experience was followed by a large number of case-reports and of patient's series confirming these findings (Dalby 1971; Kobayashi~ et al 1988). Most clinical trials have focused on its now-demonstrated efficacy as a prophylactic agent in manic depression. There are very few trials aimed at acute treatment of depression. Post et al (1986) found some acute antidepressant ,efficacy when they prescribed carbamazepine only, for an average of 45 days; the effects became apparent after only 1-2 weeks. In an open trial of carbamazepine in chronically depressed patients, Prasad (1985) reported that 11 out of 12 patients showed improvement. However, the available data suggest that carbamazepine is not very effective in the acute treatment of depression (for review, see Ballenger 1988). Here we report the case of a patient with major depression resistant to tricyclic med-
From the Department of Psychiatry, H6pital Erasme, Bmbsels, Belgium. Address reprint requests to Jos~ M. De la Fuente, Departmentof Psychiatry, HOpitaiErasme, Route de Lennik 808, B.1070 Brussels, Belgium. Received May 18, 1991; revised March 3, 1992. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
F-OFF ..........
35
J.M. De la Fuente and J. Mendlewicz
BIOL PSYCHIATRY 1992;32:369-374
370
RDD 3
l-ON ..........
MDD4
I OFF
I
ON
MDD 5
HADS
30 25 20 15 10
|
o
|
i CLOHI
a,OHl ° CBZ
P ALL
(~.,OHl, CX
Figure 1
ication who was successfully treated by the addition of carbamazepine to clomipramine. The pharmacological design was an off-on/off-on design spontaneously produced by the patient's interrupting the dn~g-combination therapy.
Case Report Ms. GV, a 7 l-year-old woman was admitted to our inpatient psychiatric unit in October 1989. The Research Diagnostic Criteria (Spit,~er et al 1978) diagnosis at admission was a major depressive disorder of primary, endogenous s~lbtype, mainly anxious, without psychotic features, unipolar and recurrent. The patient did not exhibit any cognitive impairment. The Mini Mental State Examination (Folstein et al 1975) was of 30/30 at admission and at discharge. Depression scores at admission were 31 and 32 on the Hamilton Depression Rating Scale (HRDS.24) .and the Montgomery and Asberg Depression Scale (MADS), respectively. (See Figure l.) Previously, our patient had expelienced two other depressive episodes since the age of 59. In the past she had received melitracene/flupenthixol, nortryptiline, amitryptiline, and various anxiolytic treatments, with no significant improvement. She never received lithium nor any other prophylactic medication. The former hospitalization (second depressive episode) was motivated by a serious suicidal attempt (self-poisoning) in July 1989. At that time, she received amitryptiline
Carbamazepine in Tricyclic Resistance
BIOL PSYCHIATRY 1992;32:369--374
371
(200 mg per day), which produced sufficient symptom remission to allow discharge from the hospital in September 1989. At the time of admission, she had been taking 200 mg of amitryptiline for 3 months, but suffered a severe depressive relapse for approximately 15 days prior to admission. We first proceeded to progressively withdraw all psychotropic medication within a period of 10 days. After a physical check-up and an electroencephalographic sleep recording lasting 2 consecutive nights (after 1 habituation night) thal~,showed a shortened REM-latency (43 and 13 min) and no evidence of seizure activity, we initiated clomipramine treatment with increasing doses. Dosage was adjusted during a 4-week period until the therapeutic plasma range was reached (160-192 ng/ml of clomipramine plus desmethylclomipramine corresponding to a dosis of 100 mg of clomipramine PO per day). We maintained this drug for 8 weeks, with only moderate improvement in the patient's depressive symptoms. However, the improvement was judged sufficient for her to leave the hospital with the same medication schedule. At this time depression scores were 25 on the HRDS and 21 on the MADS. Plasma clomipramine and its major metabolite levels continued to be controlled periodically and were maintained at between 160 and 200 ng/ml. Thirteen weeks after the beginning of the clomipramine therapy the patient e~perienced a clear acute relapse in mood (MDD 4 in Figure 1; HRDS, 33; and MADS, 32). At this time we proposed a cotreatment strategy, adding lithium carbonate to clomipramine. However, our patient refused to take lithium because of the possible nephrotoxicity, so we proposed carbamazepine as concomitant medication instead, which she accepted. Carbamazepine was started at a single oral dose of 200 mg/day and increased over 2 weeks to the final dose of 600 mg per day. Carbamazepine levels were monitored and plasma levels of 6 to 9.8 ttg/ml (clearly within the theoretical "therapeutic" range) were obtained after these 2 weeks without any apparent adverse effect. Plasma levels of clomipramine plus desmet~ylclomipramine fell to 70 ng/ml (for the same dose of 100 mg of clomipramine PO per day), probably because of the hepatic enzyme-inducing properties of carbamazepine. However, we did not increase the dosage of the tricyclic agent in agreement with the data reported by Baldessarini et al (1988) concerning cotreatment with tricyclic antidepressants and anticonvulsivant drugs in epileptic patients, and because a method for detecting the tricyclic hydroxy derivates was not available in our department. The patient's mood and most depressive symptoms improved rapidly, 36-48 hr after administration of the first dose of carbamazepine. This early improvement concerned both the depressive and the anxiety-type symptoms. Seven days later the patient was entirely recovered. Our patient remained euthymic for I whole year with this same combination. No adverse effects were observed. Thirteen months after the beginning of the effective treatment and against our advice, the patient interrupted her medications because "she felt well enough to stop them." Ten days after the discontinuation, she suffered another acute depressive relapse. The depression scores this time were 34 on the HDRS and 32 on the MADS. We reintroduced clomipramine alone (100 mg per day reached over a 2-week period with plasma levels of 170-200 ng/ml). This treatment was then continued for 4 weeks, again with only a very moderate improvement (HRD~, 25; MADS, 26). During the 6th week of the present relapse, carbamazepine was once more added to
372
BIOL PSYCHIATRY 1992:32:369-374
J.M. De la Fuente and J. Mendlewicz
clomipramine. An initial dose of 200 mg was progressively increased until a final dose of 600 mg per day was reached over a 2-week period. Plasma levels 8 weeks after the introduction of clomipramine (second week after the initiation of carbamazepine) were 50 ng/ml for clomipramine plus desmethylclomipramine and 4,1 p.g/ml for carbamazepine. As in our first combined trial, all the depressive as well as the anxiety-type symptoms improved rapidly within 36-48 hr and the patient was entirely recovered within 8 days. Our patient has remained euthymic on the same medication schedule for almost 8 months now.
Discussion The case reported here concerns four consecutive episodes of unipolar depression resistant to tricyclic treatment alone. This patient was then successfully treated with the addition of carbamazepine to clomipramine. After the patient discontinued her treatment and relapsed (fifth acute depressive episode), a new clinical remission was again obtained rapidly after adding carbamazepine to a 6-week treatment with clomipramine. Carbamazepine has already been reported to be an effective prophylactic agent in bipolar and unipolar depression, alone or in combination with lithium (Takezaki and Hanaoka 1971; Dalbi 1971). It has also been reported to have some efficacy when given alone in acute depression (Post et al 1986). In our opinion, the antidepressant effect in this patient is not merely a delayed effect of clomipramine alone, nor is it due to the putative antidepressant effect of carbamazepine only, but rather to its combination with the tricyclic drug. Indeed, Post et al (1986) reported that their depressive patients who responded to carbamazepine monotherapy showed improvement in a time course similar to that observed with classical antidepressant drugs, whereas our patient showed a dramatic switch of mood already 36-48 hr after we added carbamazepine. Moreover, the rapid mood switch resembles the switches observed when lithium is added to a tricyclic agent in the treatment of resistant depression (De Montigny et al 1981, 1983). On the other hand, the longer duration of the three first episodes contrasting with the rapidity of the two lasts switches of mood (when we added carbamazepine to the clomipramine) advocate against the occurrence of a spontaneous remission. Finally, the fact that the patient spontaneously stopped this combination and relapsed gave us the opportunity to confirm our initial hypothesis through a naturalistic off-on/off-on pharmacological model. As in the case of lithium, the neurobiological explanation for the present therapeutic effect of carbamazepine remains unclear. When lithium is added to tricyclic compounds (TCA) it has been postulated that its augmentation effect is mediated through an enhancement of the serotoninergic presynaptic function (release of serotonin [5-HT]) on TCA-hypersensitized postsynaptic 5-HT receptors (De Montigny et al 1981, 1983). Neuroendocrine challenge tests in humans have recently suggested that carbamazepine may also increase presynaptic 5-HT neurotransmission (Elphick et al 1990). There might be at least three mechanisms by which the serotoninergic presynaptic function could be enhanced by carbamazepine.
Carbamazepine in Tricyclic Resistance
BIOL PSYCHIATRY 1992;32:369--.374
373
1. As with lithium, carbamazepine m~,y increase total and free plasma tryptophan levels in humans (Pratt et al 1984) and is known to enhance brain levels of 5-HT and 5-Hydroxyindoleacetic acht in mice (Pratt et al 1985). 2. On the other hand, Eiphick et al (1990) observed that the carbamazepine enhancement of the 5-HT brain function i~ humans was not concomitant to any increase of total tryptophan plasma levels and so was probably independent of this effect. Unfortunately they did not measure the free fraction of this amino acid. 3. Finally, there is mounting evidence for a direct ~ction of carbamazepine on adenosine receptors. Marangos et al (1983, 1987) found a potent inhibitory effect of carbamazepine on adenosine receptor binding that is competitive. They postulated an antagonist effect of carbamazepine on the adenosine receptor. As we know that adenosine has presynaptic modula*.oryeffects on most ~'teurotransmitters (decreasing their release) including serotonin (Fredholm and Dunwiddie 1988) it seems logical to postulate a presynaptic serotoninergic enhancement of carbamazepine via the inhibition of the serotonin release-inhibitor adenosine. Thus, it seems acceptable that an enhancement of presynaptic brain 5-HT function on TCA-hypersensitized postsynaptic serotonin receptors may constitute a common neuropharmacologic effect for lithium and carbamazepine in tricyclic-addition strategies. To our knowledge this is the first observation reporting the success of adding carbamazepine to a tricyclic antidepressant (clomipramine) in the treatment of a tricyclicresistant recurrent unipolar major depression. Systematic controlled studies are needed to confirm and extend this prel:rninary observation in a sample of patients with resistant depression.
References Baldessarini RJ, Teicher MH, Cassidy JW, Stein MH (1988): Anticonvulsant cotreatment may increase toxic metabolites of antidepressants and other psychotropic drugs. J Clin Psychopharmacol 8:381-382. Ballenger JC (1988): The clinical use of carbamazepine in affective disorders. J Clin Psychiatry 49(Suppl): 13-19. Dalby MA (1971): Anti-epileptic and psychotropic effect of Carbamazepine in the treatment of psychomotor epilepsy. Epilepsia 12:325-334. De Montigny C, Grunberg F, Mayer A, Deschenes JP (1981): Lithium induces rapid relief of depression in tricyclic antidepressant drug nonresponders. Br J Psychiatry 138:252-256. De Montigny C, Cournoyer G, Morissette R, Langlois R, Caill6 G (1983): Lithium carbonate addition in tricyclic antidepressant-resistant unipelar depression. Arch Gen Psychiatry 40:13271334. Elphick M (1989): Clinical issues in the use of carbamazepine in psychiatry: A review. Psychol Med 19:591-604. Elphick M, Yang JD, Cowen PJ (1990): Effects of carbamazepine on dopamine~ and serotoninmediated neuroendocrine responses. Arch Gen Psychiatry 47:135-140. Folstein M, Folstein S, McHughTR (! 975): Mini mental state examination. J Psychiatr Res 12:189198. Fredholm BB, Dunwiddie TV (1988): How does adenosine inhibit transmitter release? TIPS 9:130134. KobayashiA, KishimotoA, InagakiT (1988): Treatmentof periodic depression with carbamazepine. Acta Psychiatr Scand 77:364-367.
374
BIOL PSYCHIATRY 1992;32:369-374
J.M. De la Fuente and J. Mendlewicz
Marangos PJ, Post RM, Patel J, Zander K, Parma A, Weiss S (1983): Specific and potent interactions of carbamazepine with brain adenosine receptors. Eur J Pharmacol 93:175-182. Marangos PJ, Patel .!, Smith KD, Post RM (1987): Epilepsia 28:387-394. Meltzer HY (1987): Psychopharmacology: A Third Generation of Progress. New York: Raven Press. Nierenberg AA, Amsterdam JD (1990): Treatment-resistant depression: Definition and treatment approaches. J Clin Psychiatry 51(6 Suppl): 39-47. Post RM, Uhde TW, Roy-Byrne PP, Joffe RT (1986): Antidepressant effects of carbamazepine. Am J Psychiatry 143:29-34. Prasad AJ (1985): Efficacy of carbamazepine as an antidepressant in chronic resistant depressives. J Indian Med Assoc 83:235-237. Pratt JA, Jenner P, Reynolds EH, Shorvon SD (1984): Anticonvulsant drugs produce different effects on plasma tryptophan concentrations in epileptic patients. In: Progress in Tryptophan and Serotonin Research (Schlossberger HG, Kochen W, Linzen B and Steinhart H Eds): 479--482. Walter de Gruyter Berlin. Pratt JA, Jenner P, Marsden CD (1985a): Comparison of the effects of benzodiazepines and other anticonvulsant drugs on synthesis and utilization of 5-HT in mouse brain. Neuropharmacology 24:59-68. Spitzer RL, Endicott J, Robins E (1978): Research diagnostic criteria: Rationale and reliability. Arch Gen Psvchiat~, ~5:773 -782. Takezaki H, Hanaoka M (1971): The use of carbamazepine in the control of manic-depressive psychosis and other manic, depressive states. Seishin igaku 13:173-183.
