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Paradoxical mood response following antidepressant withdrawal
129X
BIOLPSYCHIATRk 19X6:?I:I1YX
CASE
IW)
REPORT
-__
-_____.
.__.-..
Paradoxical Mood Response following Antidepressant Withdrawal A. Missagh Ghadirian
Introduction Abrupt cessation of tricyclic antidepressants has been reported to be followed, in certain cases, by a paradoxical response of hypomanic or manic type (Mirin et al. 1981; Nelson et al. 1983; Dilsaver and @eden, 1984). Mirin and associates (1981) were the first to report such observations in a study of seven depressed patients who developed this phenomenon 2-7 days after drug withdrawal. Nelson and coworkers (1983) reported two patients who developed hypomanic symptoms within 36 hr after discontinuation of desipramine. In both cases, symptoms disappeared upon the reinstitution of desipramine. Jones et al. ( 1984) reported a unipolar depressed patient who manifested hypomanic symptoms 2 days after the abrupt discontinuation of a long-term tricyclic antidepressant treatment. The patient subsequently developed a pattern of fast-cycling bipolar illness. These authors also reported (1983) a rebound short-lasting therapeutic effect in a subgroup of unipolar depressed patients upon abrupt withdrawal of antidepressants.
Case Report Case I Mrs. A is a 35year-old bipolar patient whose illness began in 1977 with severe depression. She responded rapidly to tricyclic antidepressant (TCA) treatment and remained euthymic for a number of years, working as an executive secretary. In January 1983, she developed elation and euphoric mood. In May, her hypomanic symptoms worsened, and she began treatment with haloperidol, and subsequently, in June, with lithium carbonate. In August. she had improved sufficiently to resume her work, but after 3 weeks she was unable to continue due to depression. In September. she began to receive desipramine in addition to lithium, 1200 mg/day. Nevertheless, depression continued and persisted for over a year, despite prolonged treatment with desipramine (up to 225 mg/day), lithium (1500 mg/day with therapeutic plasma levels), and weekly psychotherapy. She also received I.tryptophan (3 g/day) for several months and liothyronine sodium (T3) (lo-20 mglday)
From the Department
of Psychmtry.
M&III
Untverslty:
the Affective
Hospital Centre. Verdun, Quebec, Canada. Address reprint rcque\ts to Dr. A.M. Ghadirian, Royal Vlctorla Rccened
January 29.
19x6. revwd
May
14. 19X6
Disorders
Hospital.
Clonic. Royal Vlctorki
1025 Plnr
Avenue Wr\t.
Hmpiral;
Montreal.
and the Douglax Quebec. Canada
Paradoxical Mood after Antidepressant Withdrawal
BIOL PSYCHIATRY 1986:21:1298-1300
1299
for about 1 month without success. Repeated thyroid function tests (T3 and T4) showed no abnormality. On September 4, desipramine was discontinued and she began nortriptyline up to 150 mg/day without significant effect. On October 7, in anticipation of monoamine oxidase inhibitor (MAOI) treatment, nortriptyline was discontinued within 3 days, and lithium was maintained. Within 24 hr after the cessation, she began to feel much better: her mood and affect improved significantly, she was active and mildly euphoric. A week later, her elation subsided and she remained euthymic. On November 7, during a trip to Europe, she abruptly discontinued her lithium. Initially she was euthymic, but as of the third week she became elated. In the following weeks she was increasingly euphoric, excited, and irritable. On January 4, 1985, she appeared clearly hypomanic. She resumed lithium carbonate (1500 mg/day) and began perphenazine (12 mg/day with subsequent increase to 24 mg/day). During the following 4 months, although her hypomanic symptoms subsided, she nevertheless remained relatively euphoric. She subsequently improved and returned to her job in September, almost 2 years after her depression began. This patient has a strong family history of bipolar affective disorder.
Case 2 Mr. B is a 55-year-old patient with a history of depression and alcoholism. His first major depression appeared after his divorce in July 1984. He began psychiatric treatment, but failed to continue and resumed drinking. On May 4, 1985, he was hospitalized for severe depression, excessive drinking, and suicidal ideas. He was treated with an increasing dosage of nomifersin, up to 300 mg/day, for 5 weeks without success. On June 12, imipramine was started and increased up to 300 mg/day. He responded poorly and his thyroid function tests (T3, T4) were normal. On July 4, lithium carbonate was added to his antidepressant with a dosage of 600 mg/day (plasma level 0.32 meq/liter), which was then increased to 900 mg/day. This combination led to no clinical improvement. Because of resistance to treatment, MAOI was considered, and on July 10, lithium and imipramine were discontinued. Within 48 hr of the cessation he showed a dramatic improvement. Accordingly, between 1:00 and 4:00 AM of July 12, he began to improve rapidly. At 4:00 AM, he was up and jovial, whistling in the ward. At 6:00 AM he was in a euphoric mood, cracking jokes with patients and playing the harmonica. He found this rapid mood change in the early hours of morning quite startling. The patient was kept under observation without medications for a week. He appeared mildly euphoric, but remained mostly euthymic. On July 18, he resumed lithium (900 mg/day) and was discharged on August 12. He remained stable and euthymic throughout that period. His plasma lithium levels ranged from 0.57 to 0.91 meq/liter.
Discussion Although, as stated earlier, a manic or hypomanic episode has been reported to occur after antidepressant withdrawal, it seems that all those patients, with the exception of one case (Mirin et al. 198 l), were not on a lithium-antidepressant combination. In Mirin’s report, one of the seven patients developed hypomanic symptoms after the cessation of antidepressant, despite maintenance lithium treatment. Case 1 of this study showed rapid mood change from prolonged depression to a subclinical hypomanic state, lasting about 1 week after TCA discontinuation. Lithium probably suppressed or prevented the appearance of mania. Discontinuation of lithium 1
month later removed this inhibition, and subsequently, the patient developed clear hypomanic state. It is also possible that long-term treatment with lithium given in combination with TCAs greatly changed the sensitivity of postsynaptic receptors to various neurotransmitters. The combination treatment also changed the turnover of various neurotransmitters in the brain, and consequently, the discontinuation of medications probably enhanced this mood swing. The fact that antidepressant withdrawal was associated with a more rapid change in mood than that of lithium may support the cholinergic overdrive hypothesis of behavioral activation (Dilsaver and Greden, 1984). It supports the hypothesis that bombarding postsynaptic receptors with neurotransmitter agonist molecules for a long period of time will lead to development of a compensatory decline in receptor sensitivity, which will subsequently result in an increase in receptor sensitivity when the neurotranamitter is decreased (i.e.. TCA withdrawal) (Bunney et al. 19771. In Case 2, the paradoxical mood swing from depression to elation occurred more dramatically in the early hours of the morning. This observation supports previous findings on the switch process of manic-depressive illness (Bunney et al. 1972). In both cases, the TCA alone or in combination with lithium has possibly perpetuated depression. This finding is at variance with previous reports (De Montigny et al. 1981) suggesting a synergistic effect of TCA with lithium in the treatment of refractory depression. Further research is needed to explore the effects of tricyclic antidepressant in bipolar patients during its long-term administration and upon its withdrawal.
References Bunney WE Jr, Goodwin FK, Murphy DL, ct al (1972): The “switch process” in manic-deprcssivc illness. Arch Cm Psyc’hiatyv 27:304-309. Bunney WE Jr. Post RM, Andersen AE. Kopanda RT (1977): A neuronal receptor sensitivity mechanism in affective illness (a review of evidence). Commun P .sychopharmocol 1:393%405. De Montigny depression
C, Grunberg F. Mayer A, Deschenes J-P (1981): Lithium induces rapid relief of in tricyclic antidepressant drug non-responders. Br J P.s~chiat~ I38:252-256.
Dilsaver SC, Greden JF (1984): Antidepressant withdrawal-induced activation mania): Mechanism and theoretical significance. Bruin Res Rev 319:29-48.
(hypomania
and
Jones BD, Bradwejn J, Chouinard G, Annablc L. Young T (1983): Paradoxical therapeutic response to antidepressant withdrawal. Scientific program of the 38th Annual Meeting of the Society of Biological Psychiatry, no. 45. p 79. Jones BD. Steinberg S. Chouinard G ( 1984): Fast-cycling bipolar disorder induced by withdrawal from long-term treatment with a tricyclic antidepressant. Am J Ps~chiar~ I41 : 108- 109. Mirin SM. Schatzberg AF, Creasey DE (1981): Hypomania and mania after withdrawal of tricychc antidepressants. Am J Pswshiaty l38:87 -89. Nelson JC. Schottenfeld KS. Conrad CD ( 1983): Hypomania Psychiatyv 140:624-X525.
after desipramine
withdrawal.
Am J
BIOLPSYCHIATRk 19X6:?I:I1YX
CASE
IW)
REPORT
-__
-_____.
.__.-..
Paradoxical Mood Response following Antidepressant Withdrawal A. Missagh Ghadirian
Introduction Abrupt cessation of tricyclic antidepressants has been reported to be followed, in certain cases, by a paradoxical response of hypomanic or manic type (Mirin et al. 1981; Nelson et al. 1983; Dilsaver and @eden, 1984). Mirin and associates (1981) were the first to report such observations in a study of seven depressed patients who developed this phenomenon 2-7 days after drug withdrawal. Nelson and coworkers (1983) reported two patients who developed hypomanic symptoms within 36 hr after discontinuation of desipramine. In both cases, symptoms disappeared upon the reinstitution of desipramine. Jones et al. ( 1984) reported a unipolar depressed patient who manifested hypomanic symptoms 2 days after the abrupt discontinuation of a long-term tricyclic antidepressant treatment. The patient subsequently developed a pattern of fast-cycling bipolar illness. These authors also reported (1983) a rebound short-lasting therapeutic effect in a subgroup of unipolar depressed patients upon abrupt withdrawal of antidepressants.
Case Report Case I Mrs. A is a 35year-old bipolar patient whose illness began in 1977 with severe depression. She responded rapidly to tricyclic antidepressant (TCA) treatment and remained euthymic for a number of years, working as an executive secretary. In January 1983, she developed elation and euphoric mood. In May, her hypomanic symptoms worsened, and she began treatment with haloperidol, and subsequently, in June, with lithium carbonate. In August. she had improved sufficiently to resume her work, but after 3 weeks she was unable to continue due to depression. In September. she began to receive desipramine in addition to lithium, 1200 mg/day. Nevertheless, depression continued and persisted for over a year, despite prolonged treatment with desipramine (up to 225 mg/day), lithium (1500 mg/day with therapeutic plasma levels), and weekly psychotherapy. She also received I.tryptophan (3 g/day) for several months and liothyronine sodium (T3) (lo-20 mglday)
From the Department
of Psychmtry.
M&III
Untverslty:
the Affective
Hospital Centre. Verdun, Quebec, Canada. Address reprint rcque\ts to Dr. A.M. Ghadirian, Royal Vlctorla Rccened
January 29.
19x6. revwd
May
14. 19X6
Disorders
Hospital.
Clonic. Royal Vlctorki
1025 Plnr
Avenue Wr\t.
Hmpiral;
Montreal.
and the Douglax Quebec. Canada
Paradoxical Mood after Antidepressant Withdrawal
BIOL PSYCHIATRY 1986:21:1298-1300
1299
for about 1 month without success. Repeated thyroid function tests (T3 and T4) showed no abnormality. On September 4, desipramine was discontinued and she began nortriptyline up to 150 mg/day without significant effect. On October 7, in anticipation of monoamine oxidase inhibitor (MAOI) treatment, nortriptyline was discontinued within 3 days, and lithium was maintained. Within 24 hr after the cessation, she began to feel much better: her mood and affect improved significantly, she was active and mildly euphoric. A week later, her elation subsided and she remained euthymic. On November 7, during a trip to Europe, she abruptly discontinued her lithium. Initially she was euthymic, but as of the third week she became elated. In the following weeks she was increasingly euphoric, excited, and irritable. On January 4, 1985, she appeared clearly hypomanic. She resumed lithium carbonate (1500 mg/day) and began perphenazine (12 mg/day with subsequent increase to 24 mg/day). During the following 4 months, although her hypomanic symptoms subsided, she nevertheless remained relatively euphoric. She subsequently improved and returned to her job in September, almost 2 years after her depression began. This patient has a strong family history of bipolar affective disorder.
Case 2 Mr. B is a 55-year-old patient with a history of depression and alcoholism. His first major depression appeared after his divorce in July 1984. He began psychiatric treatment, but failed to continue and resumed drinking. On May 4, 1985, he was hospitalized for severe depression, excessive drinking, and suicidal ideas. He was treated with an increasing dosage of nomifersin, up to 300 mg/day, for 5 weeks without success. On June 12, imipramine was started and increased up to 300 mg/day. He responded poorly and his thyroid function tests (T3, T4) were normal. On July 4, lithium carbonate was added to his antidepressant with a dosage of 600 mg/day (plasma level 0.32 meq/liter), which was then increased to 900 mg/day. This combination led to no clinical improvement. Because of resistance to treatment, MAOI was considered, and on July 10, lithium and imipramine were discontinued. Within 48 hr of the cessation he showed a dramatic improvement. Accordingly, between 1:00 and 4:00 AM of July 12, he began to improve rapidly. At 4:00 AM, he was up and jovial, whistling in the ward. At 6:00 AM he was in a euphoric mood, cracking jokes with patients and playing the harmonica. He found this rapid mood change in the early hours of morning quite startling. The patient was kept under observation without medications for a week. He appeared mildly euphoric, but remained mostly euthymic. On July 18, he resumed lithium (900 mg/day) and was discharged on August 12. He remained stable and euthymic throughout that period. His plasma lithium levels ranged from 0.57 to 0.91 meq/liter.
Discussion Although, as stated earlier, a manic or hypomanic episode has been reported to occur after antidepressant withdrawal, it seems that all those patients, with the exception of one case (Mirin et al. 198 l), were not on a lithium-antidepressant combination. In Mirin’s report, one of the seven patients developed hypomanic symptoms after the cessation of antidepressant, despite maintenance lithium treatment. Case 1 of this study showed rapid mood change from prolonged depression to a subclinical hypomanic state, lasting about 1 week after TCA discontinuation. Lithium probably suppressed or prevented the appearance of mania. Discontinuation of lithium 1
month later removed this inhibition, and subsequently, the patient developed clear hypomanic state. It is also possible that long-term treatment with lithium given in combination with TCAs greatly changed the sensitivity of postsynaptic receptors to various neurotransmitters. The combination treatment also changed the turnover of various neurotransmitters in the brain, and consequently, the discontinuation of medications probably enhanced this mood swing. The fact that antidepressant withdrawal was associated with a more rapid change in mood than that of lithium may support the cholinergic overdrive hypothesis of behavioral activation (Dilsaver and Greden, 1984). It supports the hypothesis that bombarding postsynaptic receptors with neurotransmitter agonist molecules for a long period of time will lead to development of a compensatory decline in receptor sensitivity, which will subsequently result in an increase in receptor sensitivity when the neurotranamitter is decreased (i.e.. TCA withdrawal) (Bunney et al. 19771. In Case 2, the paradoxical mood swing from depression to elation occurred more dramatically in the early hours of the morning. This observation supports previous findings on the switch process of manic-depressive illness (Bunney et al. 1972). In both cases, the TCA alone or in combination with lithium has possibly perpetuated depression. This finding is at variance with previous reports (De Montigny et al. 1981) suggesting a synergistic effect of TCA with lithium in the treatment of refractory depression. Further research is needed to explore the effects of tricyclic antidepressant in bipolar patients during its long-term administration and upon its withdrawal.
References Bunney WE Jr, Goodwin FK, Murphy DL, ct al (1972): The “switch process” in manic-deprcssivc illness. Arch Cm Psyc’hiatyv 27:304-309. Bunney WE Jr. Post RM, Andersen AE. Kopanda RT (1977): A neuronal receptor sensitivity mechanism in affective illness (a review of evidence). Commun P .sychopharmocol 1:393%405. De Montigny depression
C, Grunberg F. Mayer A, Deschenes J-P (1981): Lithium induces rapid relief of in tricyclic antidepressant drug non-responders. Br J P.s~chiat~ I38:252-256.
Dilsaver SC, Greden JF (1984): Antidepressant withdrawal-induced activation mania): Mechanism and theoretical significance. Bruin Res Rev 319:29-48.
(hypomania
and
Jones BD, Bradwejn J, Chouinard G, Annablc L. Young T (1983): Paradoxical therapeutic response to antidepressant withdrawal. Scientific program of the 38th Annual Meeting of the Society of Biological Psychiatry, no. 45. p 79. Jones BD. Steinberg S. Chouinard G ( 1984): Fast-cycling bipolar disorder induced by withdrawal from long-term treatment with a tricyclic antidepressant. Am J Ps~chiar~ I41 : 108- 109. Mirin SM. Schatzberg AF, Creasey DE (1981): Hypomania and mania after withdrawal of tricychc antidepressants. Am J Pswshiaty l38:87 -89. Nelson JC. Schottenfeld KS. Conrad CD ( 1983): Hypomania Psychiatyv 140:624-X525.
after desipramine
withdrawal.
Am J