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Persistent supersensitivity vomiting following neuroleptic withdrawal in an adolescent
398
BIOLPSYCHIATRY 1986:21:398-401
_-~~~~______._ -..__.
..~~..._
CASE REPORT
Persistent Supersensitivity Vomiting Following Neuroleptic Withdrawal in an Adolescent Charles S. Grob
Introduction Since the advent of antipsychotic medications in the 1950s. the syndrome of neuroleptic wrthdrawal has been described (Brooks 1959; Gallant et al. 1964). Symptoms observed following the abrupt discontinuation of neuroleptics have included movement disorders. insomnia, headaches, increased sweating, restlessness. muscular tension, aches and pains. abdominal discomfort, and nausea and vomiting (Melnyk et al. 1966). Withdrawal 01 neuroleptic medication has also been associated with the exacerbation of underlying psychotic symptomatology (Chouinard and Jones 1980). Other than studies focusing specifically on movement disorders (Gualtieri ct al. 1984). we have located only one report that briefly described neuroleptic-induced withdrawal symptoms in two children (Yepes and Winsberg 1977). All other studies have focused exclusively on the adult population. as well as on only those patients experiencing withdrawal symptoms after abrupt discontinuation of their medication (Lacoursiere et al. 1976). This report presents a young adolescent who sustained a rather surprising and marked response to the gradual discontinuation of high-dose. high-potency neuroleptic medication
Case Report “A” was a l4.5-year-old hoy who had had a 2-year history ot. global psychiatric detcrioration, marked by severe anorexia. social withdrawal, obsesstonal preoccupations, deteriorating speech function. severe ambivalent states, and, on two previous occasions. profound reduction of spontaneous movement to the point of catatonia of several weeks duration. At various times during this 2- year period of devastating illness. “A” had been alternatively diagnosed as having a major depression with psychotic features, a schizophrenic illness. and an organic brain syndrome (in spite of normal neurological evaluation). Although a variety of treatment approaches had been utilized (including 3 months of lowdose thioridazine, and later, 6 months of low-dose haloperidol), none had achieved marked reduction in symptoms. Prior to the period of time in question, “A” had been treated for
Neuroleptic Withdrawal: Supersensitivity Vomiting
BIOL PSYCHIATRY 1986;21:398-401
399
the preceding 2 months of inpatient hospitalization with high dosages of the high-potency neuroleptic halopetidol (27 mg/day), the antiparkinsonian agent benztropine (4 mg/day), and the tticyclic antidepressant imipramine (100 mg/day). Because of his poor progress, a decision was reached to alter the treatment plan. Accordingly, the haloperidol was gradually tapered over a 28-day period and then discontinued. In addition, the benztropine was tapered beginning on day 16 of haloperidol reduction and discontinued on day 6 following haloperidol discontinuation. Beginning on day 26 of haloperidol reduction, at which point he was receiving 1 mg/day haloperidol and 1 mg/day benztropine, “A” began to experience significant nausea, initially manifested by “gagging” behavior, and on the following day (day 27 of haloperidol reduction) by frequent emesis. For the following 2 weeks, “A” was essentially unable to tolerate oral or nasogastric intake and would be observed to experience repeated episodes of retching and vomiting during the course of each day. Because of his frequent emesis, the actual oral intake of imipramine during this period may have been less than the prescribed dose. During this entire period of neuroleptic discontinuation and withdrawal, “A” sustained weight loss totaling 5.4 kg, from 49.3 kg to 43.9 kg. At no time did he have fever or other signs of infectious gastroenteritis. Because of pronounced dehydration and severe orthostatic hypotension and tachycardia, he received intravenous solutions of sodium chloride, glucose, and potassium chloride. “A” continued to have nausea and retching despite rehydration and electrolyte replacement. Finally, on day 15 after the discontinuation of haloperidol, treatment with low-dose haloperidol was resumed. Within several hours after the administration of 1 mg haloperidol orally, the nausea and vomiting ceased entirely and did not recur. The patient has remained on low-dose haloperidol for the year that has elapsed since the reported unsuccessful attempt at neuroleptic discontinuation, without a recurrence of persistent emesis. Another interesting component of “A”‘s presentation was that coincident with his discontinuation of haloperidol, he began to manifest severe insomnia, irritability, heightened anxiety, excessive and inappropriate laughing, and marked mood lability. This condition ultimately manifested itself as a rapid cycling bipolar disorder, for which treatment with lithium became necessary.
Discussion This case of an adolescent who had marked neuroleptic withdrawal symptoms following gradual discontinuation of high-dose haloperidol raises several interesting issues. The butyrophenone haloperidol, a high-potency neuroleptic, is not frequently implicated in this phenomenon (Byck 1975; Luchin et al. 1980). Investigators (Gardos et al. 1978; Chouinard et al. 1984) have demonstrated the greater risk of low-potency neuroleptic withdrawal as compared to high-potency neuroleptic withdrawal and attribute the emergence of undesirable side effects to the action of low-potency neuroleptics on receptor sites other than those of the dopaminergic system. These other receptor sites, which include the muscarinic, histaminic, alpha-adrenergic, and serotonin systems, are not strongly affected during administration of the high-potency neuroleptics. It is the greater anticholinergic activity resulting from muscarinic receptor blockade by the low-potency neuroleptics that is felt to be responsible for the higher incidence of unwanted side effects provoked by withdrawal. Investigators have therefore concluded that neuroleptic withdrawal symptoms are caused by rebound cholinergic hypersensitivity (Luchin et al. 1980). The anticholinergic, antiparkinsonian agents (e.g., benztropine) often administered con-
400
BIOL PSYCHIATRY 1986:21:398-401
C.S. Groh
comitently with antipsychotic medication also appear to play a strong role in the prevention and/or production of neuroleptic withdrawal symptoms. Because of their own intrinsic cholinergic rebound effects when withdrawn (Innes and Nickerson 1975), discontinuation of the antiparkinsonian drugs may further exacerbate the rebound chohnergic hypersen sitivity induced effects already initiated by neuroleptic withdrawal, An alternative explanation for the induction of the neuroleptic withdrawal syndrome is the role of dopamine receptor supersensitivity in the chemoreceptor trigger zone (Shen et al. 1983). This explanation has been controversial. Luchins et al. proposed that previous reports attempting to attribute neuroleptic withdrawal symptoms to pure dopamine supersensitivity may have been somewhat misleading. They postulate that the simultaneous withdrawal of antiparkinsonian agents, causing chohnergic hypersensitivity, could have been the primary factor. However, Shen et al. recently reported a patient who, after abruptly discontinuing a high-potency neuroleptic (thiothixene), apparently in the absence of an antiparkinsonian or other anticholinergic agent, experienced a strong withdrawal syndrome. Further evidence for the influence of the dopamine system on neuroleptic withdrawal is provided by the induction of similar withdrawal symptoms after the discontinuation of reserpine (Kent and Wilber 1982), a medication effecting the dopamine. norepinephrine, and serotonin systems, but without effect on the cholinergic system. In the present patient, it is difficult to ascribe withdrawal symptoms, marked primarily by emesis. to discontinuation of muscarinic receptor antagonists. Although benztropine doses were also tapered, they were not discontinued until well after the syndrome had developed. Furthermore, although the doses of the anticholinergic antidepressant imipramine were eventually eliminated because of repeated retching, there were active blood levels at the onset of the withdrawal syndrome. Finally, the symptoms abated immediately after reinstitution of low-dose haloperidol. In light of evidence of increased vulnerability of children to neuroleptic withdrawal-induced dyskinesias, it seems reasonable to hypothesize that the present syndrome of persistent vomiting reflected dopamine receptor supersensitivity of the chemoreceptor zone. The degree to which neuroleptics may induce alterations of an irreversible nature remains speculative. Persistent vomiting has not been sufficiently appreciated as a neuroleptic withdrawal symptom. In this regard, we arc aware of one other child in our clinic who developed persistent vomiting upon abrupt withdrawal of haloperidol. which was reversed by reintroduction of the neuroleptic. In patients who develop severe nausea and vomiting upon reduction or withdrawal of neuroleptic medications, the possibility of neuroleptic withdrawal syndrome must be considered, and I[ indicated, ameliorated by the temporary resumption of low-dose neuroleptic. The florid mental status changes experienced by the patient following discontinuation of neuroleptic medication may be further evidence of rebound hypersensitivity of the dopamine neurotransmitter system. The role of supersensitivity phenomena in the emer gence of neuroleptic withdrawal-induced psychotic symptoms is an additional area in need of further elucidation.
References Brooks GM (1959): Withdrawal
from neuroleptic drugs. Am J P.syvchiatry 115:9X1 -932.
Byck R (1975): Drugs and the treatment ofpsychiatric disorders. In Goodman CS, Gilman A (eds). The Pharmacofogic~ Basis of Therapeutics (ed 5). New York: MacMillen, pp 152-200. Chouinard G, Jones BD (1980): Neuroleptic-induced supersensitivity psychosis: Clinical and phar
macological characteristics Am / Psvchiotrv 137: 16-2 1.
Neuroleptic Withdrawal:
Supersensitivity
BIOL PSYCHIATRY 1986;21:398401
Vomiting
‘to1
Chouinard G, Bradwein J, Annable L, Jones BD, Ross-Chouinard A (1984): Withdrawal symptoms after long-term treatment with low-potency neuroleptics. J Clin Psychiatty 45:X0-502. Gallant DM, Edwards CC, Bishop MP, Galbraith GC (1964): Withdrawal symptoms after abrupt cessation of antipsychotic compounds: Clinical confirmation in chronic schizophrenics. Am J Psychiatry
121:491493.
Gardos G, Cole JO, Tarsy D (1978): Withdrawal Am J Psychiatry
symptoms
associated with antipsychotic
drugs.
135:1321-1324.
Gualtieri CT, Quade D, Hicks RE, Mayo JP, Schroeder SR (1984): Tardive dyskinesia and other clinical consequences of neuroleptic treatment in children and adolescents. Am J Psychiatry 141:20-23.
Innes IR, Nickerson M ( 1975): Atropine, scopolamine and related antimuscarinic drugs. In Goodman CS, Gillman A (eds), The Pharmacologic Basis of Therapeutics(ed 5). New York: MacMillen, pp 5 14-532. Kent TA, Wilber RD (1982): Single case study. Reserpine withdrawal psychosis: The possible role of denervation supersensitivity of receptors. J Nerv Ment Dis 170:502-504. Lacoursiere RB, Spohn HD, Thompson K (1976): Medical effects of abrupt neuroleptic withdrawal. Compr Psychiatry
17:285-294.
Luchin DJ, Freed WJ, Wyatt RJ (1980): The role of cholinergic supersensitivity in the medical symptoms associated with withdrawal of antipsychotic drugs. Am J Psychiatry 137: 1395-1398. Melnyk WT, Worthington AG, Laverty SG (1966): Abrupt withdrawal of chlorpromazine thioridazine from schizophrenic inpatients. Can Psychiatr Assoc J 11:4 104 13. Shen WW, Baig MSA, Sata LS, Hoffstatter L (1983): Dopamine receptor supersensitivity chemoreceptor trigger zone. Biol Psychiaty 18:9 17-92 1.
and
and the
Yepes LE, Winsberg BG (1977): Vomiting during neuroleptic withdrawal in children. Am J Psychiatry 134:574.
BIOLPSYCHIATRY 1986:21:398-401
_-~~~~______._ -..__.
..~~..._
CASE REPORT
Persistent Supersensitivity Vomiting Following Neuroleptic Withdrawal in an Adolescent Charles S. Grob
Introduction Since the advent of antipsychotic medications in the 1950s. the syndrome of neuroleptic wrthdrawal has been described (Brooks 1959; Gallant et al. 1964). Symptoms observed following the abrupt discontinuation of neuroleptics have included movement disorders. insomnia, headaches, increased sweating, restlessness. muscular tension, aches and pains. abdominal discomfort, and nausea and vomiting (Melnyk et al. 1966). Withdrawal 01 neuroleptic medication has also been associated with the exacerbation of underlying psychotic symptomatology (Chouinard and Jones 1980). Other than studies focusing specifically on movement disorders (Gualtieri ct al. 1984). we have located only one report that briefly described neuroleptic-induced withdrawal symptoms in two children (Yepes and Winsberg 1977). All other studies have focused exclusively on the adult population. as well as on only those patients experiencing withdrawal symptoms after abrupt discontinuation of their medication (Lacoursiere et al. 1976). This report presents a young adolescent who sustained a rather surprising and marked response to the gradual discontinuation of high-dose. high-potency neuroleptic medication
Case Report “A” was a l4.5-year-old hoy who had had a 2-year history ot. global psychiatric detcrioration, marked by severe anorexia. social withdrawal, obsesstonal preoccupations, deteriorating speech function. severe ambivalent states, and, on two previous occasions. profound reduction of spontaneous movement to the point of catatonia of several weeks duration. At various times during this 2- year period of devastating illness. “A” had been alternatively diagnosed as having a major depression with psychotic features, a schizophrenic illness. and an organic brain syndrome (in spite of normal neurological evaluation). Although a variety of treatment approaches had been utilized (including 3 months of lowdose thioridazine, and later, 6 months of low-dose haloperidol), none had achieved marked reduction in symptoms. Prior to the period of time in question, “A” had been treated for
Neuroleptic Withdrawal: Supersensitivity Vomiting
BIOL PSYCHIATRY 1986;21:398-401
399
the preceding 2 months of inpatient hospitalization with high dosages of the high-potency neuroleptic halopetidol (27 mg/day), the antiparkinsonian agent benztropine (4 mg/day), and the tticyclic antidepressant imipramine (100 mg/day). Because of his poor progress, a decision was reached to alter the treatment plan. Accordingly, the haloperidol was gradually tapered over a 28-day period and then discontinued. In addition, the benztropine was tapered beginning on day 16 of haloperidol reduction and discontinued on day 6 following haloperidol discontinuation. Beginning on day 26 of haloperidol reduction, at which point he was receiving 1 mg/day haloperidol and 1 mg/day benztropine, “A” began to experience significant nausea, initially manifested by “gagging” behavior, and on the following day (day 27 of haloperidol reduction) by frequent emesis. For the following 2 weeks, “A” was essentially unable to tolerate oral or nasogastric intake and would be observed to experience repeated episodes of retching and vomiting during the course of each day. Because of his frequent emesis, the actual oral intake of imipramine during this period may have been less than the prescribed dose. During this entire period of neuroleptic discontinuation and withdrawal, “A” sustained weight loss totaling 5.4 kg, from 49.3 kg to 43.9 kg. At no time did he have fever or other signs of infectious gastroenteritis. Because of pronounced dehydration and severe orthostatic hypotension and tachycardia, he received intravenous solutions of sodium chloride, glucose, and potassium chloride. “A” continued to have nausea and retching despite rehydration and electrolyte replacement. Finally, on day 15 after the discontinuation of haloperidol, treatment with low-dose haloperidol was resumed. Within several hours after the administration of 1 mg haloperidol orally, the nausea and vomiting ceased entirely and did not recur. The patient has remained on low-dose haloperidol for the year that has elapsed since the reported unsuccessful attempt at neuroleptic discontinuation, without a recurrence of persistent emesis. Another interesting component of “A”‘s presentation was that coincident with his discontinuation of haloperidol, he began to manifest severe insomnia, irritability, heightened anxiety, excessive and inappropriate laughing, and marked mood lability. This condition ultimately manifested itself as a rapid cycling bipolar disorder, for which treatment with lithium became necessary.
Discussion This case of an adolescent who had marked neuroleptic withdrawal symptoms following gradual discontinuation of high-dose haloperidol raises several interesting issues. The butyrophenone haloperidol, a high-potency neuroleptic, is not frequently implicated in this phenomenon (Byck 1975; Luchin et al. 1980). Investigators (Gardos et al. 1978; Chouinard et al. 1984) have demonstrated the greater risk of low-potency neuroleptic withdrawal as compared to high-potency neuroleptic withdrawal and attribute the emergence of undesirable side effects to the action of low-potency neuroleptics on receptor sites other than those of the dopaminergic system. These other receptor sites, which include the muscarinic, histaminic, alpha-adrenergic, and serotonin systems, are not strongly affected during administration of the high-potency neuroleptics. It is the greater anticholinergic activity resulting from muscarinic receptor blockade by the low-potency neuroleptics that is felt to be responsible for the higher incidence of unwanted side effects provoked by withdrawal. Investigators have therefore concluded that neuroleptic withdrawal symptoms are caused by rebound cholinergic hypersensitivity (Luchin et al. 1980). The anticholinergic, antiparkinsonian agents (e.g., benztropine) often administered con-
400
BIOL PSYCHIATRY 1986:21:398-401
C.S. Groh
comitently with antipsychotic medication also appear to play a strong role in the prevention and/or production of neuroleptic withdrawal symptoms. Because of their own intrinsic cholinergic rebound effects when withdrawn (Innes and Nickerson 1975), discontinuation of the antiparkinsonian drugs may further exacerbate the rebound chohnergic hypersen sitivity induced effects already initiated by neuroleptic withdrawal, An alternative explanation for the induction of the neuroleptic withdrawal syndrome is the role of dopamine receptor supersensitivity in the chemoreceptor trigger zone (Shen et al. 1983). This explanation has been controversial. Luchins et al. proposed that previous reports attempting to attribute neuroleptic withdrawal symptoms to pure dopamine supersensitivity may have been somewhat misleading. They postulate that the simultaneous withdrawal of antiparkinsonian agents, causing chohnergic hypersensitivity, could have been the primary factor. However, Shen et al. recently reported a patient who, after abruptly discontinuing a high-potency neuroleptic (thiothixene), apparently in the absence of an antiparkinsonian or other anticholinergic agent, experienced a strong withdrawal syndrome. Further evidence for the influence of the dopamine system on neuroleptic withdrawal is provided by the induction of similar withdrawal symptoms after the discontinuation of reserpine (Kent and Wilber 1982), a medication effecting the dopamine. norepinephrine, and serotonin systems, but without effect on the cholinergic system. In the present patient, it is difficult to ascribe withdrawal symptoms, marked primarily by emesis. to discontinuation of muscarinic receptor antagonists. Although benztropine doses were also tapered, they were not discontinued until well after the syndrome had developed. Furthermore, although the doses of the anticholinergic antidepressant imipramine were eventually eliminated because of repeated retching, there were active blood levels at the onset of the withdrawal syndrome. Finally, the symptoms abated immediately after reinstitution of low-dose haloperidol. In light of evidence of increased vulnerability of children to neuroleptic withdrawal-induced dyskinesias, it seems reasonable to hypothesize that the present syndrome of persistent vomiting reflected dopamine receptor supersensitivity of the chemoreceptor zone. The degree to which neuroleptics may induce alterations of an irreversible nature remains speculative. Persistent vomiting has not been sufficiently appreciated as a neuroleptic withdrawal symptom. In this regard, we arc aware of one other child in our clinic who developed persistent vomiting upon abrupt withdrawal of haloperidol. which was reversed by reintroduction of the neuroleptic. In patients who develop severe nausea and vomiting upon reduction or withdrawal of neuroleptic medications, the possibility of neuroleptic withdrawal syndrome must be considered, and I[ indicated, ameliorated by the temporary resumption of low-dose neuroleptic. The florid mental status changes experienced by the patient following discontinuation of neuroleptic medication may be further evidence of rebound hypersensitivity of the dopamine neurotransmitter system. The role of supersensitivity phenomena in the emer gence of neuroleptic withdrawal-induced psychotic symptoms is an additional area in need of further elucidation.
References Brooks GM (1959): Withdrawal
from neuroleptic drugs. Am J P.syvchiatry 115:9X1 -932.
Byck R (1975): Drugs and the treatment ofpsychiatric disorders. In Goodman CS, Gilman A (eds). The Pharmacofogic~ Basis of Therapeutics (ed 5). New York: MacMillen, pp 152-200. Chouinard G, Jones BD (1980): Neuroleptic-induced supersensitivity psychosis: Clinical and phar
macological characteristics Am / Psvchiotrv 137: 16-2 1.
Neuroleptic Withdrawal:
Supersensitivity
BIOL PSYCHIATRY 1986;21:398401
Vomiting
‘to1
Chouinard G, Bradwein J, Annable L, Jones BD, Ross-Chouinard A (1984): Withdrawal symptoms after long-term treatment with low-potency neuroleptics. J Clin Psychiatty 45:X0-502. Gallant DM, Edwards CC, Bishop MP, Galbraith GC (1964): Withdrawal symptoms after abrupt cessation of antipsychotic compounds: Clinical confirmation in chronic schizophrenics. Am J Psychiatry
121:491493.
Gardos G, Cole JO, Tarsy D (1978): Withdrawal Am J Psychiatry
symptoms
associated with antipsychotic
drugs.
135:1321-1324.
Gualtieri CT, Quade D, Hicks RE, Mayo JP, Schroeder SR (1984): Tardive dyskinesia and other clinical consequences of neuroleptic treatment in children and adolescents. Am J Psychiatry 141:20-23.
Innes IR, Nickerson M ( 1975): Atropine, scopolamine and related antimuscarinic drugs. In Goodman CS, Gillman A (eds), The Pharmacologic Basis of Therapeutics(ed 5). New York: MacMillen, pp 5 14-532. Kent TA, Wilber RD (1982): Single case study. Reserpine withdrawal psychosis: The possible role of denervation supersensitivity of receptors. J Nerv Ment Dis 170:502-504. Lacoursiere RB, Spohn HD, Thompson K (1976): Medical effects of abrupt neuroleptic withdrawal. Compr Psychiatry
17:285-294.
Luchin DJ, Freed WJ, Wyatt RJ (1980): The role of cholinergic supersensitivity in the medical symptoms associated with withdrawal of antipsychotic drugs. Am J Psychiatry 137: 1395-1398. Melnyk WT, Worthington AG, Laverty SG (1966): Abrupt withdrawal of chlorpromazine thioridazine from schizophrenic inpatients. Can Psychiatr Assoc J 11:4 104 13. Shen WW, Baig MSA, Sata LS, Hoffstatter L (1983): Dopamine receptor supersensitivity chemoreceptor trigger zone. Biol Psychiaty 18:9 17-92 1.
and
and the
Yepes LE, Winsberg BG (1977): Vomiting during neuroleptic withdrawal in children. Am J Psychiatry 134:574.