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POSSIBLE ZIPRASIDONE-INDUCED MANIA
LETTERS TO THE EDITOR
POSSIBLE ZIPRASIDONE-INDUCED MANIA To the Editor: Atypical antipsychotics, with their unique and often variable receptor profile, provide psychiatrists with new options for the treatment of schizophrenia, schizoaffective disorder, and bipolar affective disorder. Just as varied are the receptor profiles as are the side effects and clinical responses, making the choice of an atypical antipsychotic a conundrum. The following is a case showing ziprasidone-induced mania in an adolescent while trials of other atypical antipsychotics did not, raising the question: why did ziprasidone induce mania and not the other atypical antipsychotics? S.A., a 17-year-old Greek and Middle Eastern female, with no history of substance abuse or previous psychiatric treatment, presented with severe paranoid ideations, auditory hallucinations, tactile hallucinations, and negative symptoms of psychosis in the absence of mood symptoms. Family history is significant for schizophrenia in the mother and 16-year-old brother who is being treated for prodromal symptoms of schizophrenia. Ziprasidone was started at 20 mg at night and tapered up within 1 week to 80 mg twice per day, and within 3 days of the maximal dose symptoms of mania developed evidenced by decreased need for sleep, hypervigilance, pressured elevated speech, worsening psychosis, agitation, and intrusiveness. Ziprasidone was stopped and symptoms resolved without the use of a mood stabilizer. On a subsequent hospitalization 1 year later for breakthrough psychosis, a review of all outpatient medication trials and one other hospitalization revealed adequate trials on risperidone, olanzapine, and quetiapine, all with fair effect on improving psychosis. Sertraline 100 mg had been used for the last 8 months for a major depressive episode that developed after her first hospitalization. No mood stabilizers were tried or considered. Throughout these trials no symptoms of hypomania or mania were observed, even in the presence of a selective serotonin reuptake inhibitor (SSRI). The patient’s diagnosis was consistently seen as schizophrenia, paranoid type and major depression. A review of the literature shows no cases of ziprasidoneinduced mania in an adolescent; only one report was found of ziprasidone-induced hypomania in adults (Stigler et al., 2001). Other atypical antipsychotics such as risperidone, quetiapine, and olanzapine have also been reported to induce hypomania and mania in adults (Audry et al., 2000; Benazzi, 2001; Simon et al., 2001). Tolerability of atypical antipsychotic has been of growing interest in the child and adolescent population due to their increased use (Stigler et al., 2001). These cases suggest our need for further exploration into the effects of atypical antipsychotics and how they may induce mania. Although there may be other suggestions, in this case it is thought that ziprasidone, with its characteristically high 5-
1012
HT1A receptor affinity compared with dopamine, was the cause behind the symptoms of mania. When comparing the other atypicals (risperidone, olanzapine, quetiapine), which have a high affinity to the serotonin 5-HT2A receptors compared with D2 receptors, ziprasidone shows high affinity to the 5-HT1A receptors compared with D2. Ziprasidone’s high 5-HT1A affinity and moderate 5-HT and norepinephrine uptake inhibition are thought to provide an antidepressant effect and specifically target the negative symptoms in schizophrenia. It is thought that the different receptor affinity explains why ziprasidone and not the other atypical antipsychotics caused mania. Furthermore, SSRI’s high 5-HT1A affinity is reported in the literature to sometimes induce mania in children and adolescents with and without a bipolar disorder, lending further support to the theory that ziprasidone’s high 5-HT1A affinity induced mania (Rollema et al., 2000). Although the true cause of mania in this case may remain unknown, one should always be vigilant to the potential induction of hypomania or mania with the use of atypical antipsychotics. Michael F. Larson, D.O. Adam Hauser, M.D. Adolescent Assessment Unit Cambridge Health Alliance Harvard Medical School Somerville, MA Audry JM, Simon AE, Bertschy G (2000), Possible induction of mania and hypomania by olanzapine or risperidone: a critical review of reported cases. J Clin Psychiatry 61:649–655 Benazzi F (2001), Quetiapine-associated hypomania in a women with schizoaffective disorder. Can J Psychiatry 46:182–183 Rollema H, Lu Y, Schmidt AW, Sprouse JS, Zorn SH (2000), 5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Soc Biol Psychiatry 48:229–237 Simon AE, Audry JM, Malky L, Bertschy G (2001), Hypomania-like syndrome induced by olanzapine. Int Clin Psychopharmacol 14:377–378 Stigler KA, Potenza MN, McDougle CJ (2001), Tolerability profile of atypical antipsychotics in children and adolescents. Pediatr Drugs 3:927–942 DOI: 10.1097/01.CHI.0000070255.24125.03
Commentary: Ziprasidone is an atypical antipsychotic that has been reported to be superior to placebo in the treatment of adults with mania (Keck et al., 2003), schizophrenia (Daniel et al., 1999), and schizoaffective disorder (Keck et al., 2001). Unfortunately, there is only one placebo-controlled trial that has rigorously tested ziprasidone in young people with a neuropsychiatric condition. In that one study, ziprasidone was found to be superior to placebo in the treatment of tics in children and adolescents with Tourette’s syndrome (Sallee et al., 2000). With great interest, we read Larson and Hauser’s letter, which suggests that ziprasidone may have induced mania in a 17-yearold girl. Although this may be an explanation for what the authors observed, it would be premature to assert that mania
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 9 , S E P T E M B E R 2 0 0 3
LETTERS TO THE EDITOR
is a side effect caused by treatment with ziprasidone. There are several reasons for this. First, it is not clear this patient had mania. Although many symptoms of disinhibition are noted, the fundamental mood states that characterize mania are not described. Second, was the dosing of the ziprasidone appropriate? This youngster experienced substantial difficulties at a dose of 160 mg of ziprasidone per day. There are presently no data available regarding the use of ziprasidone at this dose level. The study of Sallee et al. (2000) used a maximum total daily dose of 40 mg. It is possible that this patient received too high a dose of medication or that her medication was increased too rapidly. Third, this youth’s diagnosis is unclear. Although the authors assert that this patient has a primary diagnosis of schizophrenia, it appears that this youth has schizoaffective disorder. If this is the case and this patient did indeed develop mania, it is possible that the mania was an expression of the patient’s underlying condition. Also, the fact that this patient did not develop mania while receiving treatment with sertraline does not support the suggestion that ziprasidone has potent mood-elevating properties. The other antipsychotics that were given to this patient have all been reported to have mood-stabilizing effects. This case highlights some important considerations regarding the clinical use of any new psychotropic drug in young people. First, diagnostic rigor is essential. In addition, it is important that we as clinicians practice evidence-based medicine. There are prospective studies that have described the safe, successful use of antipsychotics in the treatment of psychotic teenagers. In the absence of failing to respond to treatments with a more extensive evidence base, it is difficult to justify the prescription of untested agents. In adults, open label and pharmacokinetic studies are completed to develop dosing paradigms for drugs in development. Because what is true regarding efficacy and safety in adults is not necessarily true in youths, a similar “drug development” approach that focuses on pharmacokinetic and open-label dose ranging trials should be pursued for young people. Newer antipsychotic agents are important therapeutic advances for adults. As these agents hold promise as being significant new additions to our treatment armamentarium, they are worthy of careful, thoughtful study in pediatric patients. Only then will we know how best to use these agents in our vulnerable patients. Note: Dr. Findling is a consultant to and has his research funded in part by Pfizer, the manufacturers of ziprasidone (Geodon威). Robert L. Findling, M.D Nora K. McNamara, M.D. Robert J. Stansbrey, M.D. University Hospitals of Cleveland
Daniel DG, Zimbroff DL, Potkin SG, Reeves KR, Harrigan EP, Lakshminarayanan M (1999), Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebocontrolled trial. Neuropsychopharmacology 20:491–505 Keck PE Jr, Reeves KR, Harrigan EP, Ziprasidone Study Group (2001), Ziprasidone in the short-term treatment of patients with schizoaffective disorder: results from two double-blind, placebo-controlled, multicenter studies. J Clin Psychopharmacol 21:27–35 Keck PE Jr, Versiani M, Potkin S, West SA, Giller E, Ice K (2003), Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry 160:741–748 Sallee FR, Kurlan R, Goetz CG et al. (2000), Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry 39:292–299 DOI: 10.1097/01.CHI.0000070256.24125.D8
ZIPRASIDONE-INDUCED OCULOGYRIC CRISIS To the Editor: Ziprasidone is a new atypical antipsychotic with a reported low potential for extrapyramidal side effects (Gerlach and Peacock, 1995). To our knowledge, dystonic reactions with ziprasidone in children have not been reported. We report an acute dystonic reaction with an oculogyric crisis in an 11-year-old boy with complex presentation of pervasive developmental disorder not otherwise specified, mild mental retardation, tics, and psychotic symptoms. The patient was an 11.6-year-old white male, whose parents were concerned about his “inappropriate behavior”; talking to himself, difficulties distinguishing fantasy from reality, withdrawn and inattentive behavior, and cognitive limitation. He had also displayed compulsive tendencies, difficulties with transition times, and mild motor and vocal tics. He had been seen by several professionals (including neurologists, child and adolescent psychiatrists, psychologists, and developmental pediatricians) in the past and had been diagnosed with developmental delays, attention-deficit/hyperactivity disorder, and cognitive delays. A prior EEG found “occasional spike discharges over the left hemisphere.” Cognitive testing identified him as functioning in the mild mental retardation range. His behavior and school performance deteriorated as he grew older. He had been treated with several medications (valproic acid, gabapentin, risperidone, olanzapine, and stimulants), but each trial ended shortly after beginning due to side effects. On Risperdal he developed a reaction characterized by sticking his tongue out. He was started on olanzapine (with some improvement of symptoms, but he gained 10 lb in 3 months, and diurnal and nocturnal enuresis resulted in parents discontinuing the medication). While on no medication, the patient continued to display significant symptoms impairing his school performance and overall functioning. For example, he reported hearing voices, was paranoid of “toys attacking me,” and continued to have poor peer interaction.
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 9 , S E P T E M B E R 2 0 0 3
1013
POSSIBLE ZIPRASIDONE-INDUCED MANIA To the Editor: Atypical antipsychotics, with their unique and often variable receptor profile, provide psychiatrists with new options for the treatment of schizophrenia, schizoaffective disorder, and bipolar affective disorder. Just as varied are the receptor profiles as are the side effects and clinical responses, making the choice of an atypical antipsychotic a conundrum. The following is a case showing ziprasidone-induced mania in an adolescent while trials of other atypical antipsychotics did not, raising the question: why did ziprasidone induce mania and not the other atypical antipsychotics? S.A., a 17-year-old Greek and Middle Eastern female, with no history of substance abuse or previous psychiatric treatment, presented with severe paranoid ideations, auditory hallucinations, tactile hallucinations, and negative symptoms of psychosis in the absence of mood symptoms. Family history is significant for schizophrenia in the mother and 16-year-old brother who is being treated for prodromal symptoms of schizophrenia. Ziprasidone was started at 20 mg at night and tapered up within 1 week to 80 mg twice per day, and within 3 days of the maximal dose symptoms of mania developed evidenced by decreased need for sleep, hypervigilance, pressured elevated speech, worsening psychosis, agitation, and intrusiveness. Ziprasidone was stopped and symptoms resolved without the use of a mood stabilizer. On a subsequent hospitalization 1 year later for breakthrough psychosis, a review of all outpatient medication trials and one other hospitalization revealed adequate trials on risperidone, olanzapine, and quetiapine, all with fair effect on improving psychosis. Sertraline 100 mg had been used for the last 8 months for a major depressive episode that developed after her first hospitalization. No mood stabilizers were tried or considered. Throughout these trials no symptoms of hypomania or mania were observed, even in the presence of a selective serotonin reuptake inhibitor (SSRI). The patient’s diagnosis was consistently seen as schizophrenia, paranoid type and major depression. A review of the literature shows no cases of ziprasidoneinduced mania in an adolescent; only one report was found of ziprasidone-induced hypomania in adults (Stigler et al., 2001). Other atypical antipsychotics such as risperidone, quetiapine, and olanzapine have also been reported to induce hypomania and mania in adults (Audry et al., 2000; Benazzi, 2001; Simon et al., 2001). Tolerability of atypical antipsychotic has been of growing interest in the child and adolescent population due to their increased use (Stigler et al., 2001). These cases suggest our need for further exploration into the effects of atypical antipsychotics and how they may induce mania. Although there may be other suggestions, in this case it is thought that ziprasidone, with its characteristically high 5-
1012
HT1A receptor affinity compared with dopamine, was the cause behind the symptoms of mania. When comparing the other atypicals (risperidone, olanzapine, quetiapine), which have a high affinity to the serotonin 5-HT2A receptors compared with D2 receptors, ziprasidone shows high affinity to the 5-HT1A receptors compared with D2. Ziprasidone’s high 5-HT1A affinity and moderate 5-HT and norepinephrine uptake inhibition are thought to provide an antidepressant effect and specifically target the negative symptoms in schizophrenia. It is thought that the different receptor affinity explains why ziprasidone and not the other atypical antipsychotics caused mania. Furthermore, SSRI’s high 5-HT1A affinity is reported in the literature to sometimes induce mania in children and adolescents with and without a bipolar disorder, lending further support to the theory that ziprasidone’s high 5-HT1A affinity induced mania (Rollema et al., 2000). Although the true cause of mania in this case may remain unknown, one should always be vigilant to the potential induction of hypomania or mania with the use of atypical antipsychotics. Michael F. Larson, D.O. Adam Hauser, M.D. Adolescent Assessment Unit Cambridge Health Alliance Harvard Medical School Somerville, MA Audry JM, Simon AE, Bertschy G (2000), Possible induction of mania and hypomania by olanzapine or risperidone: a critical review of reported cases. J Clin Psychiatry 61:649–655 Benazzi F (2001), Quetiapine-associated hypomania in a women with schizoaffective disorder. Can J Psychiatry 46:182–183 Rollema H, Lu Y, Schmidt AW, Sprouse JS, Zorn SH (2000), 5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Soc Biol Psychiatry 48:229–237 Simon AE, Audry JM, Malky L, Bertschy G (2001), Hypomania-like syndrome induced by olanzapine. Int Clin Psychopharmacol 14:377–378 Stigler KA, Potenza MN, McDougle CJ (2001), Tolerability profile of atypical antipsychotics in children and adolescents. Pediatr Drugs 3:927–942 DOI: 10.1097/01.CHI.0000070255.24125.03
Commentary: Ziprasidone is an atypical antipsychotic that has been reported to be superior to placebo in the treatment of adults with mania (Keck et al., 2003), schizophrenia (Daniel et al., 1999), and schizoaffective disorder (Keck et al., 2001). Unfortunately, there is only one placebo-controlled trial that has rigorously tested ziprasidone in young people with a neuropsychiatric condition. In that one study, ziprasidone was found to be superior to placebo in the treatment of tics in children and adolescents with Tourette’s syndrome (Sallee et al., 2000). With great interest, we read Larson and Hauser’s letter, which suggests that ziprasidone may have induced mania in a 17-yearold girl. Although this may be an explanation for what the authors observed, it would be premature to assert that mania
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 9 , S E P T E M B E R 2 0 0 3
LETTERS TO THE EDITOR
is a side effect caused by treatment with ziprasidone. There are several reasons for this. First, it is not clear this patient had mania. Although many symptoms of disinhibition are noted, the fundamental mood states that characterize mania are not described. Second, was the dosing of the ziprasidone appropriate? This youngster experienced substantial difficulties at a dose of 160 mg of ziprasidone per day. There are presently no data available regarding the use of ziprasidone at this dose level. The study of Sallee et al. (2000) used a maximum total daily dose of 40 mg. It is possible that this patient received too high a dose of medication or that her medication was increased too rapidly. Third, this youth’s diagnosis is unclear. Although the authors assert that this patient has a primary diagnosis of schizophrenia, it appears that this youth has schizoaffective disorder. If this is the case and this patient did indeed develop mania, it is possible that the mania was an expression of the patient’s underlying condition. Also, the fact that this patient did not develop mania while receiving treatment with sertraline does not support the suggestion that ziprasidone has potent mood-elevating properties. The other antipsychotics that were given to this patient have all been reported to have mood-stabilizing effects. This case highlights some important considerations regarding the clinical use of any new psychotropic drug in young people. First, diagnostic rigor is essential. In addition, it is important that we as clinicians practice evidence-based medicine. There are prospective studies that have described the safe, successful use of antipsychotics in the treatment of psychotic teenagers. In the absence of failing to respond to treatments with a more extensive evidence base, it is difficult to justify the prescription of untested agents. In adults, open label and pharmacokinetic studies are completed to develop dosing paradigms for drugs in development. Because what is true regarding efficacy and safety in adults is not necessarily true in youths, a similar “drug development” approach that focuses on pharmacokinetic and open-label dose ranging trials should be pursued for young people. Newer antipsychotic agents are important therapeutic advances for adults. As these agents hold promise as being significant new additions to our treatment armamentarium, they are worthy of careful, thoughtful study in pediatric patients. Only then will we know how best to use these agents in our vulnerable patients. Note: Dr. Findling is a consultant to and has his research funded in part by Pfizer, the manufacturers of ziprasidone (Geodon威). Robert L. Findling, M.D Nora K. McNamara, M.D. Robert J. Stansbrey, M.D. University Hospitals of Cleveland
Daniel DG, Zimbroff DL, Potkin SG, Reeves KR, Harrigan EP, Lakshminarayanan M (1999), Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebocontrolled trial. Neuropsychopharmacology 20:491–505 Keck PE Jr, Reeves KR, Harrigan EP, Ziprasidone Study Group (2001), Ziprasidone in the short-term treatment of patients with schizoaffective disorder: results from two double-blind, placebo-controlled, multicenter studies. J Clin Psychopharmacol 21:27–35 Keck PE Jr, Versiani M, Potkin S, West SA, Giller E, Ice K (2003), Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry 160:741–748 Sallee FR, Kurlan R, Goetz CG et al. (2000), Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry 39:292–299 DOI: 10.1097/01.CHI.0000070256.24125.D8
ZIPRASIDONE-INDUCED OCULOGYRIC CRISIS To the Editor: Ziprasidone is a new atypical antipsychotic with a reported low potential for extrapyramidal side effects (Gerlach and Peacock, 1995). To our knowledge, dystonic reactions with ziprasidone in children have not been reported. We report an acute dystonic reaction with an oculogyric crisis in an 11-year-old boy with complex presentation of pervasive developmental disorder not otherwise specified, mild mental retardation, tics, and psychotic symptoms. The patient was an 11.6-year-old white male, whose parents were concerned about his “inappropriate behavior”; talking to himself, difficulties distinguishing fantasy from reality, withdrawn and inattentive behavior, and cognitive limitation. He had also displayed compulsive tendencies, difficulties with transition times, and mild motor and vocal tics. He had been seen by several professionals (including neurologists, child and adolescent psychiatrists, psychologists, and developmental pediatricians) in the past and had been diagnosed with developmental delays, attention-deficit/hyperactivity disorder, and cognitive delays. A prior EEG found “occasional spike discharges over the left hemisphere.” Cognitive testing identified him as functioning in the mild mental retardation range. His behavior and school performance deteriorated as he grew older. He had been treated with several medications (valproic acid, gabapentin, risperidone, olanzapine, and stimulants), but each trial ended shortly after beginning due to side effects. On Risperdal he developed a reaction characterized by sticking his tongue out. He was started on olanzapine (with some improvement of symptoms, but he gained 10 lb in 3 months, and diurnal and nocturnal enuresis resulted in parents discontinuing the medication). While on no medication, the patient continued to display significant symptoms impairing his school performance and overall functioning. For example, he reported hearing voices, was paranoid of “toys attacking me,” and continued to have poor peer interaction.
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 9 , S E P T E M B E R 2 0 0 3
1013