Case Study Mania Associated with Fluoxetine Treatment in Adolescents SANJEEV VENKATARAMAN, M.D., MICHAEL W. NAYLOR, M.D.,
AND
CHERYL A. KING, PH.D.
Abstract. Fluoxetine, a selective serotonin reuptake inhibitor, is gaining increased acceptance in the treatment of adolescent depression. Generally safe and well tolerated by adults, fluoxetine has been reported to induce mania. The cases of five depressed adolescents, 14-16 years of age, who developed mania during pharmacotherapy with fluoxetine, are reported here. Apparent risk factors for the development of mania or hypomania during fluoxetine pharmacotherapy in this population were the combination of attention-deficit hyperactivity disorder and affective instability; major depression with psychotic features; a family history of affective disorder, especially bipolar disorder; and a diagnosis of bipolar disorder. Further study is needed to determine the optimal dosage and to identify risk factors that increase individual vulnerability to fluoxetine induced mania in adolescents. I. Am. Acad. Child Adolesc. Psychiatry, 1992,31,2:276-281. Key Words: adolescent depression, fluoxetine, mania. Fluoxetine is an atypical antidepressant that selectively inhibits serotonin reuptake (Wong et aI., 1974, 1983). Since its introduction to the United States, fluoxetine has been used in the treatment of obsessive compulsive disorder (Fontaine and Chouinard, 1986; Jenike et aI., 1989; King et aI., 1991), Tourette's syndrome (King et aI., 1991; Riddle et aI., 1990), anorexia nervosa (Gwirtsman et aI., 1990), bulimia (Freeman and Hampson, 1988; Marcus et aI., 1990), trichotillomania (Alexander, 1991), attention-deficit hyperactivity disorder (ADHD) (Barrickman et aI., 1991), and depression (Feighner, 1981; Sommi et aI., 1987; Stark and Hardison, 1985). Several articles have presented evidence strongly implicating antidepressants in the induction of hypomania or mania in bipolar patients (Bunney et aI., 1972, 1978; Prien et aI., 1973; Wehr and Goodwin, 1979). Since the initial case report of mania associated with fluoxetine treatment in a 28year-old woman (Settle and Settle, 1984), several reports of fluoxetine-induced mania in adults have been reported (Chouinard and Steiner, 1986; Lensgraf and Favazza, 1990; Nakra et aI., 1989; Turner et aI., 1985). There has been one report of a case of hypomania with fluoxetine use in a lO-year-old child (Jerome, 1991) and a recent report of fluoxetine-induced mania in an adolescent boy (Achamallah and Decker, 1991). This paper presents the case histories of five adolescents who developed mania during a course of treatment with fluoxetine, proposes potential risk factors, and discusses the differential diagnosis of fluoxetine induced mania.
Accepted October 21, 1991. From the University of Michigan Department of Psychiatry, Ann Arbor, MI. The authors would like to thank the faculty and staff on the Adolescent Psychiatry Inpatient Program at the University of Michigan Medical Center for their contributions to this paper. Reprint requests to Dr. Venkataraman, University ofMichigan Department of Psychiatry, 200 E. Hospital Center Drive, L5020, Box 0290, Ann Arbor, MI 48109-0290. 0890-8567/92/3102-0276$03.00/0©1992 by the American Academy of Child and Adolescent Psychiatry.
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Case Reports Case 1 (1991) A. was a 15-year-old girl hospitalized emergently for depression and severe suicidal ideation. At the time of admission, A. demonstrated symptoms of isolation, psychomotor retardation, hypersomnia, marked irritability, anorexia, fatigue, and anhedonia. She complained of hopelessness, worthlessness, and suicidal ideation. A. had no prior history of depression or suicide attempts. Her family history was significant for depression and a suicide attempt by a maternal aunt. The diagnosis of major depression, single episode, severe, was made based on information gained from a multidisciplinary evaluation and a structured diagnostic interview, the Schedule for Affective Disorders and Schizophrenia for School-Aged Children - Present Episode (K-SADS-P) (Puig-Antich and Ryan, 1986). A. was begun on fluoxetine 20 mg p.o. q.a.m. The dose was increased to 40 mg approximately 3 weeks after starting fluoxetine with a good clinical response. Her score on the Hamilton Rating Scale for Depression (Hamilton, 1960) decreased from 15 to 1, and her score on the Children's Depression Rating Scale-Revised Edition (Poznanski et aI., 1984) decreased from 53 to 22. She was discharged on 40 mg of fluoxetine and followed in the outpatient clinic weekly for psychotherapy and biweekly for medication monitoring. After 5 months on this regimen, A. became increasingly irritable, grandiose, impulsive, and distractible. She felt elated, had a decreased need for sleep, and had mild logorrhea. Her judgment was quite impaired, and A. attempted to "take off' in her mother's car without permission and without a planned destination. Upon reaching the car, however, she found she did not have the key and attempted to start the car using a screwdriver, ruining the ignition switch in the process. She began skipping school and stealing for the first time. On mental status evaluation, her mood was expansive, her speech was pressured, and her thought processes were circumstantial. Her fluoxetine was decreased to 20 mg p.o. q.a.m., and she was closely monitored for recurI. Am. Acad. Child Adolesc. Psychiatry, 31 :2, March 1992
FLUOXETINE AND MANIA IN ADOLESCENTS
rence of her depression and suicidal ideation and continuing signs and symptoms of mania. There was a clear decrease in symptomatology after 1 week, with complete resolution of the manic symptoms within 2 weeks of the decrease in fluoxetine dose. A. continues to be maintained on fluoxetine 20 mg p.o. q.d. Case 2 (1990) B. was a 14-year-old white girl with a previous diagnosis of ADHD treated unsuccessfully with methylphenidate and individual psychotherapy. She was first hospitalized for impulsivity, affective lability, and suicidal ideations with plans 6 months before the index hospitalization. At that time, B. met DSM-/II-R criteria for bipolar disorder not otherwise specified and ADHD based on information from the K-SADS-P interview and a multidisciplinary treatment team evaluation. Her methylphenidate was discontinued, and treatment with lithium carbonate was initiated. One week after discharge from the hospital, her parents reported that she was depressed, feeling "blah" all the time, and exhibiting decreased motor activity. On evaluation, B. appeared depressed and complained of feeling empty and of being unable to concentrate. Her psychomotor activity was decreased and her grooming and hygiene were poor. B. was begun on a regimen of fluoxetine 20 mg p.o. q.a.m. On the combined regimen of lithium carbonate and fluoxetine, her mother and school personnel reported marked improvement in symptoms. Except for an increase in her lithium carbonate to 900 mg q.d., B. remained on this regimen for 5 months. Lithium levels obtained periodically throughout the course of her treatment were always within maintenance range (0.59 to 1.06 meqlL). Five months after starting fluoxetine, B. became increasingly agitated, irritable, and labile. Her motor activity increased, she noted a decreased need for sleep, and her concentration was poor. On evaluation, her lithium level was 0.8 meqlL. Despite discontinuation of fluoxetine, her condition continued to deteriorate with a progressive increase in impulsivity, sexual promiscuity, alcohol abuse, truancy, and running away from home. Her insight and judgment were markedly impaired. She was rehospitalized, and stabilized on lithium carbonate and clonazepam before transfer to a long-term treatment facility. Case 3 (199/) C. was a 14-year-old girl referred for an outpatient evaluation by her mother for depression, anxiety, and "spells" of unknown etiology. C. was previously evaluated for depression and separation anxiety disorder at the age of 9. At that time, the recommendation for a medication trial was made, but her mother was reluctant to consider medications. C. and her mother participated in individual psychotherapy and parent guidance for several years with a mild improvement in her symptoms of depression and anxiety. Therapy was terminated 2 years before this evaluation, and C. did reasonably well in the interim. On evaluation, C. demonstrated symptoms of impaired sleep, decreased appetite, anhedonia, irritability, and suicidal ideation. Her self-esteem was poor and she harbored guilt feelings. She worried excessively about competency, J. Am. Acad. Child Adolesc. Psychiatry, 31:2, March 1992
the future, and her relationships with others. Additionally, she had episodes of lack of responsiveness to her environment with feelings of unreality and unilateral muscle weakness. An extensive neurological evaluation revealed no electrophysiological abnormalities or mass lesions that would account for the spells or the neurological symptoms. Family history was significant for bipolar affective disorder in her maternal grandfather, depression with pharmacologically induced mania in her mother, and mixed substance dependence in her father. Based on a clinical interview, the presumptive diagnoses of major depression (recurrent, moderate); conversion disorder; and parent/child problem were made. Individual psychotherapy with parent guidance was initiated to which C. initially responded favorably with complete resolution of her conversion symptoms and improvement in mood. She maintained her improvement for 6 months until December 1990, when she became progressively more depressed. At that time, C. was reevaluated using the K-SADS-P, and the diagnosis of major depression (recurrent, moderate) and social phobia were made according to DSM-II/-R criteria. She was started on fluoxetine 20 mg p.o. q.a.m. with an initial improvement in her mood. She rapidly relapsed, however, and the dose was increased to 40 mg p.o. q.a.m. Again, she experienced a brief, but substantial, improvement in her mood and the dose was further increased to 60 mg p.o. q.a.m. and in 4 weeks to 80 mg p.o. q.a.m. On this dose, she and her mother noted a marked improvement in her mood. She became less isolative and more interactive with peers. Her sleep, and appetite also showed marked improvement. This lasted for approximately 4 weeks, at which time she developed a rapidly cycling mood disorder. Her mood varied between extreme depression characterized by sadness, isolation, hypersomnia, and anhedonia and hypomania with euphoria, marked increase in energy, decreased need for sleep, increased social interactions, and mild logorrhea. She acknowledged having racing thoughts and felt more creative than usual. The depressive periods alternated every 3 days with hypomania. Her dose of fluoxetine was decreased to 40 mg daily with complete resolution of her mania. Her depressive signs and symptoms returned in full force after 3 weeks on this dose, and the fluoxetine was again increased to 60 mg p.o. q.a.m. On this regimen, her mood normalized, and she demonstrated no further signs or symptoms of either depression or hypomania. She has remained stable on this dose for greater than 5 months. Case 4 (1990) D. was a I5-year-old white female admitted emergently to an adolescent psychiatric unit for evaluation and treatment of depression, suicidal ideation, and bulimia. At the time of admission, D. complained of insomnia in all phases of sleep, loss of appetite, an inability to enjoy herself, social isolation, and suicidal ideations without plans. She exhibited psychomotor retardation, hopelessness, and pathological guilt. She reported binging on a variety of foods and inducing vomiting immediately afterward. D. had been in a group home for the 2 months before hospitalization because of alleged sexual abuse. She had no prior psychiatric history.
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D.'s family history was significant for completed suicide by her maternal grandmother and post-traumatic stress disorder (PTSD) in her father, a Vietnam veteran. D. underwent a thorough psychiatric, psychoeducational, and psychological evaluation and was interviewed using the K-SADS-P. She was diagnosed as having dysthymia (additional questions were asked to clarify this diagnosis), major depression with mood congruent psychotic features, and bulimia nervosa according to DSM-III-R criteria based on all available information. Pharmacotherapy was initiated with fluoxetine 20 mg p.o. q.a.m. Her dose was increased to 40 mg p.o. q.a.m. after 1 week with a mild improvement in her mood. After 2 weeks on fluoxetine, D. began to demonstrate loose associations, tangentiality, flight of ideas, and increasing agitation. She was irritable, at times euphoric, and had a decreased need for sleep. The fluoxetine was discontinued and thiothixene was begun to treat her psychotic symptoms. D.'s psychosis improved markedly; however, her affective symptomatology continued unabated. Her mood ranged from euphoric, giddy, and irritable to sad, tearful, hopeless, and depressed. She was begun on lithium carbonate with complete resolution of the manic symptoms. Despite this, she remained extremely depressed. Trials of imipramine and desipramine were terminated because of severe urinary retention and orthostasis. Trazodone was begun, and her mood normalized on 250 mg. She was discharged on thiothixene 4 mg q.d., lithium carbonate 1,500 mg q.d. in divided doses, and trazodone. She was on a taper of thiothixine at the time of discharge, and its discontinuation was recommended on an outpatient basis. She is lost to follow-up at this time.
Case 5 (1990) E., a I5-year-old white girl, was admitted emergently to an adolescent psychiatric unit for symptoms of mania. Presenting complaints included marked increase in anxiety, restlessness, increased motor activity, impulsivity, decreased need for sleep, pressured speech, school refusal, and extreme lability of mood over the 2-week period before admission. E. was well until age 13 years when she sought treatment for multiple phobias, anxiety, and hyperactivity. She was treated unsuccessfully with various pharmacological agents including imipramine, methylphenidate, diazepam, and alprazolam. Six months before the index hospitalization, E. was hospitalized for agitation, anxiety, and school refusal. Based on information gleaned from a multidisciplinary evaluation and a K-SADS-P interview, the diagnoses of overanxious disorder and ADHD, and possible bipolar affective disorder were made. The patient was discharged on methylphenidate 15 mg p.o. bj.d., and did reasonably well for several weeks following discharge. In the subsequent weeks, however, E. became quite depressed with sadness, tearfulness, hopelessness, and impaired self-esteem. She was prescribed imipramine and desipramine without benefit. Her methylphenidate and antidepressant were discontinued, and she was started on fluoxetine 20 mg p.o. q.a.m. 4 weeks before her second admission. E., her parents, and her teachers reported a marked initial improvement; however, she soon developed hypomania that led to fluoxe278
tine being discontinued 1 week before admission. Despite discontinuation of the fluoxetine, E.' s condition continued to deteriorate. She became floridly manic with irritability, expansive affect, extremely poor insight and judgment, marked increase in motor activity, and pressured speech with flight of ideas. Her thought processes were tangential; however, there was no additional evidence of psychosis at the time of admission. E. was treated with clonazepam and lithium carbonate with fair resolution of her symptoms at the time of discharge.
Discussion The authors report here a case series of five adolescents, aged 14 to 16 years, who developed mania or hypomania while receiving fluoxetine for treatment of depressive episodes. A summary of these findings are given in Table 1. Three of the five patients carried a K-SADS-PfDSM-III-R diagnosis of major depression, unipolar. One patient carried the diagnosis of bipolar disorder, depressed type, and was on lithium carbonate at the time of initiation of fluoxetine treatment. Patient 5 was diagnosed as having ADHD and possible bipolar disorder, depressed type. The comorbid diagnoses at the time of the evaluation included ADHD (N = 2), bulimia nervosa (N = 1), borderline personality disorder (N = 2), social phobia (N = 1), overanxious disorder (N = 1), and dysthymia (N = 1). All five patients had significant family histories for affective disorders. The patients' family history included major depression (N = 4), suicide attempts or completion (N = 3), bipolar affective disorder (N = 2), and PTSD (N = 1). Of note, all of the patients reported on were female. This represents a selection bias in that, during the time period of this report, aggressive patients, patients who abused drugs or alcohol, and conduct disordered patients were referred elsewhere. Thus few males were admitted to the unit over the time period described. In this series, adolescents became hypomanic or manic at fluoxetine dosages between 20 and 60 mg per day. Although fluoxetine blood levels were not obtained to ensure compliance, the parents took full responsibility for monitoring the administration of fluoxetine to their children to assure compliance. On the inpatient unit, mouth checks were done to enhance compliance. The time frame of onset of symptoms varied from 2 weeks (case 4) to 5 months (case 1) from the time of initiation of treatment. The relationship between the onset of manic symptomatology and the patients therapeutic response to fluoxetine was variable. One patient (case 1) experienced a substantial improvement in mood of 5 months' duration on a dose of 40 mg of fluoxetine per day before demonstrating the first symptoms of hypomania. Two patient (cases 2 and 5) with a diagnosis of bipolar disorderdepressed type at the initiation of fluoxetine showed a substantial initial antidepressant response before the onset of hypomania, one for 3 months and the other for 2 weeks following initiation of treatment. Two patients (cases 1 and 3) responded with abatement of their manic symptomatology upon decrease in fluoxetine dosage, whereas the others required pharmacological interventions to treat the mania. In two of the five patients (cases 2 and 5), symptoms were severe enough to warrant inpatient hospitalization. J. Am. Acad. Child Adolesc. Psychiatry, 31:2, March 1992
FLUOXETINE AND MANIA IN ADOLESCENTS
TABLE 1. Clinical Characteristics of Depressed Adolescents Who Developed Mania during Treatment with Fluoxetine Patient
Age (yrs)
Diagnoses
Dosage (mg)
Duration
Responses
Family History
15
Major depression, single episode Bipolar disorder NOS ADHD Borderline personality disorder Major depression, recurrent Social phobia Major depression, single episode, with psychotic features Dysthymia Bulimia nervosa Borderline personality disorder Bipolar affective disorder
40
5 months
Mania
Major depression, suicide
20
4 months
Mania
Major depression
80
8 weeks
Rapid cycling mania
Bipolar affective disorder, major depression
40
1 week
Mania with psychotic features
Suicide, PTSD
20
3 weeks
2
14
3
14
4
15
5
15
Mania
Bipolar affective disorder, major depression, suicide
ADHD Overanxious disorder
Note: NOS = not otherwise specified; ADHD = attention-deficit hyperactivity disorder; PTSD = post-traumatic stress disorder.
Mania is a symptom, not a diagnosis and there are several possible explanations for the occurrence of mania during treatment with fluoxetine. For the two patients with bipolar disorder, cases 2 and 5, mania likely represents a pharmacologically induced switch from depression to mania (Chouinard and Steiner, 1986; Nakra et aI., 1989; Settle and Settle, 1984; Turner et aI., 1985). This explanation is unsatisfactory for cases 1 and 3. The rapid resolution of their mania with downward adjustment in dosage is most consistent with the diagnosis of organic mood syndrome, manic type (Lensgraf and Favazza, 1990). It is surprising that their mania resolved so quickly, given the long elimination half-lives of fluoxetine (2-3 days; Aronoff et aI., 1984; Lemberger et aI., 1985) and its pharmacologically active metabolite, norfluoxetine (7-9 days; Lemberger et aI., 1985; Nash et aI., 1982). It may be that fluoxetine is the agent most responsible for the organic mood syndrome. Thus, the decrease in the levels of fluoxetine would coincide with resolution of manic symptoms. It is tempting to hypothesize that the organic mood syndrome in these adolescents represents a variant of the' 'serotonin syndrome" a clinical entity characterized by mental status changes such as hypomania, confusion, agitation, restlessness, myoclonus, hyperreflexia, tremors, diaphoresis, diarrhea, incoordination, and fever (Baloh et aI., 1982; Pope et aI., 1985; Price et aI., 1986; Sternbach, 1988, 1991; Thomas and Ruben, 1984). Specific physical findings may be subtle. Since first reported in man by Insel et aI. (1982), this phenomenon has been reported as an adverse consequence of pharmacotherapy with medications or medication combinations, such as fluoxetine and a monoamine oxidase inhibitor, which induce serotonin overload (Feighner et al., 1990; Price et aI., 1986). Whether the serotonin syndrome J. Am. Acad. Child Adolesc. Psychiatry, 31:2, March 1992
is due specifically to alteration in the serotonergic system of the CNS is debatable. Neurotransmitter systems other than the serotonergic system are almost certainly involved, especially the noradrenergic system (Sternbach, 1991). Cases 1 and 3 possibly represent a variant of the serotonin syndrome, as the patients' symptoms disappeared with a reduction in the dose of fluoxetine. It could be argued that the manic symptoms described simply represent an exaggerated form of agitation as described by Riddle et aI. (1990). This is an unlikely explanation as all of the adolescents presented with euphoria or expansive affect, symptoms not consistent with nonspecific agitation. These results also suggest that fluoxetine induced mania may be dose dependent for some adolescents. Recent research suggests that maximal efficacy of fluoxetine treatment is reached at 20 mg p.o. q.d. (Altamura et aI., 1988; Fabre and Putman, 1987; Schweizer et aI., 1990). Increasingly the dose may yield no additional clinical gains but predispose patients to adverse effects. Alternatively, the rate of increase in dosage may have been too great in the current group of adolescents. Clinical experience with tricyclic antidepressants in children indicates that the incidence of adverse neuropsychiatric side effects, such as agitation, may be related to the rate of increase of the tricyclic. A similar mechanism may be responsible for neuropsychiatric side effects of atypical antidepressants such as fluoxetine and needs to be studied further. Case 4 is different in that there was no prior history of bipolar illness. It is likely she had a predisposition to developing bipolar illness, and the fluoxetine triggered her first manic episode. That fluoxetine, a selective serotonin reuptake inhibitor, devoid of noradrenergic and dopaminer279
VENKATARAMAN ET AL.
gic effects (Bergstrom et aI., 1988), may induce mania raises interesting questions about the pathophysiology of bipolar affective disorder. The most subscribed to theory that attempts to explain the etiology of manic depressive illness focuses on the balance between the noradrenergic and cholinergic systems in the CNS (Janowsky, 1981). According to this theory, depression results from cholinergic (Ach) supersensitivity and mania from noradrenergic (NA) overdrive. Alteration in the NAJAch balance through enhanced noradrenergic activity induced by antidepressants has been proposed as the cause of antidepressant induced mania. The fact that a selective inhibitor of serotonin reuptake can induce mania demands that the NAJAch balance theory be reexamined, and provides further evidence for an interaction between the serotonergic and noradrenergic systems. In retrospect, the risk factors for developing mania or hypomania with fluoxetine pharmacotherapy in this sample were the combination of ADHD and affective instability, major depression with psychotic features, a family history of bipolar disorder or a strong family history of affective disorder, and a clinical history suggestive of bipolar disorder. These are not entirely surprising findings. Storber and Carlson (1982) found that bipolarity in adolescents with major depression is predicted by mood congruent psychotic features and genetic loading for affective disorders. Additionally, there have been several reports of children initially diagnosed with ADHD developing bipolar affective disorder at a later date. (Dvoredsky and Stewart, 1981; Potter, 1983; Schmidt and Freidson, 1990), and many children with atypical variants of ADHD have been shown to actually suffer form bipolar affective disorder (Isaac, 1991). One must be cautious in drawing conclusions about the safety of fluoxetine pharmacotherapy in adolescents based on this small clinical sample. Two of the five patients were referred specifically for treatment of pharmacologically induced mania by clinicians with no connection to the hospital. A third adolescent (the outpatient) is from a clinic unconnected with the authors' inpatient practice. It is hazardous, therefore, to estimate the incidence of fluoxetine induced mania in adolescents based on this report. With the increasing use of fluoxetine in child and adolescent psychiatry, it is important to ascertain the frequency and severity of side effects of fluoxetine in this age group. The authors are aware of only one previous study addressing this topic, that of Riddle et al. (1990), who found that 40% of children in a small clinical sample experienced behavioral agitation on fluoxetine. Hopefully these findings, and those of others, will enable child psychiatrists to determine those clinical characteristics that predict a good clinical response and those that predispose children and adolescents to adverse reactions to fluoxetine. The authors conclude that fluoxetine should be used cautiously in depressed adolescents with treatment being initiated at 20 mg daily and increased only after several weeks (4 or more) of pharmacotherapy. The lowest possible effective dose should be used, and the first response to the development of symptoms of hypomania or mania should be to decrease the dosage or discontinue the medication altogether. 280
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Psychiatry, 141:281-283. Turner, S. M., Jacob, R. G., Beide1, D. C. & Griffin, S. (1985), A second case of mania associated with fluoxetine (letter). Am. J.
Psychiatry, 142:274-275. Wehr, T. A. & Goodwin, F. K. (1979), Rapid cycling of manic depressives induced by tricyclic antidepressants. Arch. Gen. Psychia-
try, 36:555-559. Wong, D. T., Horng, J. S., Bymaster, F. P. et al. (1974), A selective inhibitor of serotonin uptake: Lillie 110140, 3-(p-trifluoromethylphenoxy)-n-methyl-3-phenylpropyl-amine. Lifesciences, 15:471479. - - Bymaster, F. P., Reid, L. R., et al (1983), Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors. Biochem. Pharmacal., 32: 1287-1293.
281
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CHERYL A. KING, PH.D.
Abstract. Fluoxetine, a selective serotonin reuptake inhibitor, is gaining increased acceptance in the treatment of adolescent depression. Generally safe and well tolerated by adults, fluoxetine has been reported to induce mania. The cases of five depressed adolescents, 14-16 years of age, who developed mania during pharmacotherapy with fluoxetine, are reported here. Apparent risk factors for the development of mania or hypomania during fluoxetine pharmacotherapy in this population were the combination of attention-deficit hyperactivity disorder and affective instability; major depression with psychotic features; a family history of affective disorder, especially bipolar disorder; and a diagnosis of bipolar disorder. Further study is needed to determine the optimal dosage and to identify risk factors that increase individual vulnerability to fluoxetine induced mania in adolescents. I. Am. Acad. Child Adolesc. Psychiatry, 1992,31,2:276-281. Key Words: adolescent depression, fluoxetine, mania. Fluoxetine is an atypical antidepressant that selectively inhibits serotonin reuptake (Wong et aI., 1974, 1983). Since its introduction to the United States, fluoxetine has been used in the treatment of obsessive compulsive disorder (Fontaine and Chouinard, 1986; Jenike et aI., 1989; King et aI., 1991), Tourette's syndrome (King et aI., 1991; Riddle et aI., 1990), anorexia nervosa (Gwirtsman et aI., 1990), bulimia (Freeman and Hampson, 1988; Marcus et aI., 1990), trichotillomania (Alexander, 1991), attention-deficit hyperactivity disorder (ADHD) (Barrickman et aI., 1991), and depression (Feighner, 1981; Sommi et aI., 1987; Stark and Hardison, 1985). Several articles have presented evidence strongly implicating antidepressants in the induction of hypomania or mania in bipolar patients (Bunney et aI., 1972, 1978; Prien et aI., 1973; Wehr and Goodwin, 1979). Since the initial case report of mania associated with fluoxetine treatment in a 28year-old woman (Settle and Settle, 1984), several reports of fluoxetine-induced mania in adults have been reported (Chouinard and Steiner, 1986; Lensgraf and Favazza, 1990; Nakra et aI., 1989; Turner et aI., 1985). There has been one report of a case of hypomania with fluoxetine use in a lO-year-old child (Jerome, 1991) and a recent report of fluoxetine-induced mania in an adolescent boy (Achamallah and Decker, 1991). This paper presents the case histories of five adolescents who developed mania during a course of treatment with fluoxetine, proposes potential risk factors, and discusses the differential diagnosis of fluoxetine induced mania.
Accepted October 21, 1991. From the University of Michigan Department of Psychiatry, Ann Arbor, MI. The authors would like to thank the faculty and staff on the Adolescent Psychiatry Inpatient Program at the University of Michigan Medical Center for their contributions to this paper. Reprint requests to Dr. Venkataraman, University ofMichigan Department of Psychiatry, 200 E. Hospital Center Drive, L5020, Box 0290, Ann Arbor, MI 48109-0290. 0890-8567/92/3102-0276$03.00/0©1992 by the American Academy of Child and Adolescent Psychiatry.
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Case Reports Case 1 (1991) A. was a 15-year-old girl hospitalized emergently for depression and severe suicidal ideation. At the time of admission, A. demonstrated symptoms of isolation, psychomotor retardation, hypersomnia, marked irritability, anorexia, fatigue, and anhedonia. She complained of hopelessness, worthlessness, and suicidal ideation. A. had no prior history of depression or suicide attempts. Her family history was significant for depression and a suicide attempt by a maternal aunt. The diagnosis of major depression, single episode, severe, was made based on information gained from a multidisciplinary evaluation and a structured diagnostic interview, the Schedule for Affective Disorders and Schizophrenia for School-Aged Children - Present Episode (K-SADS-P) (Puig-Antich and Ryan, 1986). A. was begun on fluoxetine 20 mg p.o. q.a.m. The dose was increased to 40 mg approximately 3 weeks after starting fluoxetine with a good clinical response. Her score on the Hamilton Rating Scale for Depression (Hamilton, 1960) decreased from 15 to 1, and her score on the Children's Depression Rating Scale-Revised Edition (Poznanski et aI., 1984) decreased from 53 to 22. She was discharged on 40 mg of fluoxetine and followed in the outpatient clinic weekly for psychotherapy and biweekly for medication monitoring. After 5 months on this regimen, A. became increasingly irritable, grandiose, impulsive, and distractible. She felt elated, had a decreased need for sleep, and had mild logorrhea. Her judgment was quite impaired, and A. attempted to "take off' in her mother's car without permission and without a planned destination. Upon reaching the car, however, she found she did not have the key and attempted to start the car using a screwdriver, ruining the ignition switch in the process. She began skipping school and stealing for the first time. On mental status evaluation, her mood was expansive, her speech was pressured, and her thought processes were circumstantial. Her fluoxetine was decreased to 20 mg p.o. q.a.m., and she was closely monitored for recurI. Am. Acad. Child Adolesc. Psychiatry, 31 :2, March 1992
FLUOXETINE AND MANIA IN ADOLESCENTS
rence of her depression and suicidal ideation and continuing signs and symptoms of mania. There was a clear decrease in symptomatology after 1 week, with complete resolution of the manic symptoms within 2 weeks of the decrease in fluoxetine dose. A. continues to be maintained on fluoxetine 20 mg p.o. q.d. Case 2 (1990) B. was a 14-year-old white girl with a previous diagnosis of ADHD treated unsuccessfully with methylphenidate and individual psychotherapy. She was first hospitalized for impulsivity, affective lability, and suicidal ideations with plans 6 months before the index hospitalization. At that time, B. met DSM-/II-R criteria for bipolar disorder not otherwise specified and ADHD based on information from the K-SADS-P interview and a multidisciplinary treatment team evaluation. Her methylphenidate was discontinued, and treatment with lithium carbonate was initiated. One week after discharge from the hospital, her parents reported that she was depressed, feeling "blah" all the time, and exhibiting decreased motor activity. On evaluation, B. appeared depressed and complained of feeling empty and of being unable to concentrate. Her psychomotor activity was decreased and her grooming and hygiene were poor. B. was begun on a regimen of fluoxetine 20 mg p.o. q.a.m. On the combined regimen of lithium carbonate and fluoxetine, her mother and school personnel reported marked improvement in symptoms. Except for an increase in her lithium carbonate to 900 mg q.d., B. remained on this regimen for 5 months. Lithium levels obtained periodically throughout the course of her treatment were always within maintenance range (0.59 to 1.06 meqlL). Five months after starting fluoxetine, B. became increasingly agitated, irritable, and labile. Her motor activity increased, she noted a decreased need for sleep, and her concentration was poor. On evaluation, her lithium level was 0.8 meqlL. Despite discontinuation of fluoxetine, her condition continued to deteriorate with a progressive increase in impulsivity, sexual promiscuity, alcohol abuse, truancy, and running away from home. Her insight and judgment were markedly impaired. She was rehospitalized, and stabilized on lithium carbonate and clonazepam before transfer to a long-term treatment facility. Case 3 (199/) C. was a 14-year-old girl referred for an outpatient evaluation by her mother for depression, anxiety, and "spells" of unknown etiology. C. was previously evaluated for depression and separation anxiety disorder at the age of 9. At that time, the recommendation for a medication trial was made, but her mother was reluctant to consider medications. C. and her mother participated in individual psychotherapy and parent guidance for several years with a mild improvement in her symptoms of depression and anxiety. Therapy was terminated 2 years before this evaluation, and C. did reasonably well in the interim. On evaluation, C. demonstrated symptoms of impaired sleep, decreased appetite, anhedonia, irritability, and suicidal ideation. Her self-esteem was poor and she harbored guilt feelings. She worried excessively about competency, J. Am. Acad. Child Adolesc. Psychiatry, 31:2, March 1992
the future, and her relationships with others. Additionally, she had episodes of lack of responsiveness to her environment with feelings of unreality and unilateral muscle weakness. An extensive neurological evaluation revealed no electrophysiological abnormalities or mass lesions that would account for the spells or the neurological symptoms. Family history was significant for bipolar affective disorder in her maternal grandfather, depression with pharmacologically induced mania in her mother, and mixed substance dependence in her father. Based on a clinical interview, the presumptive diagnoses of major depression (recurrent, moderate); conversion disorder; and parent/child problem were made. Individual psychotherapy with parent guidance was initiated to which C. initially responded favorably with complete resolution of her conversion symptoms and improvement in mood. She maintained her improvement for 6 months until December 1990, when she became progressively more depressed. At that time, C. was reevaluated using the K-SADS-P, and the diagnosis of major depression (recurrent, moderate) and social phobia were made according to DSM-II/-R criteria. She was started on fluoxetine 20 mg p.o. q.a.m. with an initial improvement in her mood. She rapidly relapsed, however, and the dose was increased to 40 mg p.o. q.a.m. Again, she experienced a brief, but substantial, improvement in her mood and the dose was further increased to 60 mg p.o. q.a.m. and in 4 weeks to 80 mg p.o. q.a.m. On this dose, she and her mother noted a marked improvement in her mood. She became less isolative and more interactive with peers. Her sleep, and appetite also showed marked improvement. This lasted for approximately 4 weeks, at which time she developed a rapidly cycling mood disorder. Her mood varied between extreme depression characterized by sadness, isolation, hypersomnia, and anhedonia and hypomania with euphoria, marked increase in energy, decreased need for sleep, increased social interactions, and mild logorrhea. She acknowledged having racing thoughts and felt more creative than usual. The depressive periods alternated every 3 days with hypomania. Her dose of fluoxetine was decreased to 40 mg daily with complete resolution of her mania. Her depressive signs and symptoms returned in full force after 3 weeks on this dose, and the fluoxetine was again increased to 60 mg p.o. q.a.m. On this regimen, her mood normalized, and she demonstrated no further signs or symptoms of either depression or hypomania. She has remained stable on this dose for greater than 5 months. Case 4 (1990) D. was a I5-year-old white female admitted emergently to an adolescent psychiatric unit for evaluation and treatment of depression, suicidal ideation, and bulimia. At the time of admission, D. complained of insomnia in all phases of sleep, loss of appetite, an inability to enjoy herself, social isolation, and suicidal ideations without plans. She exhibited psychomotor retardation, hopelessness, and pathological guilt. She reported binging on a variety of foods and inducing vomiting immediately afterward. D. had been in a group home for the 2 months before hospitalization because of alleged sexual abuse. She had no prior psychiatric history.
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D.'s family history was significant for completed suicide by her maternal grandmother and post-traumatic stress disorder (PTSD) in her father, a Vietnam veteran. D. underwent a thorough psychiatric, psychoeducational, and psychological evaluation and was interviewed using the K-SADS-P. She was diagnosed as having dysthymia (additional questions were asked to clarify this diagnosis), major depression with mood congruent psychotic features, and bulimia nervosa according to DSM-III-R criteria based on all available information. Pharmacotherapy was initiated with fluoxetine 20 mg p.o. q.a.m. Her dose was increased to 40 mg p.o. q.a.m. after 1 week with a mild improvement in her mood. After 2 weeks on fluoxetine, D. began to demonstrate loose associations, tangentiality, flight of ideas, and increasing agitation. She was irritable, at times euphoric, and had a decreased need for sleep. The fluoxetine was discontinued and thiothixene was begun to treat her psychotic symptoms. D.'s psychosis improved markedly; however, her affective symptomatology continued unabated. Her mood ranged from euphoric, giddy, and irritable to sad, tearful, hopeless, and depressed. She was begun on lithium carbonate with complete resolution of the manic symptoms. Despite this, she remained extremely depressed. Trials of imipramine and desipramine were terminated because of severe urinary retention and orthostasis. Trazodone was begun, and her mood normalized on 250 mg. She was discharged on thiothixene 4 mg q.d., lithium carbonate 1,500 mg q.d. in divided doses, and trazodone. She was on a taper of thiothixine at the time of discharge, and its discontinuation was recommended on an outpatient basis. She is lost to follow-up at this time.
Case 5 (1990) E., a I5-year-old white girl, was admitted emergently to an adolescent psychiatric unit for symptoms of mania. Presenting complaints included marked increase in anxiety, restlessness, increased motor activity, impulsivity, decreased need for sleep, pressured speech, school refusal, and extreme lability of mood over the 2-week period before admission. E. was well until age 13 years when she sought treatment for multiple phobias, anxiety, and hyperactivity. She was treated unsuccessfully with various pharmacological agents including imipramine, methylphenidate, diazepam, and alprazolam. Six months before the index hospitalization, E. was hospitalized for agitation, anxiety, and school refusal. Based on information gleaned from a multidisciplinary evaluation and a K-SADS-P interview, the diagnoses of overanxious disorder and ADHD, and possible bipolar affective disorder were made. The patient was discharged on methylphenidate 15 mg p.o. bj.d., and did reasonably well for several weeks following discharge. In the subsequent weeks, however, E. became quite depressed with sadness, tearfulness, hopelessness, and impaired self-esteem. She was prescribed imipramine and desipramine without benefit. Her methylphenidate and antidepressant were discontinued, and she was started on fluoxetine 20 mg p.o. q.a.m. 4 weeks before her second admission. E., her parents, and her teachers reported a marked initial improvement; however, she soon developed hypomania that led to fluoxe278
tine being discontinued 1 week before admission. Despite discontinuation of the fluoxetine, E.' s condition continued to deteriorate. She became floridly manic with irritability, expansive affect, extremely poor insight and judgment, marked increase in motor activity, and pressured speech with flight of ideas. Her thought processes were tangential; however, there was no additional evidence of psychosis at the time of admission. E. was treated with clonazepam and lithium carbonate with fair resolution of her symptoms at the time of discharge.
Discussion The authors report here a case series of five adolescents, aged 14 to 16 years, who developed mania or hypomania while receiving fluoxetine for treatment of depressive episodes. A summary of these findings are given in Table 1. Three of the five patients carried a K-SADS-PfDSM-III-R diagnosis of major depression, unipolar. One patient carried the diagnosis of bipolar disorder, depressed type, and was on lithium carbonate at the time of initiation of fluoxetine treatment. Patient 5 was diagnosed as having ADHD and possible bipolar disorder, depressed type. The comorbid diagnoses at the time of the evaluation included ADHD (N = 2), bulimia nervosa (N = 1), borderline personality disorder (N = 2), social phobia (N = 1), overanxious disorder (N = 1), and dysthymia (N = 1). All five patients had significant family histories for affective disorders. The patients' family history included major depression (N = 4), suicide attempts or completion (N = 3), bipolar affective disorder (N = 2), and PTSD (N = 1). Of note, all of the patients reported on were female. This represents a selection bias in that, during the time period of this report, aggressive patients, patients who abused drugs or alcohol, and conduct disordered patients were referred elsewhere. Thus few males were admitted to the unit over the time period described. In this series, adolescents became hypomanic or manic at fluoxetine dosages between 20 and 60 mg per day. Although fluoxetine blood levels were not obtained to ensure compliance, the parents took full responsibility for monitoring the administration of fluoxetine to their children to assure compliance. On the inpatient unit, mouth checks were done to enhance compliance. The time frame of onset of symptoms varied from 2 weeks (case 4) to 5 months (case 1) from the time of initiation of treatment. The relationship between the onset of manic symptomatology and the patients therapeutic response to fluoxetine was variable. One patient (case 1) experienced a substantial improvement in mood of 5 months' duration on a dose of 40 mg of fluoxetine per day before demonstrating the first symptoms of hypomania. Two patient (cases 2 and 5) with a diagnosis of bipolar disorderdepressed type at the initiation of fluoxetine showed a substantial initial antidepressant response before the onset of hypomania, one for 3 months and the other for 2 weeks following initiation of treatment. Two patients (cases 1 and 3) responded with abatement of their manic symptomatology upon decrease in fluoxetine dosage, whereas the others required pharmacological interventions to treat the mania. In two of the five patients (cases 2 and 5), symptoms were severe enough to warrant inpatient hospitalization. J. Am. Acad. Child Adolesc. Psychiatry, 31:2, March 1992
FLUOXETINE AND MANIA IN ADOLESCENTS
TABLE 1. Clinical Characteristics of Depressed Adolescents Who Developed Mania during Treatment with Fluoxetine Patient
Age (yrs)
Diagnoses
Dosage (mg)
Duration
Responses
Family History
15
Major depression, single episode Bipolar disorder NOS ADHD Borderline personality disorder Major depression, recurrent Social phobia Major depression, single episode, with psychotic features Dysthymia Bulimia nervosa Borderline personality disorder Bipolar affective disorder
40
5 months
Mania
Major depression, suicide
20
4 months
Mania
Major depression
80
8 weeks
Rapid cycling mania
Bipolar affective disorder, major depression
40
1 week
Mania with psychotic features
Suicide, PTSD
20
3 weeks
2
14
3
14
4
15
5
15
Mania
Bipolar affective disorder, major depression, suicide
ADHD Overanxious disorder
Note: NOS = not otherwise specified; ADHD = attention-deficit hyperactivity disorder; PTSD = post-traumatic stress disorder.
Mania is a symptom, not a diagnosis and there are several possible explanations for the occurrence of mania during treatment with fluoxetine. For the two patients with bipolar disorder, cases 2 and 5, mania likely represents a pharmacologically induced switch from depression to mania (Chouinard and Steiner, 1986; Nakra et aI., 1989; Settle and Settle, 1984; Turner et aI., 1985). This explanation is unsatisfactory for cases 1 and 3. The rapid resolution of their mania with downward adjustment in dosage is most consistent with the diagnosis of organic mood syndrome, manic type (Lensgraf and Favazza, 1990). It is surprising that their mania resolved so quickly, given the long elimination half-lives of fluoxetine (2-3 days; Aronoff et aI., 1984; Lemberger et aI., 1985) and its pharmacologically active metabolite, norfluoxetine (7-9 days; Lemberger et aI., 1985; Nash et aI., 1982). It may be that fluoxetine is the agent most responsible for the organic mood syndrome. Thus, the decrease in the levels of fluoxetine would coincide with resolution of manic symptoms. It is tempting to hypothesize that the organic mood syndrome in these adolescents represents a variant of the' 'serotonin syndrome" a clinical entity characterized by mental status changes such as hypomania, confusion, agitation, restlessness, myoclonus, hyperreflexia, tremors, diaphoresis, diarrhea, incoordination, and fever (Baloh et aI., 1982; Pope et aI., 1985; Price et aI., 1986; Sternbach, 1988, 1991; Thomas and Ruben, 1984). Specific physical findings may be subtle. Since first reported in man by Insel et aI. (1982), this phenomenon has been reported as an adverse consequence of pharmacotherapy with medications or medication combinations, such as fluoxetine and a monoamine oxidase inhibitor, which induce serotonin overload (Feighner et al., 1990; Price et aI., 1986). Whether the serotonin syndrome J. Am. Acad. Child Adolesc. Psychiatry, 31:2, March 1992
is due specifically to alteration in the serotonergic system of the CNS is debatable. Neurotransmitter systems other than the serotonergic system are almost certainly involved, especially the noradrenergic system (Sternbach, 1991). Cases 1 and 3 possibly represent a variant of the serotonin syndrome, as the patients' symptoms disappeared with a reduction in the dose of fluoxetine. It could be argued that the manic symptoms described simply represent an exaggerated form of agitation as described by Riddle et aI. (1990). This is an unlikely explanation as all of the adolescents presented with euphoria or expansive affect, symptoms not consistent with nonspecific agitation. These results also suggest that fluoxetine induced mania may be dose dependent for some adolescents. Recent research suggests that maximal efficacy of fluoxetine treatment is reached at 20 mg p.o. q.d. (Altamura et aI., 1988; Fabre and Putman, 1987; Schweizer et aI., 1990). Increasingly the dose may yield no additional clinical gains but predispose patients to adverse effects. Alternatively, the rate of increase in dosage may have been too great in the current group of adolescents. Clinical experience with tricyclic antidepressants in children indicates that the incidence of adverse neuropsychiatric side effects, such as agitation, may be related to the rate of increase of the tricyclic. A similar mechanism may be responsible for neuropsychiatric side effects of atypical antidepressants such as fluoxetine and needs to be studied further. Case 4 is different in that there was no prior history of bipolar illness. It is likely she had a predisposition to developing bipolar illness, and the fluoxetine triggered her first manic episode. That fluoxetine, a selective serotonin reuptake inhibitor, devoid of noradrenergic and dopaminer279
VENKATARAMAN ET AL.
gic effects (Bergstrom et aI., 1988), may induce mania raises interesting questions about the pathophysiology of bipolar affective disorder. The most subscribed to theory that attempts to explain the etiology of manic depressive illness focuses on the balance between the noradrenergic and cholinergic systems in the CNS (Janowsky, 1981). According to this theory, depression results from cholinergic (Ach) supersensitivity and mania from noradrenergic (NA) overdrive. Alteration in the NAJAch balance through enhanced noradrenergic activity induced by antidepressants has been proposed as the cause of antidepressant induced mania. The fact that a selective inhibitor of serotonin reuptake can induce mania demands that the NAJAch balance theory be reexamined, and provides further evidence for an interaction between the serotonergic and noradrenergic systems. In retrospect, the risk factors for developing mania or hypomania with fluoxetine pharmacotherapy in this sample were the combination of ADHD and affective instability, major depression with psychotic features, a family history of bipolar disorder or a strong family history of affective disorder, and a clinical history suggestive of bipolar disorder. These are not entirely surprising findings. Storber and Carlson (1982) found that bipolarity in adolescents with major depression is predicted by mood congruent psychotic features and genetic loading for affective disorders. Additionally, there have been several reports of children initially diagnosed with ADHD developing bipolar affective disorder at a later date. (Dvoredsky and Stewart, 1981; Potter, 1983; Schmidt and Freidson, 1990), and many children with atypical variants of ADHD have been shown to actually suffer form bipolar affective disorder (Isaac, 1991). One must be cautious in drawing conclusions about the safety of fluoxetine pharmacotherapy in adolescents based on this small clinical sample. Two of the five patients were referred specifically for treatment of pharmacologically induced mania by clinicians with no connection to the hospital. A third adolescent (the outpatient) is from a clinic unconnected with the authors' inpatient practice. It is hazardous, therefore, to estimate the incidence of fluoxetine induced mania in adolescents based on this report. With the increasing use of fluoxetine in child and adolescent psychiatry, it is important to ascertain the frequency and severity of side effects of fluoxetine in this age group. The authors are aware of only one previous study addressing this topic, that of Riddle et al. (1990), who found that 40% of children in a small clinical sample experienced behavioral agitation on fluoxetine. Hopefully these findings, and those of others, will enable child psychiatrists to determine those clinical characteristics that predict a good clinical response and those that predispose children and adolescents to adverse reactions to fluoxetine. The authors conclude that fluoxetine should be used cautiously in depressed adolescents with treatment being initiated at 20 mg daily and increased only after several weeks (4 or more) of pharmacotherapy. The lowest possible effective dose should be used, and the first response to the development of symptoms of hypomania or mania should be to decrease the dosage or discontinue the medication altogether. 280
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