Neural dysfunction in ADHD with Reading Disability during a word rhyming Continuous Performance Task.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous, neurodevelopmental disorder which co-occurs often with Reading Disability (RD). ADHD with and without RD consistently have higher inattentive ratings compared with typically developing controls, with co-occurring ADHD and RD also demonstrating impaired phonological processing. Accordingly, inattention has been associated with greater phonological impairment, though the neural correlates of the association are poorly understood from a functional neuroimaging perspective. It was postulated that only the co-occurring subgroup would demonstrate hypoactivation of posterior, left hemispheric, reading-related areas and, to a lesser extent, alterations in right hemispheric, attention areas compared with controls. METHODS: A novel word rhyming Continuous Performance Task assesses functional activation differences in phonology- and attention-related areas between three groups: ten boys with ADHD and RD, fourteen boys with ADHD without RD, and fourteen typically developing controls. Subjects respond to words that rhyme with a target word as mono- and disyllabic, English words are visually presented over 90s blocks. RESULTS: Behavioral performance was not different between groups. Some hypoactivation of left hemispheric, reading-related areas was apparent in ADHD and RD, but not ADHD without RD, compared with controls. Right hemispheric, attention areas showed alterations in both ADHD subgroups relative to controls; however, the differences for each subgroup were dissimilar. CONCLUSIONS: The dorsal decoding subnetwork may not be grossly compromised in ADHD with Reading Disability. The role of cognitive impairments, including the level of inattention, on phonology requires clarification from a neuroimaging perspective.

Decrease in thalamic volumes of pediatric patients with obsessive-compulsive disorder who are taking paroxetine.

BACKGROUND: Thalamic dysfunction has been implicated in obsessive-compulsive disorder (OCD). While OCD frequently has its onset during childhood, to our knowledge, no prior study has measured neuroanatomical changes in the thalamus of patients with OCD near the onset of illness, and before and after treatment. METHODS: Volumetric magnetic resonance imaging studies were conducted in 21 psychotropic drug-naive children, aged 8 to 17 years, with OCD and 21 case-matched healthy comparison subjects. Magnetic resonance imaging studies were also conducted in 10 of the 21 patients with OCD after 12 weeks of monotherapy with the selective serotonin reuptake inhibitor, paroxetine hydrochloride. RESULTS: Thalamic volumes were significantly greater in treatment-naive patients with OCD than in controls but declined significantly after paroxetine monotherapy to levels comparable with those of controls. Decrease in thalamic volume in patients with OCD was associated with reduction in OCD symptom severity. CONCLUSIONS: Our findings provide new evidence of thalamic abnormalities in pediatric OCD and further suggest that paroxetine treatment may be paralleled by a reduction in thalamic volume. These reductions may, however, not be specific to paroxetine treatment and could be due to a more general treatment response, and/or spontaneous improvement in symptoms. Our findings are preliminary given the small sample size and our inability to measure discrete thalamic nuclei.

Oculomotor response inhibition abnormalities in pediatric obsessive-compulsive disorder.

BACKGROUND: Disturbances in the orbital prefrontal cortex and its ventral striatal target fields have been identified in neuroimaging studies of obsessive-compulsive disorder (OCD). In animal models and studies of patients with lesions to this brain circuitry, a selective disturbance in the ability to suppress responses to irrelevant stimuli has been demonstrated. Such a deficit in response suppression might underlie the apparent inhibitory deficit suggested by the symptoms of OCD. To date, little direct evidence of such a deficit has been reported. Further, although OCD commonly emerges during childhood or adolescence, few studies have examined psychotropic-naive pediatric patients near the onset of illness to find the possible role of atypical developmental processes in this disorder. METHODS: Oculomotor tests were administered to 18 psychotropic medication-naive, nondepressed patients with OCD aged 8.8 to 16.9 years and 18 case-matched healthy comparison subjects to assess the following 3 well-delineated aspects of prefrontal cortical function: the ability to suppress responses, the volitional execution of delayed responses, and the anticipation of predictable events. RESULTS: A significantly higher percentage of response suppression failures was observed in patients with OCD (P = .003), particularly in younger patients compared with their case-matched controls. No significant differences between patients with OCD and controls were observed on other prefrontal cortical functions. Severity of OCD symptoms was related to response suppression deficits. CONCLUSIONS: A basic disturbance of behavioral inhibition in OCD was detected that may underlie the repetitive symptomatic behavior that characterizes the illness.

Frontostriatal measurement in treatment-naive children with obsessive-compulsive disorder.

BACKGROUND: Abnormalities in frontostriatal circuits have been implicated in obsessive-compulsive disorder (OCD). Although OCD commonly emerges during childhood or adolescence, few studies have examined frontostriatal anatomy in psychotropic-naive children with OCD near the onset of illness to determine the possible role of atypical developmental processes in this disorder. METHODS: Magnetic resonance imaging scans from 19 children with OCD who had not been exposed to psychotropic drugs, aged 7 to 18 years, and 19 case-matched healthy control subjects were analyzed to determine the volumes of the following structures: prefrontal cortex, striatum (caudate and putamen), lateral and third ventricles, and intracranial volume. RESULTS: Patients with OCD had significantly smaller striatal volumes and significantly larger third ventricle volumes than controls, but did not differ in prefrontal cortical, lateral ventricular, or intracranial volumes. Striatal volumes were inversely correlated with OCD symptom severity but not illness duration. CONCLUSIONS: Our findings provide new evidence of abnormalities of the striatum in pediatric OCD. These results are preliminary, given the small sample size.

A.E. Bennett Research Award. Toward a neurodevelopmental model of of obsessive--compulsive disorder.

BACKGROUND: Neurobiological models for obsessive-compulsive disorder (OCD) have consistently implicated ventral prefrontal cortical and striatal circuits in the pathophysiology of this disorder, but typically have not utilized a developmental framework for conceptualizing the illness. METHODS: We describe an integrated series of neurobiologic studies aimed at testing the hypothesis that neurodevelopmental abnormalities of ventral prefrontal-striatal circuits may be involved in and contribute to the etiology and presentation of the illness. RESULTS: Using studies of oculomotor physiology, we have identified a selective deficit in neurobehavioral response suppression in OCD that may be related to failures in the developmental maturation of frontostriatal circuitry. Magnetic resonance imaging studies showed that treatment-naive pediatric OCD patients had significant volumetric abnormalities in ventral prefrontal cortical and striatal regions but no abnormalities in dorsolateral prefrontal cortex. Severity of OCD symptoms but not illness duration was related to ventral prefrontal cortical and striatal volumes. CONCLUSIONS: Critical neurodevelopmental changes in ventral prefrontal-striatal circuitry may be associated with the initial presentation of OCD, and a developmentally mediated network dysplasia may underlie OCD. Such dysplasia in ventral prefrontal cortical circuits could manifest clinically by disrupting brain functions that mediate ongoing purposive behaviors.

Genetic and imaging strategies in obsessive-compulsive disorder: potential implications for treatment development.

In recent years, advances in brain research have resulted in a striking strategic shift in studies designed to develop new, effective treatments for neuropsychiatric disorders. This involves a multidisciplinary approach with recursive interactions among respective disciplines with the ultimate goal of contributing to treatment development. In this review we focus on treatment implications of brain imaging and molecular and pharmacogenetic studies in obsessive-compulsive disorder. Translational components of this research are addressed, including the potential for integrating advances in brain imaging and molecular and pharmacogenetic assessments as they may potentially relate to neurodiagnostic assessment and treatment development. Studies of putative susceptibility alleles in obsessive-compulsive disorder involving the serotonergic, glutamatergic, and dopaminergic systems may provide a focus for these divergent approaches. Taken together, neuroimaging and genetic methods may ultimately lead to a mechanistic understanding of the pathogenesis and maintenance of neuropsychiatric disorders such as obsessive-compulsive disorder that may, in turn, result in the development of new neurodiagnostic and treatment approaches.

Proton spectroscopic imaging of the thalamus in treatment-naive pediatric obsessive-compulsive disorder.

BACKGROUND: Neurobiological abnormalities in the thalamus, particularly the dorsomedial nucleus of the thalamus, are believed to be involved in the pathophysiology of obsessive-compulsive disorder. Although obsessive-compulsive disorder commonly arises in childhood and adolescence, no prior study has examined the thalamus in pediatric obsessive-compulsive disorder patients. METHODS: In this study, N-acetyl-aspartate, a putative marker of neuronal viability, creatine/phosphocreatine, and choline levels were measured in the lateral and medical subregions of the left and right thalami using a multislice proton magnetic resonance spectroscopic imaging sequence in 11 treatment-naive, nondepressed obsessive-compulsive disorder outpatients, 8-15 years old, and 11 case-matched control subjects. RESULTS: A significant reduction in N-acetyl-aspartate/choline and N-acetyl-aspartate/(creatine/phosphocreatine + choline) was observed in both the right and left medial thalami in obsessive-compulsive disorder patients compared with control subjects. The N-acetyl-aspartate/choline and N-acetyl-aspartate/(creatine/phosphocreatine + choline) levels did not differ significantly between case-control pairs in either the left or the right lateral thalamus. Reduction in N-acetyl-aspartate levels in the left medial thalamus was inversely correlated with increased obsessive-compulsive disorder symptom severity. CONCLUSIONS: These findings provide new evidence of localized functional neurochemical marker abnormalities in the thalamus in pediatric obsessive-compulsive disorder. Our results must be considered preliminary, however, given the small sample size.

Thalamic volume in pediatric obsessive-compulsive disorder patients before and after cognitive behavioral therapy.

BACKGROUND: Neurobiologic abnormalities in the thalamus have been implicated in the pathophysiology of obsessive-compulsive disorder. We recently reported increased thalamic volume in treatment-naive pediatric obsessive-compulsive disorder patients versus case-matched healthy comparison subjects that decreased to levels comparable to control subjects after effective paroxetine therapy. To our knowledge, no prior study has measured neuroanatomic changes in the thalamus of obsessive-compulsive disorder patients near illness onset before and after cognitive behavioral therapy. METHODS: Volumetric magnetic resonance imaging studies were conducted in 11 psychotropic drug-naive 8-17-year-old children with obsessive-compulsive disorder before and after 12 weeks of effective cognitive behavioral therapy monotherapy (> or =30% reduction in obsessive-compulsive disorder symptom severity). RESULTS: No significant change in thalamic volume was observed in obsessive-compulsive disorder patients before and after cognitive behavioral therapy. CONCLUSIONS: Our findings suggest that reduction in thalamic volume after paroxetine therapy may be specific to paroxetine treatment and not the result of a general treatment response or spontaneous improvement. These results are preliminary in view of the small sample studied.

Thalamic volumes in patients with first-episode schizophrenia.

OBJECTIVE: The thalamus, a highly evolved sensory and motor gateway to the cortex, has been implicated in the pathophysiology of several illnesses, including schizophrenia. Several studies have suggested thalamic volume differences in patients with schizophrenia, although only a few studies have examined thalamic structure in new-onset patients. METHOD: The authors used magnetic resonance imaging to measure thalamic volumes in previously untreated patients with first-episode schizophrenia (N=16) relative to those of healthy comparison subjects (N=25). The age range of the patients and comparison subjects was 15 to 45 years of age. Thalamic volumes in the right and left hemispheres were segmented and analyzed, both separately and as total thalamic volume, by a rater blind to clinical data. The thalamus was further segmented into regions that roughly reflected individual thalamic nuclei. Analysis of covariance was used to control for intracranial volume. RESULTS: Right, left, and total thalamic volumes of the patients with schizophrenia were significantly smaller than those of the comparison subjects. Significantly smaller volumes were found in the left central medial subdivision of the patients as well as a smaller volume in the right central medial subdivision that approached significance. These regions primarily comprised the dorsomedial nucleus, a thalamic nucleus thought to be an important component of aberrant circuitry in schizophrenia. Significant volume differences were also seen in the left anterior, right anterior, and right posterior medial subdivisions. CONCLUSIONS: These findings suggest significant thalamic volumetric differences between patients with newly diagnosed schizophrenia and healthy comparison subjects. Future analysis of individual thalamic nuclei may reveal important, specific relationships between thalamic abnormalities and schizophrenia.

Neuropsychological study of frontal lobe function in psychotropic-naive children with obsessive-compulsive disorder.

OBJECTIVE: The authors' goal was to evaluate cognition in children with obsessive-compulsive disorder (OCD) early in their illness. METHOD: They administered neuropsychological tests to 21 pediatric patients with OCD and 21 healthy children matched for age, sex, socioeconomic status, and intelligence. The children with OCD were not depressed, and none had ever received psychotropic medication. The neuropsychological tests were used to assess the relationship between psychiatric symptoms and cognitive function. RESULTS: The children with OCD performed as well as the healthy children on the neuropsychological tests. Psychiatric symptoms and cognitive performance were not related. CONCLUSIONS: Nondepressed children with recently diagnosed OCD who had never received psychotropic medication demonstrated no cognitive impairment according to their performance on neuropsychological tests. The authors conclude that OCD symptoms may not interfere with cognitive abilities early in the illness.

Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis.

The mature functional architecture of the primate prefrontal cortex arises during a protracted period of postnatal development. Although catecholaminergic afferents arrive in the primate cortex quite early during fetal development, several lines of evidence suggest that substantial changes in the dopaminergic innervation of prefrontal cortex may occur during postnatal development. In this study, we used immunocytochemical techniques and antibodies against tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, to examine the precise time course from birth to adulthood of the maturational changes of tyrosine hydroxylase-labeled axons in prefrontal cortical areas 9 and 46 and primary motor cortex (area 4) of rhesus monkeys. In area 9, the densities of tyrosine hydroxylase-labeled axons and varicosities in the superficial and deep cortical layers remained relatively constant during postnatal development. In contrast, marked developmental changes in innervation density occurred in the middle cortical layers. For example, in deep layer III, the density of tyrosine hydroxylase-positive varicosities was relatively low and uniform in animals under 1 month of age but then increased by a factor of three in animals 2-3 months of age. The density of labeled varicosities continued to increase, reaching a peak (sixfold greater than in the youngest animals) in animals 2-3 years of age before declining to stable adult levels. Similar laminar-specific patterns of change also occurred in areas 46 and 4, although regional differences were present in the magnitude and precise time course of these developmental changes. These findings demonstrate that the innervation of monkey frontal cortex by tyrosine hydroxylase-immunoreactive axons undergoes a protracted, laminar-specific pattern of change during postnatal development that continues through adolescence and into early adulthood. These developmental refinements may interact with other modifications of cortical circuitry that underlie the functional maturation of these regions.

Case study: caudate glutamatergic changes with paroxetine therapy for pediatric obsessive-compulsive disorder.

Neurobiological models for obsessive-compulsive disorder (OCD) have consistently implicated the caudate nucleus in the pathophysiology of this disorder. OCD symptoms improved markedly in a 9-year-old boy treated with paroxetine, a selective serotonin reuptake inhibitor, for whom pre/posttreatment proton magnetic resonance spectroscopic examinations were acquired to assess the relationship between neurochemical profile in the caudate nucleus, symptom severity, and treatment with paroxetine. Striking changes of the glutamate resonance in the caudate were observed after 12 weeks of paroxetine treatment. These data provide further support for glutamatergic-serotonin pathway involvement in the caudate nucleus of OCD patients.

Paroxetine open-label treatment of pediatric outpatients with obsessive-compulsive disorder.

OBJECTIVE: Paroxetine is a selective serotonin reuptake inhibitor with demonstrated efficacy in treating obsessive-compulsive disorder (OCD) in adults. This study evaluates the safety and effectiveness of paroxetine in pediatric OCD patients. METHOD: In a 12-week, open-label trial of paroxetine, 20 OCD outpatients, aged 8 to 17 years, were treated for OCD with daily doses ranging from 10 to 60 mg. Target symptoms were rated at regular intervals with the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the Children's Global Assessment Scale, the Clinical Global Impression Scale, the Hamilton Anxiety Rating Scale, and the Yale Global Tic Severity Scale. RESULTS: Paroxetine proved relatively safe in this brief trial with a small sample and appeared to be effective in patients with OCD; mean CY-BOCS scores decreased significantly (z = 3.49, p = .0005) from 30.6 +/- 3.5 to 21.6 +/- 6.8 on medication. The most common side effects (n > or = 2) were hyperactivity/behavioral activation, headache, insomnia, nausea, and anxiety. Paroxetine did not have to be discontinued in any of the patients because of side effects; the most serious side effects included hyperactivity/behavioral activation in 3 younger patients (< 10 years) necessitating dosage reduction but not discontinuation. CONCLUSIONS: Preliminary evidence suggests that short-term treatment of pediatric OCD outpatients with paroxetine may be relatively safe and effective.

Case study: caudate glutamatergic changes with paroxetine persist after medication discontinuation in pediatric OCD.

Proton magnetic resonance spectroscopy (1H-MRS) was used to examine glutamatergic (Glx) abnormalities in the caudate nucleus in pediatric obsessive-compulsive disorder (OCD), associated with severity of illness and response to acute (12 weeks) treatment with paroxetine. In this report, OCD symptoms improved markedly in an 8-year-old girl treated for 14 months with the selective serotonin reuptake inhibitor paroxetine (titrated from 10 to 40 mg/day). Paroxetine dose was then decreased in 10-mg decrements and discontinued without symptom recurrence. Serial 1H-MRS examinations were acquired before and after 12 weeks of paroxetine treatment (40 mg/day) and 3 months after medication discontinuation. A striking decrease in caudate Glx was observed after 12 weeks of treatment which persisted after medication discontinuation. These data provide further support for a reversible glutamatergically mediated dysfunction of the caudate nucleus in OCD that may serve as a pathophysiological and treatment response marker.

Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine.

OBJECTIVE: To measure in vivo neurochemical changes in the caudate nucleus in pediatric obsessive-compulsive disorder (OCD) before and after treatment. METHOD: Single-voxel proton magnetic resonance spectroscopic (1H-MRS) examinations of the left caudate were conducted in 11 psychotropic drug-naive children, aged 8 to 17 years, with OCD before and after 12 weeks of monotherapy with the selective serotonin reuptake inhibitor paroxetine (10-60 mg/day) and 11 healthy children aged 8 to 17 years. A different sample of 8 pediatric OCD patients and 8 healthy children had a 1H-MRS examination of occipital cortex. RESULTS: Caudate glutamatergic concentrations (Glx) were significantly greater in treatment-naive OCD patients than in controls but declined significantly after paroxetine treatment to levels comparable with those of controls. Decrease in caudate Glx was associated with decrease in OCD symptom severity. Occipital Glx did not differ between OCD patients and controls. CONCLUSIONS: These preliminary findings provide new evidence of Glx abnormalities in the caudate nucleus in pediatric OCD and suggest that paroxetine treatment may be mediated by a serotonergically modulated reduction in caudate Glx.

Magnetic resonance imaging of children without sedation: preparation with simulation.

OBJECTIVE: It was hypothesized that a scanner simulator that replicates the magnetic resonance imaging (MRI) environment could be used to prepare pediatric subjects for successful completion of a diagnostic-quality MRI examination without pharmacological sedation. METHOD: Sixteen healthy children, 6 to 17 years of age, were matched for age and sex with 16 psychotropic medication-naive children with obsessive-compulsive disorder. Distress was measured throughout simulation and scanning procedures using heart rate and a self-report distress scale. Ten healthy children, 6 to 17 years of age, also underwent the same actual MRI scanning procedure but did not undergo the simulation scanning procedure. RESULTS: Significant decreases in heart rate and self-reported distress level were observed in all subjects during the simulator session that were maintained to the end of the actual scanner experience. All subjects successfully completed MRI examinations without chemical restraint. Subjects who were not trained in the simulator had higher heart rates and self-reported distress levels in the actual scanner than did simulation-trained subjects. CONCLUSIONS: Simulation without pharmacological sedation successfully prepared pediatric subjects in this pilot study for high-quality MRI studies. Subject preparation may be an alternative procedure to sedation for routine MRI examination in healthy and anxious children 6 years of age and older.

Corpus callosal signal intensity in treatment-naive pediatric obsessive compulsive disorders.

1. Obsessive compulsive disorder (OCD) is increasingly recognized as a severe, highly prevalent and chronically disabling disorder, emerging during childhood in as many as 80% of cases. The authors previously found significant abnormalities in the region of the corpus callosum (CC) connecting ventral prefrontal cortex and striatum in pediatric OCD patients compared to controls that correlated significantly with OCD symptom severity. We speculated that this abnormality might reflect aberrant myelinization in OCD patients. 2. In order to better characterize the abnormality, the authors examined CC signal intensity (SI), believed to be a reliable index of myelinization of the CC. Lower numbers would indicate a greater concentration of white matter, while higher numbers indicate higher concentrations of gray matter. We compared the SI from midsagittal magnetic resonance images of 21 treatment-naive OCD patients, 7.2-17.7 years, and 21 case-matched healthy controls to examine regional CC signal intensity of the anterior, middle and posterior genu, body, isthmus, and the anterior, middle and the posterior splenii. 3. Mean total genu SI for the patient group (.993 + .006) was significantly less than the total genu SI of controls (.994 + .006) at F(1,37) = 4.73; p = .036. This abnormality in SI was localized to the CC region connecting ventral PFC and striatum, the anterior genu for the OCD group (.991 + .007) which was also less than control (.995 + .007) at F(1,37) = 5.47; p = .025., with no abnormality observed in middle or posterior genu regions. Genu SI was also inversely correlated with OCD symptom severity (r = -.55, p = .013) but not illness duration. Genu SI also correlated positively with genu area (r = .52, p = .020) in OCD patients but not controls. 4. Developmental abnormalities in genu size may arise from abnormalities in myelination in early onset OCD patients. The increased genu myelination observed in OCD patients may alter signal transduction and function of VPFC-striatal association circuits.

Corpus callosal morphology in treatment-naive pediatric obsessive compulsive disorder.

1. Abnormalities in association circuits have been described in Obsessive Compulsive Disorder (OCD) and may reflect neurodevelopmental abnormalities. Primary and association cortices are topographically mapped in the corpus callosum (CC). The authors hypothesized alterations in CC subdivisions that connect association, but not primary cortices in pediatric OCD. The authors predicted that normal age-related increases in CC area would be absent in OCD. 2. The authors compared the midsagittal magnetic resonance images of 21 psychotropic-naive, nondepressed OCD patients, 7.2-17.7 years, and 21 case-matched healthy controls. Total CC area as well as that of the anterior, middle and posterior genu, anterior and posterior bodies, isthmus, and the anterior, middle and the posterior splenii were measured. 3. All of the CC regions except the isthmus were significantly larger in OCD patients than in controls. CC area correlated significantly with OCD symptom severity but not illness duration. The age-related increase in CC size seen in normal subjects was absent in OCD patients. 4. These findings support theories of abnormal association cortex development in OCD but also suggest possible abnormalities of other primary cortical regions as well.

Eye-tracking dysfunction in offspring from the New York High-Risk Project: diagnostic specificity and the role of attention.

Eye tracking abnormalities were studied in the offspring of schizophrenic, unipolar depressed and bipolar probands from the New York High-Risk Project to examine their familial specificity. Offspring of schizophrenic and depressed probands both had significant global performance deficits based on spectral purity measurements, but only the offspring of schizophrenic probands had an increased rate of intrusive anticipatory saccades. The greater specificity of high anticipatory saccade rate than global performance impairment suggests that this eye movement abnormality may provide a more specific biological marker of risk for schizophrenia than the global measure of eye tracking performance used in this study. Attention facilitation effectively normalized all performance deficits in the offspring of schizophrenic patients, suggesting that a problem sustaining focused visual attention may contribute to eye tracking deficits observed in the relatives of schizophrenic probands.

Evolving mania in an adolescent treated with low-dose fluoxetine.

ABSTRACT A 13-year-old boy with attention-deficit hyperactivity disorder and conduct disorder developed manic symptoms during a trial of fluoxetine. A prior methylphenidate trial had failed, and induced irritable and dysphoric effects at 0.5 mg/kg daily. In view of the mood symptoms, a trial of tricyclic antidepressants was recommended, but the family rejected the recommendation and preferred a trial of fluoxetine. Fluoxetine was initiated at 5 mg daily and increased at weekly intervals by 5 mg. The symptoms of ADHD were not improving, but no adverse effects were attributed to the medication. After 2 days on fluoxetine 20 mg, clear-cut symptoms of mania emerged. The manic symptoms did not subside after discontinuation of fluoxetine, but were controlled by lithium and carbamazepine. The manic symptoms returned when these medications were discontinued by the family, and were again controlled when lithium was reinstituted. The episode fulfilled DSM-III-R criteria for nonpsychotic mania. By history, this patient had not experienced a depressive, hypomanic, or manic episode prior to treatment with fluoxetine. Retrospectively, it appears that the patient began to show evidence of hypomania or mania during the second week of fluoxetine treatment while on 10 mg daily. It is recommended that clinicians be alert to the possibility of a manic switch appearing during fluoxetine treatment, even at low doses of medication.