Maxwell J. Luber

Baseline brain structural and functional predictors of clinical outcome in the early course of schizophrenia

Although schizophrenia is considered a brain disorder, the role of brain organization for symptomatic improvement remains inadequately defined. We investigated the relationship between baseline brain morphology, resting-state network connectivity and clinical response after 24-weeks of antipsychotic treatment in patients with schizophrenia ( n  = 95) using integrated multivariate analyses. There was no significant association between clinical response and measures of cortical thickness ( r  = 0.37, p  = 0.98) and subcortical volume ( r  = 0.56, p  = 0.15). By contrast, we identified a strong mode of covariation linking functional network connectivity to clinical response ( r  = 0.70; p  = 0.04), and particularly to improvement in positive (weight = 0.62) and anxious/depressive symptoms (weight = 0.49). Higher internal cohesiveness of the default mode network was the single most important positive predictor. Key negative predictors involved the functional cohesiveness of central executive subnetworks anchored in the frontoparietal cortices and subcortical regions (including the thalamus and striatum) and the inter-network integration between the default mode and sensorimotor networks. The present findings establish links between clinical response and the functional organization of brain networks involved both in perception and in spontaneous and goal-directed cognition, thereby advancing our understanding of the pathophysiology of schizophrenia.

Clozapine-Related Tachycardia in an Adolescent with Treatment-Resistant Early Onset Schizophrenia

V. was a 16-year-old Spanish-speaking female with a diagnosis of schizophrenia who was hospitalized after being brought to the emergency department by the police after an act of aggression toward her school counselor. V. first came to psychiatric care when she was 15 years old for increasing mood swings that had been occurring for the preceding few months. She reported having suicidal thoughts without any specific plans. She was observed to be laughing out loud and seemed lost in thought on many occasions. She talked to herself aloud in both Spanish and English, and walked out of the classroom on occasions. Teachers reported that V. was in a ‘‘different world.’’ She was observed singing and dancing in the hallways, or staring at herself in a mirror and making faces. Teachers noted a labile mood, laughing at one moment and crying the next. V. was subsequently started on aripiprazole 10 mg during her first hospitalization, which resulted in improvement of mood symptoms. Later her dose of aripiprazole was increased to 20 mg as an outpatient. She was hospitalized 3 months later, as she had been observed talking to people who were not around. Teachers raised concern that she was running in the school corridors. During this second hospitalization, she was treated with risperidone 3 mg and lithium 300 mg twice a day (lithium level was 0.42), and her psychotic symptoms improved. She was discharged to home. V.’s symptoms worsened a few weeks after this hospitalization. V. was then started on ziprasidone 40 mg twice daily in addition to risperidone 3 mg and escitalopram 5 mg once daily by her outpatient psychiatrist. She was hospitalized again 3 months later, when she was functioning poorly, and was actively responding to hallucinations. Her concentration was poor and her speech was disorganized. At this time, her dose of risperidone was increased to 3 mg everyday in the morning (AM) and 4 mg every night at bedtime (QHS) and quetiapine 175 mg was added in divided doses. Her dose of lithium was increased to 600 mg twice daily (lithium level of 0.74). Benztropine 1 mg twice daily was added for muscle stiffness. Again 3 months later, V. was readmitted with another exacerbation of psychotic symptoms. V. reported auditory hallucinations that would tell her to stab herself to make a spirit go away. V. reported that she did stab herself, but when she looked down she said, ‘‘No blood.God performed a miracle.’’ During this hospital stay, she continued to laugh inappropriately and was actively responding to hallucinations. She gradually improved, endorsing that she saw and heard ghosts described as ugly males that told her to do things such as wash her hands. Her quetiapine was increased to 700 mg in divided doses, risperidone was reduced to 5 mg, and her lithium was stopped. After discharge, her outpatient psychiatrist increased her quetiapine to 800 mg and reduced risperidone to 4 mg. A few weeks later, V. was observed laughing to herself and tearful in the classroom. She was sent to the school counselor’s room where she later pushed the counselor to the wall and ran onto school grounds. She was unable to explain why she assaulted the school counselor; however, she added that she was scared that there were people with knives that were going to hurt her. She reported hearing several abusive female voices saying ‘‘you are fat’’ and ‘‘f**k you; you are poor.’’ She was brought to the emergency department by police and was once again hospitalized. She had reported smelling burned food. A few weeks before her hospitalization, V. reported hallucinations of touching lampposts and that they were cold. During this hospitalization, V. had difficulty conversing in English, a language that she had used to communicate with relative fluency during a previous hospitalization. V. was on quetiapine 800 mg and risperidone 4 mg at the time of her hospitalization. Later in the course of the hospitalization, she reported experiencing hallucinations of the deceased talking to her. She sometimes laughed suddenly and denied having any control over this behavior. She reported visual hallucinations of seeing a dead family. There was no evidence of thought insertion or withdrawal. There was no indication of olfactory, gustatory, tactile, or extracampine hallucinations at this stage. In addition, there were no signs of depression, mania, or hypomania. V. was observed staring for 10–20 seconds; she would lose her train of thought and ask ‘‘what did I say?’’

Lithium and Heart Block in an Adolescent Boy

B. had a history of ADHD and aggressive behavior since the age of four. His aggressive behavior occurred in the context of multiple traumas and intermittent foster care placement. B.’s first medication trials were mixed amphetamine salts (MAS) at 2 mg po qam for ADHD symptoms and risperidone for co-occurring aggression. Risperidone was titrated to 2 mg twice a day by age 8. B. had his first hospitalization at that time for repeated violence, including punching and kicking classmates with homicidal ideation at school. Sertraline was initiated at that time at 25 mg po qam in recognition of the posttraumatic component to his presentation, as well as of mood symptoms. The introduction of sertraline and a subsequent cross-taper from risperidone to aripiprazole did not reduce frequent emergency room visits upon discharge. His presentation included suicidal ideation, homicidal ideation, and violence. He also frequented the Emergency Department with vague gastrointestinal, respiratory, and neurologic complaints. Frequent workups were usually negative. By age 8, he had been labeled a ‘‘chronic’’ patient in his medical record. B.’s course changed significantly at age 10, during his third psychiatric hospitalization, when he was first treated with lithium at a dose of 450 mg po tid. B. entered the hospital on a regimen of MAS 40 mg po qam, sertraline 100 mg po qam, and aripiprazole 10 mg po qam. An electrocardiogram (EKG) was obtained, which revealed a normal PR interval. He spoke very fast with increased verbal production and jumped from one topic to another. His thought content alternated between how much he hated his life and aggressive threats toward his peers on the unit. There were frequent physical fights. B. denied suicidal ideation or auditory hallucinations. He continued to display labile mood, flight of ideas, irritability, grandiosity, and aggression with multiple daily outbursts. Although a formal diagnosis of bipolar I disorder was not yet confirmed, his sertraline was discontinued and lithium was initiated for mood stabilization. His MAS was additionally discontinued. As B.’s lithium dose increased, his anger outbursts decreased in frequency, intensity, and duration. He was able to maintain nonviolent attendance in class several weeks in a row, and his peer relationships improved. On discharge he remained grandiose with heightened sexual interests, but was verbally redirectable and nonviolent. His discharge regimen was lithium 450 mg po tid and aripiprazole 10 mg po qhs. After the period of multiple hospitalizations, B. experienced fewer problems for over 4 years on this regimen following the most recent discharge. However, B. had continued to gain significant weight despite the transition from risperidone to aripiprazole, and by the age of 14, his body mass index (BMI) placed him well above the 95th percentile in BMI for his age (Fig. 1). His doses of lithium and aripiprazole were both tapered, from 450 to 300 mg po bid, and from 10 to 5 mg po qhs, respectively. His lithium level was 0.5mEq/L. In the context of this taper, entry into adolescence, return from foster care to his biological family, and the loss of support from a specialized school in an 8:1:1 setting, B. experienced a recurrence of problems. He developed reduced sleep, *5 to 6 hours a night, an increase in irritability and affective lability, and fluctuating sense of self from very fragile self-esteem to grandiose heightened self-concept. B.’s aripiprazole was maintained at 5 mg po qhs and his lithium increased to 450 mg po bid, yielding a lithium level of 0.7mEq/L. Despite these changes, B. remained aggressive and violent both at school and at home. The application of a Young Mania Rating Scale (YMRS) yielded a score of 23 and the parent report version yielded a score of 25, both signifying moderate symptoms of mania. A trial of guanfacine at 1 mg po bid and titrated to 2 mg po bid had little effect on reducing impulsivity as a risk factor for violence. Therefore, despite ongoing weight concerns, B.’s lithium was again titrated to a higher dose, with little response at 600 mg po bid, yielding a level of 0.8mEq/L. Despite the titration, B. remained in a period of reduced sleep and grandiosity. He began frequently avoiding school and presenting to the Emergency Department with somatic complaints, such as nonspecific abdominal cramping, difficulty breathing, and overvalued pain from minor sports injuries. His respiratory and abdominal complaints were consistently negative on medical workups, and B. was repeatedly discharged to home. However, on his fifth presentation at 14 years of age on an EKG to evaluate upper abdominal discomfort, B. was found to have firstdegree atrioventricular (AV) block. His PR interval was 234 ms, up from 178 ms before the introduction of lithium. After becoming aware of his abnormal EKG finding, B. began to report intense anxiety about his heart, endorse palpitations, and expressed greater concerns over difficulty breathing. The decision was made to taper both B.’s lithium and aripiprazole to discontinuation in a controlled inpatient setting, and to attempt a trial of outpatient care on guanfacine extended release alone. B. tolerated the washout with a decrease in his PR interval from 234 to 216 ms and 214 ms. He remained very anxious with somatic concerns, and so escitalopram was initiated at 10 mg po qam and titrated to 20 mg po qam to address his anxiety

Treatment of Hallucinations in the Context of Anxiety: When Less Is More

A. reported that 3 months prior to admission, she started experiencing panic attacks that she described as extremely high levels of anxiety accompanied by sweating, shaking, chest tightness, shortness of breath, and hyperventilation that sometimes resulted in brief episodes of loss of consciousness. The panic attacks typically resolved within about 45 minutes. During these episodes, she reported hearing an unknown male voice coming from inside her head. The voice would tell her that she would die and that it would be better to die than to experience these ongoing panic attacks. The voice would also occasionally tell her to kill herself as a means of escaping her anxiety. Apart from the male voice, the patient did not present with other symptoms suggestive of a primary psychotic disorder. Initially, these episodes occurred approximately twice weekly. However, by the time of admission, they were occurring multiple times per day. The attacks occurred most often either in the car on the way to school or at school. A. requested to be physically held during these episodes, especially by her mother. She had not been able to attend school regularly for the past month due to these panic attacks. Despite this, A. reported that she enjoyed school, had always received excellent grades, and very much wanted to be able to return. At the time of admission, she was attending a half-day of school in the morning followed by a half-day at a partial hospital program. However, more often than not, A. would experience one of these episodes while at school, arriving at the partial hospital program in a state of crisis. Because of this, she had not been able to participate in the therapy actively. Inpatient psychiatric admission for diagnostic clarification and stabilization was pursued. In addition to the panic attacks, A. reported high levels of generalized anxiety. She worried about ‘‘bad things happening to [her] family,’’ particularly when she was at school or away from home, which resulted in great difficulty separating from them and attending school. These symptoms had also worsened over the past few months. She described her mood as depressed, which she generally related to her high level of anxiety. She had difficulty initiating and maintaining sleep, poor appetite, and felt helpless and hopeless about her panic attacks resolving.