Before Clozapine
Mr. A was born without perinatal complications after a normal full-term pregnancy. His mother was a full-time homemaker, and his father a postal worker. He and his four siblings were raised with both parents present. His mother reported that he met all developmental milestones in a normal time frame and described him as a happy but quiet child who made friends easily in primary school. As an adolescent, he was “quiet and studious.” In high school, he was an honors student, developed friendships, and was actively involved in soccer and weight lifting. There was no history of child abuse, and he never used alcohol or drugs.
Mr. A’s father suffered from “depression” many years ago, for which he took an unknown medication. A striking feature of that depression is that his father began to “whisper to himself,” much as Mr. A did in the early days of his own illness. Mr. A’s oldest brother underwent counseling for “nervousness” many years ago, but he was not treated with medication. His mother thinks there were alcoholics among his father’s distant relatives, but she is unsure of specifics. She is not aware of any psychiatric problems among other siblings, grandparents, aunts, or uncles. No other family members have been psychiatrically hospitalized, and there is no known family history of suicidal behavior.
Mr. A suffered from asthma as a child, but he was never hospitalized for it and outgrew it before adulthood. He never suffered a seizure, loss of consciousness, or a neurologically significant head injury. He has no history of cardiac or cerebrovascular disease, hypertension, or renal, hepatic, or endocrine disorder. Results of a complete general physical and neurological examination were normal, as were results of serum chemistry, hematology, and thyroid studies. He never had a neuroimaging study.
Mr. A did not report a history of sustained depressed mood or hopelessness. There was no history of a diminished need for sleep with increased energy and no history of grandiosity, elation, sustained irritability, pressure of speech, or flight of ideas. He was never treated with antidepressant or mood stabilizing medication, and there was no history of suicidal, self-injurious, or assaultive behavior.
Mr. A was the only member of his family to attend college. He enrolled as an engineering technology major while still living at home with his parents. During his third semester, at age 18, his parents noticed that he began whispering to himself. He removed the mirror and television from his room without explanation and began to closely inspect the furniture on a regular basis, as if looking for something. One night, he left the house through a window and traveled to a fundamentalist church in another city. Upon his return, he refused his parents’ urging to seek treatment. He remained in school for 2 more years, until he was placed on academic leave after failing a course.
At age 21, Mr. A experienced his first psychiatric admission. Just before that admission, his mother reported that he raised all the shades in the house to let in light and drive out evil spirits, who he feared might be listening to his thoughts. All phases of his sleep were disturbed, resulting in severe fatigue. He did not report any psychiatric symptoms throughout his first admission, but his records describe bizarre facial grimacing, putting his fingers in his ears when the intercom came on, markedly impaired attention, marked social avoidance, loosening of associations, derailment of thought, and blunted affect. Staff assessed him to be neither manic nor depressed. He refused to take medication. The staff obtained a court order allowing them to treat him with oral trifluoperazine, 30 mg/day at bedtime, as well as benztropine for stiffness and tremor. He was discharged 2 months later with a diagnosis of an “acute schizophrenic episode,” and staff described some improvement in his bizarre behavior and formal thought disorder.
Mr. A continued living with his parents for 15 years after his first psychiatric admission, during which time they urged him to be more active and give more attention to his personal hygiene. He was quietly, but continuously, in conflict with his parents. He remained moderately disorganized and socially withdrawn, while continuing to deny that he had an illness. Because of his parents’ careful monitoring, he generally took his antipsychotic medication and was able to attend college courses part time. He eventually completed an associate’s degree and occasionally worked through temporary agencies at manufacturing jobs. His last employment, at age 33, lasted 2 months.
Mr. A’s second and third psychiatric admissions, both precipitated by medication noncompliance, occurred at ages 30 and 33, while he was still living with his parents. The record of his admission at age 30 noted “inappropriate affect, thought blocking, and extreme guardedness about revealing his thought content.” He denied that he had an illness but acknowledged that when he stopped taking medication, his concentration became poor. He was discharged with a diagnosis of “chronic paranoid schizophrenia” on a regimen of oral fluphenazine, 5 mg b.i.d., and oral benztropine, 2 mg b.i.d. He remained only intermittently compliant about taking his medication.
At age 37, Mr. A began living outside his parents’ home for the first time. He moved into a subsidized apartment of his own and stopped taking his oral fluphenazine almost immediately. The Boston Housing Authority reported that his housekeeping deteriorated markedly. There was so much trash in one room that an inspector was unable to enter it. When he was told that his housekeeping was causing a roach problem, he responded by putting plastic and aluminum foil on the walls, attempting to keep roaches out rather than removing the trash. He put himself at risk of injury by wandering the streets at all hours, and he took in homeless people whom he did not know, in violation of his lease. His mother became alarmed by what records describe as his poor hygiene, poor nutrition, disorganized thoughts, and paranoid delusions.
At age 39, Mr. A was admitted to a psychiatric unit. Records state that he appeared to be responding to auditory hallucinations. He exhibited markedly disorganized thought, poverty of speech, blunted affect, and social withdrawal. The institution petitioned for full guardianship, and at his request, a court-appointed attorney, rather than a family member, became his guardian. He was then treated with a regimen of oral perphenazine, 24 mg/day in the morning and 32 mg/day at bedtime, and oral benztropine, 1 mg b.i.d., for extrapyramidal symptoms.
He was subsequently transferred to a day hospital program and psychiatric shelter, both located at the Massachusetts Mental Health Center. One week after admission, Mr. A left against medical advice, reoccupied his apartment, and stopped taking his medication. When he was involuntarily hospitalized 10 days later, he stated that he needed medication for his “jumbled thoughts.” This is the first documented instance of Mr. A requesting medication to help his thinking. During this admission, he learned that he had been evicted from his apartment.
He returned to the day hospital and shelter program at the Massachusetts Mental Health Center, where he remained unwaveringly preoccupied with regaining his own apartment, speaking frequently of the preeminent importance of “my independence.” Initially, he was treated with perphenazine, which he complained caused “excretions” that he could not further define. (On good days, he would say, “The excretions are slow.”) He required benztropine treatment for parkinsonian symptoms.
Mr. A rarely spoke spontaneously, and his statements were usually brief, vague, idiosyncratic, and disorganized. When asked how he had spent his time after a weekend, he typically would say, “I rested around,” and was unable to elaborate. He had scant insight into his illness, explaining his long unemployment with vague statements such as, “I just was not in a position for it.” He remained paranoid, saying that he could not live in a group home because “I can’t trust anybody there.” He was inattentive in team meetings, was interpersonally disengaged throughout the day, sought out little activity, and expressed no interests or desires (apart from wanting his own apartment).
The typical neuroleptics with which Mr. A had been treated included haloperidol, trifluoperazine, thioridazine, and fluphenazine—all of which had produced significant stiffness and tremor, requiring up to 4 mg/day of benztropine. Given the substantially disabling impact of his symptoms, we proposed a trial of clozapine. Mr. A was initially adamantly opposed to trying clozapine. His opposition was due less to any of its known side effects than to his delusional conviction that blood testing, even using alternate arms on alternate weeks, would “destroy my veins.” However, with his reluctant agreement and the consent of his guardian, a trial of clozapine was initiated. After a 3-month cross-taper, which began in June 1995, during which clozapine treatment was started and perphenazine discontinued, his clozapine blood level, with an oral dose of 500 mg/day at bedtime, was 260 mg/dl.
Taking Clozapine
The first changes noted after Mr. A started taking clozapine were more sleepiness and salivation. However, after 6 to 8 weeks, his affect began to brighten, and he gradually became less withdrawn. After about 4 months, he acknowledged that his thoughts were clearer. His thoughts seemed better organized, and for the first time, he began to participate spontaneously in day hospital team meetings. His participation demonstrated much better attention to what was being discussed, and staff were astounded by his efforts to offer support and understanding to other patients. He began to attend a psychosocial clubhouse where, with encouragement, he participated in cooking, cleaning up, and other community projects.
For the first time, he began to acknowledge that he had a mental illness and to call it “schizophrenia.” He began to express hope of one day returning to work and finding a girlfriend. While acknowledging that his thinking was clearer with clozapine, he consistently maintained that perphenazine was the medicine that had helped him the most. He continued to fear the effects of weekly blood tests and to believe that clozapine was “one of those medicines that just destroys your health.” He still maintains these beliefs. These limitations of insight have served to spare Mr. A the emotional distress that often accompanies “awakening” because of clozapine, notwithstanding the significant improvements in his functioning and quality of life (1). He remained in a psychiatric shelter for 16 months, refusing offers of a supervised group home. Finally, in July 1996, he moved into his own apartment, which he has successfully maintained. He reported that he faithfully continued to take his oral clozapine, 500 mg/day at bedtime, as prescribed. This report is consistent with our observation of no decline in his clinical status and a clozapine blood level of 332 mg/dl 2 months after he moved into his apartment. He consistently refused offers of adjunctive medications to help with his daytime sedation and excess salivation, stating politely, “No, no. I don’t want any more drugs.”
In our efforts to persuade Mr. A to start and remain on a regimen of clozapine, we repeatedly stressed our view that it was the best drug available for him. We assured him that we could discuss switching to another medication if something potentially better came along. This approach had the unintended effect of helping to foster his preoccupation with “those new drugs coming along.”
Nonetheless, we shared his conviction that he was entitled to as much choice in his treatment as reasonable clinical judgment would permit. While we clearly did not share his fears about weekly blood testing, we thought he was entitled to be free of them if a reasonable alternative existed. We also remained concerned about the significant negative impact of his continued and obvious daytime sedation. Given his robust clinical response to clozapine, we would not have proposed a change to olanzapine simply to avoid the risks of agranulocytosis and seizures. (Both were minimal after 1.5 years of taking a stable dose of 500 mg/day of clozapine.)
When olanzapine was released for general use in October 1996, we discussed the risks of changing medication in detail with Mr. A and his guardian. We emphasized the possibility of relapse and rehospitalization, the possible need to resume clozapine treatment, and the possibility that clozapine would not work as well the second time. He might never be as well again. Both he and his guardian wished to proceed. To reduce the risk of destabilizing him, we planned a very gradual cross-taper. We also increased the frequency of his outpatient appointments from every other week to weekly. In January 1997, 1 week after adding oral olanzapine, 5 mg/day at bedtime, to his long-standing dose of oral clozapine, 500 mg/day at bedtime, we began reducing his daily clozapine dose by 50 mg each week. His dose of oral olanzapine was increased to 10 mg/day at bedtime when his dose of oral clozapine was reduced to 400 mg/day at bedtime, and his dose of oral olanzapine was again increased, to 15 mg/day at bedtime, when his dose of oral clozapine was reduced to 300 mg/day at bedtime. After Mr. A reached a clozapine dose of 100 mg/day, we decreased the rate of reduction of his daily dose to 25 mg each week. Three full months after starting this cross-taper, Mr. A took his last 25-mg dose of clozapine, and he has been receiving oral olanzapine, 15 mg/day at bedtime, and no other medications since April 1997.