Introduction
Schizophrenia is an incapacitating disease with many patients nowadays living into old-age. At any time along the disease course the question of which antipsychotic drug should be preferred is controversial; more so in the elderly due to clinical ambiguity and pharmacological safety issues (Chahine et al., Reference Chahine, Acar and Chemali2010). Recently, the boldest attempt to provide evidence-based hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs was undertaken. All drugs were superior to placebo, and clozapine was significantly more effective than all other antipsychotics (Leucht et al., Reference Leucht2013). However, no special consideration was given in the meta-analysis by Leucht and colleagues (Reference Leucht2013) to the role of antipsychotic treatment in the elderly suffering from schizophrenia.
Recommendations for the treatment of older people suffering from schizophrenia are largely based on data deduced from studies of the use of antipsychotic medications in younger adults. The Cochrane Collaboration attempted to review the data pertaining to the choice of antipsychotic medication in elderly schizophrenia patients. The authors concluded that based on systematic review there are little robust data available to guide the clinician with respect to the most appropriate drug to prescribe (Marriott et al., Reference Marriott, Neil and Waddingham2006). The issue of treating older schizophrenia patients is further complicated by most manufacturers of antipsychotic medication recommending prescription of reduced doses to the elderly. An older person might metabolize these medications less rapidly and might be more prone to adverse effects. It is unclear however if this is pertinent to those who have been on antipsychotic medication for many years. A number of open studies have been conducted with elderly participants with schizophrenia and suggest that the atypical antipsychotics may be of benefit (Czobor et al., Reference Czobor, Volavka and Meibach1995; Davidson et al., Reference Davidson2000).
Clozapine was the first atypical antipsychotic drug to be marketed and the first agent approved for the treatment of treatment-resistant schizophrenia. In early reviews focusing on safety of clozapine in the elderly the risk/benefit ratio in the elderly is distinctly higher than found in the younger population (Herst and Powell, Reference Herst and Powell1997). Clozapine treatment in the elderly is still cautiously undertaken by most clinicians as practical lore, and reviews of the published literature emphasize that its use is strongly limited by the possibility of onset of severe adverse effects such as potentially fatal agranulocytosis, myocarditis, and others such as seizures, weight gain, and metabolic adverse effects (Gareri et al., Reference Gareri, De Fazio, Russo, Marigliano, De Fazio and De Sarro2008). However, recent publications seem to have taken a far more encouraging line. Clozapine has been found in two large epidemiologic studies to have the lowest mortality of any antipsychotic drug. Alertness to the benefits and risks of clozapine is vital for increasing the use of this lifesaving agent (Meltzer, Reference Meltzer2012).
The present study aimed to retrospectively assess the safety and efficacy of clozapine in elderly schizophrenia patients unresponsive to two antipsychotic compounds requiring admission to an acute psychogeriatric ward. The university-affiliated center wherein this work was undertaken provides services to all elderly in a large urban catchment area and thus reflects “naturalistic” real-world clinical analysis.
Methods
A retrospective analysis of computerized medical charts of elderly schizophrenia inpatients treated at our center during the period January 2007–December 2012 was undertaken. The Abarbanel Mental Health Center is a university-affiliated tertiary care center servicing the urban catchment area of the greater Tel-Aviv with approximately 900,000 persons.
Elderly inpatients suffering from schizophrenia (DSM-IV-TR criteria) that were treated at our center during the study period were included in the study according to the following criteria: (1) 60 years and older; (2) patients who had been unsuccessfully treated with at least three different antipsychotic compounds during the last five years prior to the study period. All had been treated with haloperidol or perphenazine and all had been treated with risperidone as well as another second-generation antipsychotic.
This study was approved by the local internal review board (IRB).
Outcome measures
Safety was defined as the rate of mortality over the studied period. Effectiveness was assessed by comparing the number of admissions to our center in the five-year study period to that in the five years prior to exposure to clozapine. Each patient was his or her own “control” in the sense that re-admission rates were compared for the very same patient in the five years prior to clozapine exposure to rates while treated with clozapine.
Statistical analysis
Data were analyzed using a paired-samples and independent-samples approach. The two-tailed t-test and a non-parametric test were undertaken to evaluate differences between the evaluations for qualitative parameters. Examination of differences between the categorical parameters was based on the χ2 and corrected by the Fisher's exact test. All tests applied were two-tailed, and a p-value of 5% or less was considered statistically significant.
The data was analyzed using Statistical Analysis System software, version 6, 1990.
Results
During the study period, 2007 to 2012, there were 527 admissions of elderly patients with schizophrenia to our center. There were 245 men and 282 women, mean age 67.4 ± 7.0 years in this cohort. Mean disease duration for this cohort was 35.7 years. Patients treated with clozapine were compared to the rest of the cohort.
There were 19 women and 24 men in the clozapine group. Mean age was 69.4 ± 8.7 years. There were 24 (56%) patients aged 60 to 69 years; 17 (39%) aged 70 to 79 years, and two patients older than 80 years. There were no differences in clozapine dose or response between these age groups. Mean duration of disease was 38.8 years (range: 15–51). Most patients had been hospitalized many times during their lives; mean number of psychiatric admissions was 13.2 ± 8.1 (range: 6–42). All had been exposed to at least three antipsychotics (either first- or second-generation) prior to clozapine treatment. Clozapine was very well tolerated by the patients. This was reflected by the observation that not one patient had to discontinue treatment with clozapine due to side-effects. Mean clozapine dose was 264 ± 110 mgs/daily (range: 25–700 mgs/daily). Mortality rate with clozapine treatment (N = 8 vs. N = 87; 18.6% vs. 18%) was equal to that of other first- and second-generation antipsychotics (p < 0.18). Re-hospitalization rates were computed for the five-year period preceding exposure to clozapine and compared to rates after initiation of clozapine. Rates of re-admission with clozapine were 0.41 admissions over five years – lower than those with exposure to other antipsychotics (3.8 for the five-year period preceding exposure to clozapine) – reaching statistical significance (p < 0.001).
Discussion
It has been estimated that 30% of patients with schizophrenia may be considered “treatment resistant” due to lack of response to three antipsychotic drug regimes. It is thus surprising that clozapine – the only antipsychotic approved for treatment-resistant schizophrenia – is rarely used. A recent nationwide study was undertaken in 45 states in the USA among 326,119 individuals with schizophrenia. Clozapine accounted for 5.5% of medication starts among patients with treatment resistance. Clozapine initiation was significantly associated amongst other variables with male sex, younger age, and greater prior-year hospital use for mental health. The authors called for efforts to address low access to clozapine in order to improve recovery opportunities for people with schizophrenia in the USA (Stroup et al., Reference Stroup, Gerhard, Crystal, Huang and Olfson2014).
Compared to the general population, people with schizophrenia die prematurely due to different somatic illnesses. A recent study of death registers in Finland compared the cause-specific mortality in patients versus the total population over a ten-year period demonstrating decreased mortality in antipsychotic users. Schizophrenia is a lifelong disease and despite increased mortality most patients reach old age. Disease course in late life is variable but many patients remain symptomatic and it is estimated that only 20% to 30% achieve recovery in old age (Jääskeläinen et al., Reference Jääskeläinen2013). Clozapine had the most beneficial profile in this regard (Tiihonen et al., Reference Tiihonen2009). However, several methodological and conceptual issues make the interpretation of these findings problematic. Well-designed studies are needed to inform clinical practice (De Hert et al., Reference De Hert, Correll and Cohen2010).
We have reviewed the tolerability, safety, and effectiveness of clozapine in the elderly nearly 15 years ago (Barak et al., Reference Barak, Wittenberg, Naor, Kutzuk and Weizman1999). Our focus was on elderly psychiatric patients with no neurological comorbidity. We found that in over more than 30 years only 133 elderly patients suffering from “functional” psychiatric morbidity were reported in the scientific literature. The great majority of patients showed moderate-to-marked improvement of psychotic features. Clozapine at a relatively low mean dose of 134 mgs/daily seemed to be safe, but it should be noted that agranulocytosis was more frequent than in younger adults. In the present study clozapine was employed in treating elderly patients suffering from resistant schizophrenia. In this naturalistic setting clozapine had comparable safety and significantly improved effectiveness over other second-generation antipsychotics. Our findings are similar to those reported by Sajatovic and colleagues (Reference Sajatovic, Jaskiw, Konicki, Jurjus, Kwon and Ramirez1997) who reported on the outcome of clozapine therapy for elderly patients with refractory primary psychosis. In this open-label clozapine trial in elderly patients mean clozapine dosage was 204 mgs/day, comorbid physical illnesses were not worsened by clozapine and only a few patients were truly treatment intolerant. Other authors also report on similar beneficial results of treating elderly patients suffering from schizophrenia with clozapine (Frankenburg and Kalunian, Reference Frankenburg and Kalunian1994; Howanitz et al., Reference Howanitz1999; Aparasu et al., Reference Aparasu, Jano, Johnson and Chen2008) and its effectiveness in younger patients is universally accepted (McEvoy et al., Reference McEvoy2006). The present study has several limitations. The retrospective design precludes randomization, the sample size is modest, and we had no quantifiable clinical outcome measure based on accepted rating scales. Nevertheless, this work reflects clinical reality in many state tertiary care centers.
Clozapine was the first true breakthrough in schizophrenia treatment since the discovery of chlorpromazine in 1950. It effectively treats positive, negative, and some cognitive symptoms, as well as possessing unprecedented efficacy in treatment-resistant patients. Despite over 30 years of intense study, the precise molecular underpinnings that account for clozapine's unique efficacy remain elusive (Wenthur and Lindsley, Reference Wenthur and Lindsley2013). Clozapine is often known as the gold standard for the treatment of schizophrenia and yet has been underutilized in the treatment of elderly schizophrenia patients. Apprehensions over a number of safety considerations are responsible for much of the underutilization of clozapine. Notably, while the risk of neutropenia is higher in geriatric patients treated with clozapine, possibly in the range of 10% to 15%, this does not seem to translate to an increased risk of agranulocytosis or death (Guenette et al., Reference Guenette2013). The present study adds to the small database on the potential use of clozapine in the elderly. Awareness of the benefits and risks of clozapine is crucial to increase the use of this lifesaving agent (Meltzer, Reference Meltzer2012).
Conflict of interest
None.
Description of author's roles
All authors (S. Pridan, Y. Baruch, M. Swartz, S. Tadger, I. Plopski, and Y. Barak) formulated the research questions and designed the study as well as wrote the paper. S. Pridan carried out the study, collected the data, and analyzed the data. S. Tadger and I. Plopski helped in collecting the data and follow-up. M. Swartz and Y. Baruch supervised the data collection and with Y. Barak and S. Pridan wrote the paper.
