The systematic review by Renzenbrink and Wand (Reference Renzenbrink and Wand2020) in this issue draws attention to a patient population that has been largely ignored within psychiatric research, with treatment of geriatric patients often being guided by studies completed in younger patient populations. Although initially developed in the 1950s, clozapine did not see widespread use until decades later. In the United States, clozapine has been in use for just over thirty years, giving rise to an aging patient population that has either been treated with clozapine for an extended period or may need to initiate treatment with clozapine after failing alternative options.
Renzenbrink and Wand’s literature review identified seven primarily observational studies for inclusion, with a total of 128 subjects treated with clozapine aged 65–86 years with diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, or delusional disorder. It should be noted that most subjects included had a diagnosis of schizophrenia, with just 4 of the 128 subjects having a diagnosis of bipolar disorder. Of the included subjects, 87% (111 out of 128) are from a single retrospective study (Sajatovic et al., Reference Sajatovic1998) assessing the efficacy of clozapine treatment in a group of predominantly male veterans aged 55 years and older. Only those with a primary psychotic disorder which was either treatment-refractory or treatment-intolerant were included with the sample being 94.2% male and 86.5% Caucasian. The homogeneity of the included patient population and overall lower quality of included literature are two of many limitations. Having said that, the authors are transparent about these limitations and are appropriately cautious in their clinical recommendations, citing insufficient current evidence to recommend clozapine over alternative treatments in geriatric patients with psychotic or bipolar disorders.
Since clozapine’s US introduction in 1990, it has transformed the management of treatment-resistant schizophrenia, likely liberating many patients from long-term care in state hospitals. However, the original US cohort of clozapine patients are now approaching (or have reached) geriatric age, so the compelling challenge remains of how to manage these patients at their current, advanced ages. It is unlikely that many geriatric schizophrenia patients were started on clozapine when it first became available; so, the experience of long-term use of clozapine in now older patients represents a convenience sample, or a natural experiment.
At clozapine’s introduction, the main toxicity of greatest clinical concern was agranulocytosis (and other effects on hematologic cell production), which was of such great concern that clozapine monitoring initially required weekly monitoring of white blood cell counts with validation of safe range white blood cell counts before subsequent weekly prescriptions could be filled. While this remains a concerning issue with clozapine, especially early in treatment, it is not likely as great a concern in geriatric patients who have heretofore tolerated clozapine without episodes of agranulocytosis or other hematologic complications. It is the other toxicities of clozapine that are of greatest concern to geriatric patients (e.g. anticholinergic effects, delirium, seizure, orthostatic hypotension). Physicians are routinely cautious about exposing older (especially ill older) patients to these specific side effects/toxicities. This alone could account for relatively less prescribing of clozapine to older patients, especially if the putative benefits of clozapine vis-à-vis other antipsychotics are unclear considering the greater medical risks associated with clozapine more than other antipsychotics.
An additional issue to contemplate is that clozapine was the first second-generation antipsychotic approved in the United States. There are likely many patients treated with clozapine continuously since 1990 who may have responded to other subsequently approved antipsychotics but were kept on clozapine continuously; alternatively, there are likely many patients who initially were treated with clozapine who, once other antipsychotic medications with less medical risk and requirement for therapeutic drug monitoring became available, were later switched to, and subsequently maintained on, alternative second-generation antipsychotics.
The relatively few cases on clozapine’s use in geriatric patients as found by the authors may represent the latter condition, although this point could be elucidated by a study design wherein the total lifetime exposure to all antipsychotics is addressed in individual cases. Similarly, the issue of previously clozapine-treated patients who needed to be switched to other, less medically problematic antipsychotics (even at the likely cost of less efficacy in the management of treatment-resistant schizophrenia) may account for finding fewer geriatric patients on clozapine than might be expected, compared to other age groups. Again, this point could be examined in a study wherein each patient’s individual experience with all antipsychotics was ascertained in detail.
Although the dearth of literature on the 65-year-old plus population is a widespread problem in psychopharmacological literature in general (that is not exclusive to clozapine), clozapine is widely regarded as a “gold standard” treatment for refractory serious mental illness due to superior efficacy and concomitant reduction in suicide risk. The significance of these purported advantages to clozapine in a geriatric population is unclear, as pivotal clinical trials establishing clozapine’s efficacy in treatment refractory psychiatric illness (Kane et al., Reference Kane1989) and its suicide protective effects (Meltzer, Reference Meltzer2003) notably excluded subjects over 65 years. As the authors note, the severity of adverse effects associated with clozapine likely discourage its more frequent use, particularly in older patients. As the elderly population is generally more prone to experiencing adverse effects to many medications, this is an important topic to investigate further, so the risks and benefits can better be ascertained by comparing antipsychotic medications against each other in this age group. The authors outline some of the side effects of clozapine as follows:
“Older adults are known to be at greater risk of adverse effects of clozapine, and are particularly more susceptible to agranulocytosis, postural hypertension, anticholinergic effects (including constipation, urinary retention, dry eyes, blurred vision, and tachycardia), sedation, and cognitive dysfunction, and delirium…”
It is important to emphasize the increased risk of delirium associated with the use of clozapine in comparison to other antipsychotics, which is typically attributed substantially to its anticholinergic properties. Although the reported incidence rate of delirium is estimated at around 10% among the general inpatient population treated with clozapine, older age has often been reported as one of the greatest predisposing factors to delirium (Das et al., Reference Das2020), (Young, Bowers and Mazure, Reference Young, Bowers and Mazure1998). In such situations where a patient has been stable on clozapine but develops intolerable side effects with age, what is the best approach to finding alternative treatment? Common sense would suggest selection of an alternative antipsychotic (and/or other psychotropic) agent based on receptor occupancy profile and expected side effects, but there is little literature to guide the specifics of this decision-making process.
One adverse effect not mentioned by the authors is clozapine’s associated risk with reduction of the seizure threshold. Although this has typically been reported after a large dosage increase (100 mg increment in a single day) or at doses above 600 mg/day (Gareri et al., Reference Gareri2008), neither of which are likely to be seen in geriatric patients, it is a risk to actively consider in patients who may also have additional risk factors. Of the literature reviewed by Renzenbrink and Wand, the maximum reported dosage clozapine dose was 400 mg daily, but it is feasible that some individuals who have received long-term treatment with clozapine may require higher doses. On the (likely rare) occasion that clozapine must be started for the first time in a geriatric patient with schizophrenia or bipolar disorder, a cautious approach should be taken with an initial dosing of 12.5 mg per day, followed by a careful titration upward to a therapeutic dose. Although taken in large part from studies assessing the use of clozapine for psychosis in Parkinson’s, an efficacious and tolerable maximum dosage has often been reported to be around 100 mg per day (Samudra et al., Reference Samudra2016; Gareri et al. Reference Gareri2008)
There are a variety of reasons why clozapine may be used in the geriatric patient population aside from “treatment-resistance.” It is important to keep in mind that treatment history and reason for initiation of clozapine have the potential to influence measured outcomes, such as symptom response or rate of adherence. Similar to some of the individuals included in the large retrospective study on the use of clozapine in veterans (Sajatovic et al., Reference Sajatovic1998), clozapine may be picked over alternative treatments for use in patients with a history of Neuroleptic Malignant Syndrome, tardive dyskinesia, or prone to extrapyramidal side effects, due to its unique array of activity other than at the D2 receptor. Clozapine may also be chosen over other treatments specifically for its suicide protective effects or reported its ability to decrease aggressive or violent behavior.
As the average age of individuals who have received long-term treatment with clozapine increases, clozapine’s use in the treatment of geriatric cases of schizophrenia and bipolar disorder will be an increasingly important issue to address. We appreciate the authors transparency regarding the limitations of the currently available literature on the subject and agree with their call for the need for higher quality studies that are experimental rather than observational in structure. Given the varied reasons that clozapine might be started over alternative antipsychotic treatments, we believe that future, prospective and longitudinal studies could better delineate the indications for starting clozapine as well as previous treatments. Although modest positive effects were reported, it bears reemphasizing that clozapine has significant associated side effects. With the small amount of primary literature available that includes patients aged 65 years and above, caution should be used when prescribing clozapine in this age range.
As the population ages, and despite their generally shorter life expectancy, it is overwhelmingly likely that there will be more patients with schizophrenia in the geriatric age group. Some of them will, unfortunately, be treatment-refractory to first- and second-line therapy, and thus be candidates for clozapine trials. Others will be previously stabilized patients on clozapine who will age into the geriatric age group, with its attendant greater risks of side effects from all medications, notably clozapine. Still others will develop psychotic illness in the context of Parkinson’s disease and will need low D2-blocking antipsychotics for symptom relief from psychosis without further compromise of their motor status. For all these reasons, the psychopharmacology literature needs more detailed studies of the patient experience with clozapine in the geriatric age range. Study designs including lifetime antipsychotic exposure and prospective observation would be most desirable to elucidate these critical areas of inquiry to enable physicians to consider the full spectrum of risks and benefits associated with the use of clozapine in geriatric patients with psychotic illness.
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The systematic review by Renzenbrink and Wand (Reference Renzenbrink and Wand2020) in this issue draws attention to a patient population that has been largely ignored within psychiatric research, with treatment of geriatric patients often being guided by studies completed in younger patient populations. Although initially developed in the 1950s, clozapine did not see widespread use until decades later. In the United States, clozapine has been in use for just over thirty years, giving rise to an aging patient population that has either been treated with clozapine for an extended period or may need to initiate treatment with clozapine after failing alternative options.
Renzenbrink and Wand’s literature review identified seven primarily observational studies for inclusion, with a total of 128 subjects treated with clozapine aged 65–86 years with diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, or delusional disorder. It should be noted that most subjects included had a diagnosis of schizophrenia, with just 4 of the 128 subjects having a diagnosis of bipolar disorder. Of the included subjects, 87% (111 out of 128) are from a single retrospective study (Sajatovic et al., Reference Sajatovic1998) assessing the efficacy of clozapine treatment in a group of predominantly male veterans aged 55 years and older. Only those with a primary psychotic disorder which was either treatment-refractory or treatment-intolerant were included with the sample being 94.2% male and 86.5% Caucasian. The homogeneity of the included patient population and overall lower quality of included literature are two of many limitations. Having said that, the authors are transparent about these limitations and are appropriately cautious in their clinical recommendations, citing insufficient current evidence to recommend clozapine over alternative treatments in geriatric patients with psychotic or bipolar disorders.
Since clozapine’s US introduction in 1990, it has transformed the management of treatment-resistant schizophrenia, likely liberating many patients from long-term care in state hospitals. However, the original US cohort of clozapine patients are now approaching (or have reached) geriatric age, so the compelling challenge remains of how to manage these patients at their current, advanced ages. It is unlikely that many geriatric schizophrenia patients were started on clozapine when it first became available; so, the experience of long-term use of clozapine in now older patients represents a convenience sample, or a natural experiment.
At clozapine’s introduction, the main toxicity of greatest clinical concern was agranulocytosis (and other effects on hematologic cell production), which was of such great concern that clozapine monitoring initially required weekly monitoring of white blood cell counts with validation of safe range white blood cell counts before subsequent weekly prescriptions could be filled. While this remains a concerning issue with clozapine, especially early in treatment, it is not likely as great a concern in geriatric patients who have heretofore tolerated clozapine without episodes of agranulocytosis or other hematologic complications. It is the other toxicities of clozapine that are of greatest concern to geriatric patients (e.g. anticholinergic effects, delirium, seizure, orthostatic hypotension). Physicians are routinely cautious about exposing older (especially ill older) patients to these specific side effects/toxicities. This alone could account for relatively less prescribing of clozapine to older patients, especially if the putative benefits of clozapine vis-à-vis other antipsychotics are unclear considering the greater medical risks associated with clozapine more than other antipsychotics.
An additional issue to contemplate is that clozapine was the first second-generation antipsychotic approved in the United States. There are likely many patients treated with clozapine continuously since 1990 who may have responded to other subsequently approved antipsychotics but were kept on clozapine continuously; alternatively, there are likely many patients who initially were treated with clozapine who, once other antipsychotic medications with less medical risk and requirement for therapeutic drug monitoring became available, were later switched to, and subsequently maintained on, alternative second-generation antipsychotics.
The relatively few cases on clozapine’s use in geriatric patients as found by the authors may represent the latter condition, although this point could be elucidated by a study design wherein the total lifetime exposure to all antipsychotics is addressed in individual cases. Similarly, the issue of previously clozapine-treated patients who needed to be switched to other, less medically problematic antipsychotics (even at the likely cost of less efficacy in the management of treatment-resistant schizophrenia) may account for finding fewer geriatric patients on clozapine than might be expected, compared to other age groups. Again, this point could be examined in a study wherein each patient’s individual experience with all antipsychotics was ascertained in detail.
Although the dearth of literature on the 65-year-old plus population is a widespread problem in psychopharmacological literature in general (that is not exclusive to clozapine), clozapine is widely regarded as a “gold standard” treatment for refractory serious mental illness due to superior efficacy and concomitant reduction in suicide risk. The significance of these purported advantages to clozapine in a geriatric population is unclear, as pivotal clinical trials establishing clozapine’s efficacy in treatment refractory psychiatric illness (Kane et al., Reference Kane1989) and its suicide protective effects (Meltzer, Reference Meltzer2003) notably excluded subjects over 65 years. As the authors note, the severity of adverse effects associated with clozapine likely discourage its more frequent use, particularly in older patients. As the elderly population is generally more prone to experiencing adverse effects to many medications, this is an important topic to investigate further, so the risks and benefits can better be ascertained by comparing antipsychotic medications against each other in this age group. The authors outline some of the side effects of clozapine as follows:
“Older adults are known to be at greater risk of adverse effects of clozapine, and are particularly more susceptible to agranulocytosis, postural hypertension, anticholinergic effects (including constipation, urinary retention, dry eyes, blurred vision, and tachycardia), sedation, and cognitive dysfunction, and delirium…”
It is important to emphasize the increased risk of delirium associated with the use of clozapine in comparison to other antipsychotics, which is typically attributed substantially to its anticholinergic properties. Although the reported incidence rate of delirium is estimated at around 10% among the general inpatient population treated with clozapine, older age has often been reported as one of the greatest predisposing factors to delirium (Das et al., Reference Das2020), (Young, Bowers and Mazure, Reference Young, Bowers and Mazure1998). In such situations where a patient has been stable on clozapine but develops intolerable side effects with age, what is the best approach to finding alternative treatment? Common sense would suggest selection of an alternative antipsychotic (and/or other psychotropic) agent based on receptor occupancy profile and expected side effects, but there is little literature to guide the specifics of this decision-making process.
One adverse effect not mentioned by the authors is clozapine’s associated risk with reduction of the seizure threshold. Although this has typically been reported after a large dosage increase (100 mg increment in a single day) or at doses above 600 mg/day (Gareri et al., Reference Gareri2008), neither of which are likely to be seen in geriatric patients, it is a risk to actively consider in patients who may also have additional risk factors. Of the literature reviewed by Renzenbrink and Wand, the maximum reported dosage clozapine dose was 400 mg daily, but it is feasible that some individuals who have received long-term treatment with clozapine may require higher doses. On the (likely rare) occasion that clozapine must be started for the first time in a geriatric patient with schizophrenia or bipolar disorder, a cautious approach should be taken with an initial dosing of 12.5 mg per day, followed by a careful titration upward to a therapeutic dose. Although taken in large part from studies assessing the use of clozapine for psychosis in Parkinson’s, an efficacious and tolerable maximum dosage has often been reported to be around 100 mg per day (Samudra et al., Reference Samudra2016; Gareri et al. Reference Gareri2008)
There are a variety of reasons why clozapine may be used in the geriatric patient population aside from “treatment-resistance.” It is important to keep in mind that treatment history and reason for initiation of clozapine have the potential to influence measured outcomes, such as symptom response or rate of adherence. Similar to some of the individuals included in the large retrospective study on the use of clozapine in veterans (Sajatovic et al., Reference Sajatovic1998), clozapine may be picked over alternative treatments for use in patients with a history of Neuroleptic Malignant Syndrome, tardive dyskinesia, or prone to extrapyramidal side effects, due to its unique array of activity other than at the D2 receptor. Clozapine may also be chosen over other treatments specifically for its suicide protective effects or reported its ability to decrease aggressive or violent behavior.
As the average age of individuals who have received long-term treatment with clozapine increases, clozapine’s use in the treatment of geriatric cases of schizophrenia and bipolar disorder will be an increasingly important issue to address. We appreciate the authors transparency regarding the limitations of the currently available literature on the subject and agree with their call for the need for higher quality studies that are experimental rather than observational in structure. Given the varied reasons that clozapine might be started over alternative antipsychotic treatments, we believe that future, prospective and longitudinal studies could better delineate the indications for starting clozapine as well as previous treatments. Although modest positive effects were reported, it bears reemphasizing that clozapine has significant associated side effects. With the small amount of primary literature available that includes patients aged 65 years and above, caution should be used when prescribing clozapine in this age range.
As the population ages, and despite their generally shorter life expectancy, it is overwhelmingly likely that there will be more patients with schizophrenia in the geriatric age group. Some of them will, unfortunately, be treatment-refractory to first- and second-line therapy, and thus be candidates for clozapine trials. Others will be previously stabilized patients on clozapine who will age into the geriatric age group, with its attendant greater risks of side effects from all medications, notably clozapine. Still others will develop psychotic illness in the context of Parkinson’s disease and will need low D2-blocking antipsychotics for symptom relief from psychosis without further compromise of their motor status. For all these reasons, the psychopharmacology literature needs more detailed studies of the patient experience with clozapine in the geriatric age range. Study designs including lifetime antipsychotic exposure and prospective observation would be most desirable to elucidate these critical areas of inquiry to enable physicians to consider the full spectrum of risks and benefits associated with the use of clozapine in geriatric patients with psychotic illness.