Quick Check

• Introduction 10

• Principles 11

• Treatment-Resistant Schizophrenia 13

• Impact of Delays in Commencing Clozapine 16

  • Clozapine and Mortality 18

  • Psychogenic Polydipsia 21

• Treatment-Intolerant Schizophrenia 24

• Suicidality 25

• Violence and Aggression 27

• Treatment-Resistant Mania 31

• Parkinson’s Disease Psychosis (PDP) 33

• Summary Points 37

• References 38

Introduction

The 60th anniversary of clozapine’s synthesis by Schmutz and Eichenberger at Wander Pharmaceuticals was celebrated in 2018, although the chemists involved hoped that their tricyclic compound HF-1854 would possess antidepressant effects [Reference Meyer, Leckband and Domino1]. In January 1961, the first pharmacological report on HF-1854 described an agent with sedative and antiadrenergic properties that resembled chlorpromazine, but which did not induce catalepsy [Reference Meyer, Leckband and Domino1]. Further animal testing reported in December 1961 established a range of activities comparable to chlorpromazine but without the catalepsy induction seen with haloperidol. In 1962 the first open clinical trial of HF-1854 found limited efficacy at the dose of 160 mg TID (n = 19), but later that year Gross and Langer in Vienna found good results in 21 of 28 patients at similar dosing, again without neurological adverse effects [Reference Gross and Langner2]. Further trial reports to Wander Pharmaceuticals in 1966 by Hippius in Berlin and Engelmeier in Vienna indicated that this was an effective but sedating antipsychotic that appeared free of neurological side effects. Wander completed further toxicological assays in 1967 and embarked on multiple clinical trials resulting in product registration in 1971, and marketing the following year under the trade name Leponex [Reference Meyer, Leckband and Domino1]. A spate of severe neutropenia cases from Finland in 1975 led to clozapine’s withdrawal from the market in most countries, although it was available under humanitarian programs with hematological monitoring [Reference Amsler, Teerenhovi and Barth3].

Three double-blind studies comparing clozapine to other antipsychotics were published in the 1970s and 1980s based on perceived benefit in those who did not respond to other agents, or improved tolerability in patients with a history of severe intolerance to D₂ antagonism (i.e. akathisia, parkinsonism, tardive dyskinesia (TD) or neuroleptic malignant syndrome (NMS)). While clozapine was clearly better tolerated and more effective than chlorpromazine among those with a history of D₂ sensitivity [Reference Claghorn, Honigfeld and Abuzzahab4], the two large efficacy trials used modest dosages of the comparator antipsychotics (chlorpromazine 360 mg/day, haloperidol 7.6 mg/day), raising doubts about clozapine’s greater effectiveness [Reference Fischer-Cornelssen and Ferner5]. The latter question was definitively settled with publication of the pivotal clozapine trial for treatment-resistant schizophrenia in 1988, using criteria elaborated by Dr. John Kane for this purpose [Reference Kane, Honigfeld and Singer6]. A crucial element of the trial design was the third criterion for treatment resistance: demonstrating in a prospective manner failure to respond to high levels of D₂ antagonism. Fewer than 2% of patients met response criteria in the prospective haloperidol arm of the Kane study (mean dose 61 mg/day), while 80% were nonresponders and 18% intolerant of high-dose haloperidol. Using only those schizophrenia patients who met all three of the treatment-resistance criteria (n = 268), response rates in the short (6-week) double-blind, randomized trial were 4% for the chlorpromazine arm vs. 30% for the clozapine group [Reference Kane, Honigfeld and Singer6]. Additional experience over the next decade combined with insights regarding therapeutic plasma levels has increased the expected clozapine response rate to at least 40% in longer-term studies, with values up to 60% reported [Reference Siskind, Siskind and Kisely7]. Clozapine has also demonstrated efficacy in schizophrenia patients with psychogenic polydipsia, an effect seen with doses as low as 300 mg/day [Reference Canuso and Goldman8].

The unique benefits of clozapine extend beyond treatment-resistant schizophrenia and include a number of other uses, many of which are supported by rigorous double-blind, placebo or active comparator trials. In some instances, the value of clozapine lies in its low affinity for D₂ receptors, thus permitting treatment of schizophrenia patients intolerant of D₂ antagonism, or Parkinson’s disease psychosis (PDP) patients. For other applications, the underlying mechanism for clozapine’s effectiveness is unknown, but it appears independent of the antipsychotic effect when employed for treatment-resistant mania, in schizophrenia patients with persistent aggression, and in schizophrenia patients with a history of suicidality. By mastering the details of hematologic monitoring and management of adverse effects, clinicians have a range of evidence-based uses for clozapine in difficult-to-treat patient groups.

A Treatment-Resistant Schizophrenia

While inconvenient, criterion 3 of the Kane 1988 criteria is central to a research definition of treatment resistance. Studies using “modified Kane criteria” that lack this crucial element report unrealistically high response rates for atypical antipsychotics other than clozapine. The enormous impact of criterion 3 can be seen in the three double-blind studies of olanzapine for treatment-resistant schizophrenia (Table 1.1). Response rates to olanzapine at doses up to 50 mg/day were 0% and 7% in the two studies that included criterion 3 [Reference Conley, Tamminga and Bartko9,Reference Conley, Kelly and Richardson10], but response to olanzapine was 50% when this step was omitted [Reference Meltzer, Bobo and Roy11].

Unfortunately the literature is littered with numerous papers in which patients with varying degrees of treatment resistance and intolerance are grouped together, leading the unwary reader to question clozapine’s benefit in treatment-resistant patients. Adding to the confusion was a 2016 meta-analysis that included literally any definition of treatment resistance in its examination of the literature, and reviewed studies that also enrolled treatment-intolerant patients [Reference Samara, Dold and Gianatsi12]. Although that meta-analysis did not change perceptions regarding clozapine’s efficacy for treatment-resistant schizophrenia, it reinforced the concept that one must take a jaundiced view of studies for treatment-resistant schizophrenia that do not subject patients to a prospective antipsychotic trial and rely solely on historical records of prior antipsychotic treatment. Aside from treatment resistance, there are many reasons that patients may fail to respond adequately to an antipsychotic, with nonadherence, underdosing and kinetic issues playing significant roles. To further emphasize this point, in a recent outpatient study of 99 schizophrenia patients deemed treatment-resistant, 35% had plasma antipsychotic levels that were subtherapeutic [Reference McCutcheon, Beck and D’Ambrosio13].

One positive outcome of the confusing 2016 meta-analysis was a sharpening of the debate regarding the need to define treatment resistance in research and clinical settings [Reference Howes, McCutcheon and Agid14].

There is little question that, when rigorously defined using all three Kane criteria, the anticipated response rate to antipsychotics other than clozapine is < 5%, compared to rates ≥ 40% for clozapine. Because implementing criterion 3 is often impractical for routine clinical care, a consensus panel published guidelines in 2017 to help clinicians ascertain when patients are treatment-resistant. Included in this recommendation is that the term “refractory” no longer be used (Table 1.2).

These criteria emphasize that clinicians must be mindful of high nonadherence rates in schizophrenia patients before concluding that prior antipsychotic trials were failures. When prior trials lacked plasma levels, or had features associated with antipsychotic nonadherence (e.g. missed refills, homelessness, substance use, no documented adverse effects), it is not unreasonable to conduct a trial with a long-acting injectable and plasma level monitoring to confirm adequate antipsychotic exposure. If prior trials employed relatively weaker D₂ antagonists (e.g. quetiapine) or a D₂ partial agonist (e.g. aripiprazole, brexpiprazole, cariprazine), and there is no history of unusual D₂ sensitivity at routine doses, one should consider use of a stronger D₂ antagonist for the depot formulation. Clinicians can be guided by the literature in cases where exploring higher antipsychotic plasma levels appears feasible in a nonresponding and adherent patient (by plasma levels) who is not exhibiting dose-limiting adverse effects [Reference Meyer15]. Nonetheless, despite a clinician’s best efforts, at least 20–30% of schizophrenia patients will be inadequate responders to nonclozapine antipsychotics.

Outside of the academic sphere, there are large data sets that substantiate clozapine’s effectiveness in ‘real-world’ circumstances. Table 1.3 summarizes the latest and best-designed of these studies. Two of these studies examined enormous samples of schizophrenia patients (18,869 and 29,823) for up to 8 years [Reference Vanasse, Blais and Courteau16,Reference Tiihonen, Mittendorfer-Rutz and Majak17], while another looked at two matched cohorts of 3123 schizophrenia patients who met clinically defined criteria for treatment resistance [Reference Stroup, Gerhard and Crystal18].

By selecting those patients who would be deemed treatment-resistant by routine clinical standards, the latter study emphasizes the benefits of clozapine compared to other antipsychotics for that population [Reference Stroup, Gerhard and Crystal18]. As opposed to the outcomes found in an inpatient research unit or highly supervised research clinic, these naturalistic data sets provide a compelling picture of clozapine’s effectiveness in the hands of clinicians working with a challenging population with varying degrees of motivation, adherence and illness severity. Regardless of the treatment setting, clozapine remains the option with best chance of success for the treatment-resistant schizophrenia patient.

Impact of Delays in Commencing Clozapine

One important variable in maximizing the chance of clozapine response involves minimizing the time to initiation once the patient meets clinical criteria for treatment resistance. Given the reluctance of many clinicians to prescribe clozapine, it is not surprising that the literature documents unnecessary delays in commencing clozapine treatment. A clinical review of all 149 patients started on clozapine at the South London and Maudsley NHS Foundation Trust from 2006 to 2010 found that the mean delay in initiating clozapine was 47.7 months, with 36% of patients receiving antipsychotic polypharmacy and 34% receiving high-dose antipsychotic therapy during the delay [Reference Howes, Vergunst and Gee19]. A subsequent paper covering 162 clozapine starts at the Istanbul Faculty of Medicine, Department of Psychiatry noted a mean delay of 29 months after fulfilling treatment-resistance criteria [Reference Ucok, Cikrikcili and Karabulut20]. While those who responded to clozapine tended to be younger, have shorter illness duration and fewer numbers of adequate antipsychotic trials before clozapine, the extent of delay in starting clozapine was an independent contributor to the odds of clozapine response [Reference Ucok, Cikrikcili and Karabulut20]. The mean delay in initiating clozapine in the good response group was 21 months, compared to 47 months in those with minimal or no improvement (p = 0.04). Utilizing the concept that the biological onset of treatment resistance was not when the patient was finally deemed to have failed their second antipsychotic but when that period of exacerbation commenced, a group from a tertiary care inpatient hospital in Okayama, Japan analyzed data in 90 new clozapine starts who remained on treatment for at least 3 months (see Figure 1.1) [Reference Yoshimura, Yada and So21]. Using this definition, they found that a delay in clozapine initiation of 2.8 years best predicted those who would benefit from clozapine treatment. In patients with a delay ≤ 2.8 years the response rate was 81.6%, while it fell to 30.8% in those with a delay > 2.8 years. Consistent with the Turkish data, older age and longer duration of illness were associated with lower response rates.

Figure 1.1. Delaying the time to starting clozapine reduces likelihood of response in resistant schizophrenia.

(Adapted from: Yoshimura, B., Yada, Y., So, R., et al. (2017). The critical treatment window of clozapine in treatment-resistant schizophrenia: Secondary analysis of an observational study. Psychiatry Research, 250, 65–70 [Reference Yoshimura, Yada and So21].)

Psychogenic Polydipsia

Primary polydipsia is a scenario of increased water intake occurring in the absence of impairment in water excretion. This can be distinguished from the secondary polydipsia seen with lithium-treated patients who increase water intake due to obligatory losses from nephrogenic diabetes insipidus. Both groups may have low urine osmolality, but the latter group maintains normal serum osmolality and serum sodium levels, while the primary polydipsia patient will suffer from severe hyponatremia and low serum osmolality during water binges [Reference Goldman24]. The association of water intoxication and schizophrenia was reported in the pre-antipsychotic era, with a 1923 paper correlating increased water excretion with greater psychosis severity. By 1936 it was noted that excessive water intake occurred in approximately 25% of patients and was the most common metabolic abnormality in the severely mentally ill; moreover, it could be associated with life-threatening hyponatremia [Reference Goldman24]. Modern prevalence data obtained over 5 years in a state hospital (1996–200) confirm that polydipsia continues to be present in at least 20% of chronic psychiatric inpatients [Reference de Leon25]. The excessive drinking in primary polydipsia is not due to excessive thirst, but is motivated instead by delusions or psychic discomfort that is relieved by water binges [Reference Goldman24].

Shortly after clozapine’s approval in 1989, cases emerged in which water intoxication associated with schizophrenia was not addressed by typical antipsychotics, but which responded to clozapine. A 1996 case series of five state hospital patients with polydipsia who met Kane criteria reported that all were successfully discharged on clozapine and had no recurrence of polydipsia over 17 months of outpatient follow-up [Reference Fuller, Jurjus and Kwon26]. A subsequent 24-week open-label study was performed in eight male schizophrenia patients with polydipsia to document longitudinal changes in urine and serum osmolality after starting clozapine [Reference Canuso and Goldman8]. The protocol involved 6 weeks with a typical antipsychotic (per Kane criterion 3), followed by sequential 6-week periods of clozapine at 300, 600 and then 900 mg/day (if tolerated). During treatment with typical antipsychotics both serum and urine osmolality remained grossly abnormal; however, on clozapine the mean plasma osmolality normalized, and rose on average by 15.2 mosm/kg (95% CI 5.5–25.0); moreover, this effect was evident at the dose of 300 mg/day of clozapine (see Figures 1.2 and 1.3) [Reference Canuso and Goldman8]. With ongoing clozapine titration, urine osmolality also normalized. No other prospective clozapine studies have emerged for polydipsia, but the accumulated literature is substantial enough that a 2010 comprehensive review of water imbalance issues in psychosis patients concluded that primary polydipsia generally appears resistant to antipsychotics except clozapine. Evidence-based treatment options for preventing water intoxication includes targeted fluid restriction, clozapine therapy, and removal of agents that may be causing hyponatremia (e.g. carbamazepine, valproate, sodium-wasting diuretics). The titration and therapeutic plasma levels for schizophrenia spectrum polydipsia patients are consistent with the use of clozapine for treatment-resistant schizophrenia.

Figure 1.2. Mean plasma osmolality during 6 weeks of typical antipsychotic treatment followed by 6 weeks each of clozapine at 300, 600 and then 900 mg/day in schizophrenia patients with polydipsia.

(Adapted from: Canuso, C. M. and Goldman, M. B. (1999). Clozapine restores water balance in schizophrenic patients with polydipsia–hyponatremia syndrome. Journal of Neuropsychiatry and Clinical Neuroscience, 11, 86–90 [Reference Canuso and Goldman8].)

Figure 1.3. Mean urine osmolality during 6 weeks of typical antipsychotic treatment followed by 6 weeks each of clozapine at 300, 600 and then 900 mg/day in schizophrenia patients with polydipsia.

(Adapted from: Canuso, C. M. and Goldman, M. B. (1999). Clozapine restores water balance in schizophrenic patients with polydipsia–hyponatremia syndrome. Journal of Neuropsychiatry and Clinical Neuroscience, 11, 86–90 [Reference Canuso and Goldman8].)

B Treatment-Intolerant Schizophrenia

Early in its clinical development, clozapine’s extremely low rate of neurological adverse became apparent, leading to small trials in patients with tardive dyskinesia (TD), and for patients intolerant of D₂ antagonism due to akathisia, parkinsonism, acute dystonia or neuroleptic malignant syndrome (NMS) [Reference Simpson, Lee and Shrivastava27]. While use in TD patients was a focus of several studies, evidence for benefit in D₂ antagonist-intolerant patients is based on experience reported in case series where these patients were often included along with treatment-resistant individuals [Reference Small, Milstein and Marhenke28]. The conclusions from this case-based literature is that clozapine is unlikely to induce acute movement disorders, although there are a handful of NMS cases reported [Reference Sachdev, Kruk and Kneebone29]. With respect to TD, both the efficacy outcomes and quality of prior studies led the American Academy of Neurology to state that the data were insufficient to support or refute use of clozapine for tardive syndromes [Reference Bhidayasiri, Fahn and Weiner30]. Despite the abundance of case data, only three prospective studies involving a switch to clozapine for TD management were of sufficient quality to be reviewed: two were positive, one was not. A subsequent 2018 review found no further data to indicate that antipsychotic switching is an evidence-based practice for management of TD [Reference Bergman, Rathbone and Agarwal31].

Since clozapine’s reintroduction in 1989 the psychopharmacology landscape has changed in two ways: there are numerous options to high-potency typical antipsychotics, and there are three vesicular monoamine transporter type 2 (VMAT2) inhibitors available for TD treatment. The expanded group of atypical antipsychotics (including the D₂ partial agonists) provides a range of options for those with significant sensitivity to D₂ antagonism. Quetiapine has very low D₂ affinity and consequentially low rates of acute movement disorders, but enthusiasm for its use as a schizophrenia treatment has waned based on real-world effectiveness data associating quetiapine with higher rates of overall mortality [Reference Tiihonen, Lonnqvist and Wahlbeck32], rehospitalization[Reference Tiihonen, Mittendorfer-Rutz and Majak17], any mental health event (suicide, hospitalization or emergency visit) or physical health event (death other than suicide, hospitalization or emergency visit for physical disorders) [Reference Vanasse, Blais and Courteau16]. Although the pool of treatment-intolerant patients is smaller than when first-generation antipsychotics were the only available choices, these individuals do exist and should be offered clozapine. For stable TD patients who require ongoing antipsychotic therapy, the addition of a VMAT2 inhibitor is preferable to antipsychotic switching as the combination is well tolerated in severely mentally ill individuals on antipsychotic therapy (see Chapter 13). Clozapine should be considered if there are other ongoing sources of treatment intolerance (e.g. akathisia), or the patient meets clinical criteria for treatment resistance.

C Suicidality

Conceptually, suicide and violence are separate domains of schizophrenia spectrum disorders that are not necessarily driven by psychotic thought processes, and thus respond incompletely to traditional antipsychotic therapy [Reference Meyer, Cummings and Proctor33]. A review of suicidal acts among 10,118 schizophrenia patients participating in placebo-controlled clinical trials found that rates of suicide and attempted suicide did not differ significantly between the placebo-treated and drug-treated groups despite greater symptom reduction for the latter [Reference Khan, Khan and Leventhal34]. Patients with schizophrenia spectrum disorders have ninefold higher rates of unnatural causes of death (suicide, violent accidents) compared to the general population, with suicide risk especially prominent in the first 5 years after diagnosis [Reference Osby, Correia and Brandt35,Reference Palmer, Pankratz and Bostwick36]. Death from suicide comprises 30% of all causes of mortality in studies of new-onset schizophrenia patients, but wanes over ensuing decades. The estimated lifetime risk of death from suicide is 4.9% in patients with schizophrenia [Reference Palmer, Pankratz and Bostwick36].

The impact of clozapine on suicidality was first noticed in treatment-resistant schizophrenia patients, but the antisuicide effects were later seen in those without treatment resistance, and in bipolar disorder patients [Reference Meltzer and Okayli37–Reference Meltzer39]. From these observations the foundation was laid for a large international trial to examine clozapine’s comparative efficacy vs. olanzapine in a nonresistant schizophrenia population. The International Suicide Prevention Trial (InterSePT) enrolled 980 patients at high risk for suicide due to prior attempts or current symptoms, with 24 months of follow-up (see Figure 1.4) [Reference Meltzer, Alphs and Green40]. In this cohort of schizophrenia patients who were not treatment-resistant, clozapine’s superior impact on suicidality was clearly independent of the reduction in psychotic symptoms, as both clozapine and olanzapine had comparable improvements in total Positive and Negative Syndrome Scale (PANSS) scores. This principle will be echoed in data supporting clozapine’s effect on aggression: the reduction in suicidality and violence is independent of clozapine’s antipsychotic effect. The InterSePT study resulted in an indication for reducing risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder “who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state” [41]. Naturalistic data summarized in Table 1.4 substantiate the findings from InterSePT: clozapine treatment is associated with a reduction of 66–80% in deaths by suicide or other unnatural causes, and a 36% lower rate of self-harm compared with nonclozapine antipsychotics.

Figure 1.4. Time to suicidal events in the InterSePT study.

(Adapted from: Meltzer, H. Y., Alphs, L., Green, A. I., et al. (2003). Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Archives of General Psychiatry, 60, 82–91 [Reference Meltzer, Alphs and Green40].)

D Violence and Aggression

The association between psychosis and violence has been noted for over a century, but only in recent decades have there been systematic attempts to understand the intrinsic neurobiological factors and extrinsic factors (e.g. substance use) that moderate this risk. Quantifying this risk has been challenging because violence or aggression can include a spectrum of behaviors from verbal threats to physical violence or murder. The lack of consensus definitions for the term “violence” in research papers leads to a range of reported rates [Reference Rund42]. Despite these limitations, a comprehensive 2009 review noted that violence risk is increased for both male and female schizophrenia patients, and that substance use further increases risk of violence 3.7- to 4.2-fold in this population compared to psychosis patients without substance use (see Figure 1.5) [Reference Fazel, Gulati and Linsell43,Reference Fazel, Langstrom and Hjern44].

Figure 1.5. Risk estimates for violence in schizophrenia and other psychoses for male samples, female samples and mixed gender samples.

(Adapted from: Fazel, S., Gulati, G., Linsell, L., et al. (2009). Schizophrenia and violence: Systematic review and meta-analysis. PLoS Medicine, 6, e1000120 [Reference Fazel, Gulati and Linsell43].)

Aggression in undermedicated or untreated schizophrenia patients is approached with standard pharmacological interventions including antipsychotics alone or with mood stabilizers (if there is a bipolar diathesis) [Reference Meyer, Cummings and Proctor33]. The more problematic clinical scenario revolves around the type of schizophrenia patient encountered in psychiatric inpatient and forensic settings who remains persistently aggressive despite antipsychotic treatment. In addressing the persistently violent schizophrenia spectrum patient, one must first categorize the nature of the aggression. The most robust and empirically validated classification method was developed within the New York State Hospital system based on reviewed videotaped assaults supplemented with assailant and victim interviews to determine the motivation for each violent act. These detailed assessments led the authors to conclude that three categories could be used to define aggressive acts: psychotic, impulsive, and predatory (also called organized or instrumental) [Reference Meyer, Cummings and Proctor33]. The latter group comprises intentional acts for secondary gain (e.g. theft, intimidation), and requires a custodial solution, not pharmacotherapy. Psychotic violence is due to persistent delusions or hallucinations that drive behaviors, while impulsive acts involve inappropriate responses to real-world stimuli. A classic example of impulsive violence is a patient who assaults a peer after being gently bumped in a line despite the innocuous nature of the contact and the fact that the assault will have repercussions for the assailant (e.g. legal, loss of privileges, etc.). Utilizing this classification, there are two core concepts that underlie treatment of ongoing violence in medicated schizophrenia patients:

1. a. Among persistently aggressive forensic schizophrenia inpatients the most common type of assault is impulsive (54%), followed by organized (29%) and psychotic (17%) [Reference Quanbeck, McDermott and Lam45].

2. b. Impulsive violence/aggression is a separate symptom dimension of schizophrenia that may not respond to nonclozapine antipsychotics (see Figure 1.6) [Reference Meyer, Cummings and Proctor33].

Figure 1.6. Violence is a separate symptom dimension of schizophrenia.

The initial approach to any violent patient requires the clinician to classify the nature of the violence. That motivated by delusions or hallucinations involves optimization of antipsychotic treatment, and use of clozapine in those who are treatment-resistant. For those who are impulsive, further antipsychotic titration is appropriate if there are no dose-limiting adverse effects (e.g. akathisia, parkinsonism). In schizophrenia patients who continue to be impulsively violent despite maximal use of nonclozapine antipsychotics, clozapine is the preferred agent, and its anti-aggressive property in these individuals is independent of its impact on psychotic symptoms. Evidence for this assertion comes from studies summarized in Table 1.5 [Reference Frogley, Taylor and Dickens46]. The most rigorous study design was a randomized, double-blind, parallel-group, 12-week trial specifically for physically assaultive New York State Hospital patients with schizophrenia or schizoaffective disorder [Reference Krakowski, Czobor and Citrome47]. At study end there were nonsignificant numerical changes in PANSS total scores across all three drug groups, but clozapine significantly reduced verbal, physical and total aggression scores compared to haloperidol or olanzapine. Clozapine’s effect was more pronounced in those with cognitive dysfunction, despite the fact that poor executive function at study baseline predicted higher levels of aggression (see Figure 1.7) [Reference Krakowski and Czobor48].

Figure 1.7. Clozapine’s superiority for aggression compared to olanzapine and haloperidol among schizophrenia patients with cognitive dysfunction.

(Adapted from: Krakowski, M. I. and Czobor, P. (2012). Executive function predicts response to antiaggression treatment in schizophrenia: A randomized controlled trial. Journal of Clinical Psychiatry, 73, 74–80 [Reference Krakowski and Czobor48].)

Further evidence that clozapine’s anti-aggression effect is independent of its antipsychotic properties includes a small case series of clozapine therapy for impulsive aggression among nonpsychotic patients with antisocial personality disorders. Not only did clozapine significantly decrease rates of impulsive aggression and violence in this cohort, it did so at a mean plasma level of 171 ng/ml, well below the 350 ng/ml threshold used to manage treatment-resistant schizophrenia [Reference Brown, Larkin and Sengupta49]. A 2018 review outlines the challenges to prescribing clozapine in forensic settings, including the lack of an intramuscular formulation in most countries, and the greater attention required for management of adverse effects. Nonetheless, the authors note the cost-effectiveness of clozapine treatment as an important part of any strategy to manage aggressive, severely mentally ill patients in health-care and criminal justice systems [Reference Patchan, Vyas and Hackman50].

E Treatment-Resistant Mania

The value of clozapine for treatment-resistant mania was noted in case reports as early as 1977 [Reference Muller and Heipertz51], but not until 1994 was a trial conducted in patients who met a standardized definition of treatment resistance: documented response failure or intolerance to lithium, an anticonvulsant, and at least two typical antipsychotics. All subjects (n = 25) in that 13-week open-label trial met DSM-IIIR criteria for the manic phase of bipolar disorder or schizoaffective disorder, bipolar type [Reference Kimmel, Calabrese and Woyshville52]. At study endpoint, 72% of patients demonstrated at least 50% decrease in the Young Mania Rating Scale (YMRS) score. A subsequent 1-year trial with 38 treatment-resistant patients meeting DSM-IV criteria for the manic phase of schizoaffective or bipolar disorder randomly assigned subjects to adjunctive open-label clozapine (n = 19) or treatment as usual (TAU) (n = 19), with monthly ratings of mood and psychosis symptoms [Reference Suppes, Webb and Paul53]. Significant between-group differences were found in scores on all rating scales except the Hamilton Depression scale, and medication use decreased significantly in the clozapine group. Importantly, patients with nonpsychotic bipolar I disorder randomized to clozapine exhibited similar improvement in mania symptoms as did the entire clozapine-treated group, providing evidence that clozapine’s antimanic effect is independent of the antipsychotic effect [Reference Suppes, Webb and Paul53]. There were differences in mean clozapine doses between those with schizophrenia spectrum disorders (623 mg/day) and nonpsychotic bipolar I patients (234 mg/day). A subsequent 12-week trial of 22 bipolar I patients with mania and psychotic features noted a mean dose among completers of 334 mg/day [Reference Green, Tohen and Patel54]. Double-blind, placebo controlled adjunctive studies do not exist, but there are case series for use in rapid cycling bipolar disorder [Reference Suppes, Ozcan and Carmody55].

Real-world data support the conclusions of open-label studies that clozapine is effective for treatment-resistant mania in bipolar I patients. Using the Denmark national database for the years 1996–2007, investigators examined outcomes in bipolar disorder patients started on clozapine (n = 326) specifically excluding those with a schizophrenia spectrum disorder. The study used a mirror image design to look at comparative hospital days, number of psychiatric admissions, and medication usage for the 2 years before and 2 years after starting clozapine [Reference Nielsen, Kane and Correll56]. After a mean follow-up of 544 ± 280 days, the number of hospital bed days decreased by 80% from 178 to 35 (p < 0.001), and the mean number of admissions decreased by 37.5% from 3.2 to 2.0 (p < 0.001). Overall, 74% had reduced bed days and 40% were not admitted at all while on clozapine. Using defined daily doses (DDD), the number of psychotropic medications decreased by 13% from 4.5 to 3.9 DDD (p = 0.045). Nonpsychiatric hospital visits for intentional self-harm or medication overdose also decreased significantly from 8.3% to 3.1% (p = 0.004). The mean clozapine dose at the end of follow-up was 307.4 mg/day. After 1 year of clozapine exposure, use of medications to manage nonpsychiatric medical conditions did not increase. As noted in schizophrenia, clozapine is only effective for mania when patients adhere to treatment. Bipolar patients deemed “irregular” clozapine users in a Taiwan analysis by virtue of low medication possession ratios had twofold higher adjusted risk for emergency room visits, and 2.5 times greater risk for hospitalizations compared to more adherent clozapine patients [Reference Wu, Wang and Liu57].

F Parkinson’s Disease Psychosis (PDP)

Parkinson’s disease (PD) is a neurodegenerative disorder related to the neuronal accumulation of alpha-synuclein in histologically distinct complexes called Lewy bodies. The worldwide prevalence of PD is estimated at > 7 million, of which more than 50% will develop symptoms of Parkinson’s disease psychosis (PDP). The prevalence of PDP increases to 75% of patients in those with PD and related dementia. In 2007 a consensus definition for PDP was elaborated that included the existence of hallucinations, delusions, illusions or false sense of presence for at least 1 month in a patient previously diagnosed with PD and in whom other etiologies have been ruled out (e.g. delirium) [Reference Ravina, Marder and Fernandez58]. The development of PDP is associated with increased caregiver burden, increased likelihood of nursing home placement, and is associated with increased mortality [Reference Cummings, Isaacson and Mills59].

For most of the twentieth century, PD was viewed primarily as a motor disease related to loss of dopamine neurons in the nigrostriatal pathway, but PD is now recognized as a multisystem disease associated with cognitive impairment related to loss of cholinergic neurons, depression due to loss of noradrenergic neurons, autonomic and other nonmotor symptoms [Reference Giugni and Okun60]. In prior decades PDP was often referred to as levodopa psychosis under the belief that excessive dopaminergic stimulation from dopamine agonist treatment was the principal underlying cause. It is now understood that the pathophysiology of PDP is due to loss of serotonergic midbrain dorsal raphe neurons from the accumulated Lewy body burden in these cells. The loss of this serotonin signal results in upregulation and supersensitivity of postsynaptic 5HT_2A receptors, a finding confirmed by neuroimaging of PD patients with and without psychosis [Reference Ballanger, Strafella and van Eimeren61]. That increased stimulation of 5HT_2A receptors can induce psychotic symptoms has been known for decades based on elucidation of common mechanisms among hallucinogens such as psilocybin and lysergic acid diethylamide.

The therapeutic dilemma in treating PDP relates to the profound loss of dopamine neurons in the dorsal striatum, and the inability to tolerate antipsychotics that possess moderate D₂ affinity without significant worsening of motor symptoms. Recognition that clozapine was associated with extremely low risk for drug-induced parkinsonism led to a 1990 study exploring its tolerability in six PDP patients at doses ranging from 75 to 250 mg/day (mean 170.8 mg/day) [Reference Wolters, Hurwitz and Mak62]. This early study noted a 50% response rate, but 50% also experienced worsening motor symptoms at those doses. These findings informed the design of the two seminal PDP studies published in 1999, one from a French group and the second from a US consortium. Each study was a double-blind, placebo-controlled 4-week trial, and both enrolled a total of 60 subjects. Based on high rates of motoric worsening in the 1990 study, the starting clozapine dose in each trial was 6.25 mg/day, with titration every 3–4 days based on response and tolerability. In the French study mean endpoint clozapine dose was 36 mg/day, while it was 24.7 mg/day in the US-based Psychosis and Clozapine in the treatment of Parkinsonism (PSYCLOPS) trial [63,64]. At these low doses, clozapine was significantly more effective than placebo in both trials, and with large effect sizes; moreover, there was no exacerbation of parkinsonism in the PSYCLOPS study, while 22% of patients in the French trial noted mild or transient worsening of parkinsonism, although no patient discontinued the study for this reason. Results from the 12-week PSYCLOPS extension study (n = 53) confirmed the efficacy of low-dose clozapine for PDP (mean 28.8 mg/day), again without worsening of underlying Parkinson’s disease symptoms as noted by ratings of motor function or need for higher doses of dopamine agonist medications [Reference Factor, Friedman and Lannon65]. Recent naturalistic data are consistent with the clinical trials findings. A retrospective review of 36 PDP patients treated at one center (mean age 68 years) noted that 33% had complete response, and 33% a partial response to clozapine [Reference Hack, Fayad and Monari66]. Highlighting the practical issues involved with clozapine administration, the overall retention rate on clozapine was only 41%, and the most common reasons for discontinuation were frequent blood testing (28%), refusal of medical staff to continue clozapine after nursing home placement (11%) and neutropenia (8%). Only 2.8% stopped clozapine due to worsening motor symptoms, and a similar proportion discontinued treatment due to orthostasis or delirium (2.8% for each). The possible benefit of clozapine for levodopa-induced dyskinesias (LID) was later studied in 50 PD patients without psychosis in a 10-week, double-blind, placebo-controlled, multicenter trial. The principal outcome was change in the LID “on” time (hours per day). At a mean clozapine dose of 39.4 mg/day, clozapine treatment was associated with reduction in the duration of “on” periods from 5.68 h/day to 3.98 h/day, while the placebo group slightly worsened from 4.54 h/day to 5.28 h/day [Reference Durif, Debilly and Galitzky67].

Over the ensuing decade other atypical antipsychotics have been used in PDP patients with results primarily reported in case series. Most have proved ineffective and were associated with significant motoric worsening (olanzapine, risperidone, ziprasidone, aripiprazole) [Reference Borek and Friedman68]. Only olanzapine and quetiapine were examined in double-blind studies as summarized in Table 1.6. In all trials olanzapine was ineffective, and in the largest studies olanzapine exacerbated parkinsonian symptoms. Quetiapine was generally ineffective, but did not induce motoric adverse effects. Despite widespread use for PDP, a recent meta-analysis concluded that: “Given the randomized controlled trial-derived evidence, quetiapine should not be used in this indication, unless further studies have clarified this issue” [Reference Frieling, Hillemacher and Ziegenbein69]. Concerns over quetiapine were further heightened by results of a large retrospective study exploring 180-day mortality rates in 7877 PD patients starting antipsychotic treatment and 7877 PD patients who did not take an antipsychotic matched for age, sex, race, year of treatment, presence and duration of dementia, duration of PD, delirium, medical comorbidity, and hospitalization. In this study, mortality was increased by a factor of 2.16 for quetiapine [Reference Weintraub, Chiang and Kim70]. Unfortunately, the number of clozapine cases was too small to analyze separately.

Despite its efficacy data, a limiting factor in clozapine use for PDP relates to the mandatory hematological monitoring, as a weekly laboratory trip can prove daunting for a patient group comprised of older individuals with limited mobility. To obviate this issue, researchers have sought to harness clozapine’s effectiveness in a molecule that does not require laboratory monitoring. At the low doses used for PDP one of clozapine’s most prominent receptor actions is at 5HT_2A, and this is likely the primary site of action based on the known pathophysiology of this disorder. This insight led to development of the potent selective 5HT_2A antagonist pimavanserin for PDP (Ki 0.087  nM), with US FDA approval granted in 2016 [Reference Cummings, Isaacson and Mills59]. Pimavanserin lacks affinity for dopaminergic, cholinergic, alpha-adrenergic and histaminergic receptors, and in clinical trials had no impact on ratings of motor function. While pimavanserin is a promising development in PDP treatment, it is currently only available in the US, so clozapine remains the mainstay of PDP management worldwide, and for those who fail to respond to pimavanserin.