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Chapter 19 Augmentation of clozapine with amisulpride: an effective therapeutic strategy for violent treatment-resistant schizophrenia patients in a UK high-security hospital
Introduction
Clozapine is an atypical antipsychotic with actions on multiple neurotransmitter systems [1]. It is one of the few agents that have been shown to improve symptoms in patients with treatment-resistant schizophrenia and is a drug of choice, with response rates between 30% and 60% [2,3]. However, its associated side effects can be severe [4].
The potential benefit for patients who are unresponsive to clozapine alone has been sought through augmentation of its effect with other pharmacological agents [5]. This is relatively common clinical practice [6–9]; however, the evidence base behind polypharmacy is limited [10,11]. Research to date has augmented clozapine treatment with antipsychotics [5,12], antidepressants [13–16], mood stabilizers [17–20], and glutamatergic agents [21,22]. Antipsychotics used for augmentation of clozapine are often selected based on the theory that they have alternative mechanisms of action to clozapine. A number of promising small studies that have augmented clozapine with amisulpride, a selective D2 antagonist, have shown clinical improvement in patients on combination therapy versus those on clozapine alone [23–27].
Amisulpride is not approved by the Food and Drug Administration for use in the United States, but it is used in Europe (France, Germany, Italy, Switzerland, Russia, United Kingdom), Israel, India, New Zealand, and Australia to treat psychosis and schizophrenia.
A subgroup of patients with schizophrenia presents with violence [28]. In fact, men with schizophrenia have a significantly increased rate of violent offending compared with men who suffer from non-schizophrenic mental disorders [29]. Given that schizophrenia has a significant relationship with violence, specific treatments to manage this violence may be as important as those to manage the illness [30]. Clozapine has been shown to have a desirable anti-aggressive effect in this population [31–33]. For violent patients within the subgroup who do not respond to clozapine monotherapy, there is no published literature to support the use of clozapine augmentation strategies.
Here we present a case series of patients with schizophrenia who were treated in a high-security hospital and who have a history of serious violence. High-security hospitals look after mentally disordered offenders who pose the highest risk of violence to others. We report the cases of six patients from this subgroup who were treated with clozapine augmented with amisulpride.
Methods
At the time of writing of this case series, eight patients were receiving augmentation of clozapine with amisulpride in the hospital. Of these, six patients were included for this retrospective case series, as they were able to provide informed consent, and the remaining two were deemed to lack the capacity to provide consent by their treating psychiatrists. The remaining six patients did not have any history of learning disability, brain injury, epilepsy, or concurrent substance abuse. These patients are detained in a high-security hospital under the Mental Health Act 1983 (England and Wales). Patients had a median age of 33.5 years. Five patients were suffering from schizophrenia and one from schizoaffective disorder that was treatment-resistant (as per treatment-resistant schizophrenia criteria [2]). These diagnoses were made clinically by the treating consultant. Before amisulpride treatment was initiated, all patients had already received a mean clozapine dosage of 525 mg per day (range 400 mg to 600 mg per day) for at least 4.1 months (range 4.1 months to 13 years and 4 months, median 11.64 months), but were poorly treatment responsive. Clozapine serum levels noted prior to and after augmentation were in the therapeutic range for all patients. Doses of clozapine and amisulpride for each patient were recorded. Any changes in these doses and any concurrent medications, including changes after augmentation, were noted. Combined treatment duration ranged from 1.2 months to 3 years and 9.5 months (median 11.87 months). During the combined treatment period, the mean dosage for amisulpride was 667 mg per day, ranging from 400 mg to 1000 mg per day.
Clinical Global Impression (CGI) scores [34] were formulated retrospectively from clinical information for each patient by examining their illness severity before and after amisulpride augmentation, and also the degree of improvement and side effects while on this treatment. Patients were also asked for their subjective experience of their illness and side effects while taking clozapine and amisulpride combination therapy. The total duration of illness for each patient was also noted.
Case notes and information from the hospital’s information recording system were reviewed for violent/aggressive incidents under the following subcategories: (1) verbal aggression, (2) aggression against property, and (3) aggression against people. The case notes were also reviewed for episodes of seclusion and self-harm, as well as positive factors such as engagement in occupational therapy (OT), vocational therapy, and psychological therapies. Formal risk assessments (HCR-20 [35] and the hospital’s high-risk assessment) were reviewed to gauge change in risk status, and moves to lower- or higher-dependency wards were noted. Admission reports were examined for patients’ index offenses. This information was used to measure levels of aggression prior to augmentation and since augmentation commenced.
We examined metabolic parameters, where these were available, using the latest value prior to and after initiation of augmentation, including BMI (body mass index), total cholesterol:HDL ratio, and blood glucose levels.
Results
Symptom improvement
Of the six patients, three had a global improvement score of “very much improved,” one had a score of “much improved,” and two had a score of “minimally improved.” The severity of illness decreased for all patients, although to variable degrees (Table 19.1).
| Patient | Age | Duration of illness (years) | Length of current admission in HSH (months) | Duration of preaugmentation clozapine treatment (months) | Duration of augmentation so far | Original clozapine dose | Current clozapine dose | Concurrent medication | PRN medication | Amisulpride dose | Clozapine, norclozapine level (mg/l) | Severity of illness preaugmentation | Severity of illness present | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pre | Post | |||||||||||||
| A | 40–44 | 18 | 23.8 | 8.55 | 7.46 | 550 | 600** | – | 800 | 0.37, 0.19 | 0.72, 0.28 | 4 | 3 | |
| B | 30–34 | 11 | 30.5 | 13.71 | 1.22 | 500 | 500 | Sertraline | Promethazine 50 mg/day | 800 | 1.14, 0.37 | 0.81, 0.32 | 6 | 4 |
| C | 25–29 | 4 | 24.1 | 4.11 | 18.58 | 575 | 575 | Valproate, zopiclone | Chlorpromazine 200 mg/day | 600 | 0.37, 0.18 | 0.45, 0.23 | 5 | 4 |
| D | 35–39 | 15 | 44.2 | 27.81 | 16.27 | 400 | 300 | – | 400 | 0.74, 0.39 | 0.67, 0.37 | 5 | 2 | |
| E | 40–44 | 17 | 45.5 | 159.75 | 42.90 | 600 | 750 | Valproate, sertraline | 1000 | 0.87, 0.26 | 0.88, 0.24 | 7 | 5 | |
| F | 20–24 | 7 | 8.7 | 9.57 | 6.90 | 525 | 400 | – | 400 | 0.46, 0.33 | 0.46, 0.48 | 5 | 3 | |
Notes: HSH=High-security hospital. CGI=Clinical Global Improvement. CGI Severity of illness: 1 = normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients; 0=not assessed.
Clozapine and norclozapine serum levels, PRN medication
Data were available for pre- and post-amisulpride clozapine and norclozapine levels and PRN medication where applicable (Table 19.1).
Improvement in violence
All patients’ risk of violence and aggression to others was reduced following treatment with amisulpride and clozapine, as quantified by percentage reduction in the 90 days pre-amisulpride augmentation and most recent 90 days (where applicable) after augmentation on various parameters (Table 19.2). This risk reduction was generally associated with clinical improvement in symptoms. However, in three cases this reduction in aggression was greater than their overall clinical improvement. This is demonstrated further in individual patient case reports.
| Violence | |||||||
|---|---|---|---|---|---|---|---|
| Patient | Age | Verbal aggressiona | Aggression against propertya | Aggression against othersa | Self-harm | Risk of violence to othersb | Dependency |
| A | 40–44 | 70 | 100 | 50 | 100 | ↓ | = |
| B | 30–34 | 50 | 100 | 50 | 100 | ↓ | = |
| C | 25–29 | 20 | 100 | 80 | n/a | ↓ | = |
| D | 35–39 | = | = | = | n/a | ↓ | ↓ |
| E | 40–44 | 50 | = | 100 | n/a | ↓ | ↓ |
| F | 20–24 | = | = | 100 | n/a | ↓ | ↓* |
Metabolic parameters
One patient’s BMI increased from 31.4 to 37.4, but other metabolic parameters appeared to be largely unaffected in all patients (Table 19.3).
| Pre-Augmentation | Present | |||||||
|---|---|---|---|---|---|---|---|---|
| Patient | BMI | Glucose | Total cholesterol:HDL ratio | Side effect profile | BMI | Glucose | Total cholesterol:HDL ratio | Side effect profile |
| A | 33 | 5.0 | 4.8 | Sedation, hypersalivation. | 33 | 5.2 | 4.6 | nc |
| B | 35 | 6.0 | 10 | Occasional hypersalivation | 33 | 4.9 | 10.9 | nc |
| C | 39 | 5.2 | 3.8 | Sedation | 37 | 4.7 | – | Sedation, weight gain, joint stiffness |
| D | 31 | – | 5 | Weight gain, sedation, hypersalivation, constipation | 37 | – | 5.4 | Weight gain, sedation, hypersalivation, constipation, raised prolactin |
| E | 32 | – | – | None | 33 | 7.6 | 4.6 | None |
| F | 26 | – | – | Hypersalivation | 47 | 4.1 | 5.4 | nc |
Notes: BMI=Body Mass Index; HDL=high density lipoprotein; nc=no change.
Patient case reports
Patient A was referred for treatment in a high-security setting following multiple assaults driven by delusions in a medium-security unit (MSU). Until two months after initiation of augmentation, he remained in long-term segregation (LTS) due to his high risk of assaulting others. During this time, he self-harmed and damaged property, including smashing his TV, and made several threats to assault staff. Following the augmentation strategy, his socialization time on the ward out of LTS has been increased. While he has made threats to assault, he now denies thoughts or intentions of harming others. He is also now engaging in off-ward activities and psychological therapies, and is awaiting a move from high dependency to an assertive rehabilitation ward. Before treatment, patient A was classified as moderately ill, and he is now considered only mildly ill. His side effects of sialorrhea and sedation do not significantly interfere with function.
Patient B was admitted to the high-security hospital following incidents of setting fires, absconding, and multiple assaults on staff, all driven by psychotic symptoms. This included one serious assault, wherein the victim required hospitalization. In the months leading up to augmentation, he exhibited multiple episodes of violence, verbal aggression, and self-harm. The self-harm was severe, including a suicide attempt that required medical attention for broken bones. He also made a serious assault on a member of staff and was being nursed continuously in LTS. Once augmentation was initiated, he was able to engage in ward activities; his aggression was generally improved, and self-harm ceased. He made one assault on another patient, requiring LTS to be resumed. Before augmentation, patient B was severely ill and is now considered only moderately ill; he is still psychotic, and his side effects of sedation and sialorrhea have not worsened.
Patient C was admitted to high-security facilities following his index offence of robbery and assault and his consistently aggressive behavior toward staff while in prison, which was linked to paranoid delusions. He also has a history of extensive property damage and arson, and has a high risk of harm to others. Since initiation of augmentation therapy, he has had his escort requirements reduced, been taken off the high-risk register, and been given more grounds privileges. He has had only one incident of verbal aggression, one incident of aggression against property, and one episode of seclusion. His engagement with OT is generally improving. After treatment, his mental state is minimally improved, and he is now considered moderately ill. His side effects of sialorrhea and sedation are no worse and do not significantly interfere with function.
Patient D was admitted to the high-security hospital following an index offence of homicide, which was driven by delusional symptoms. He has a long history of violence prior to this offense. Since admission, he has not been violent and his behavior has remained nonviolent throughout the addition of amisulpride to his treatment regimen. The reduction in his risk of violence has facilitated a move from a high-dependency ward to a low-dependency one. He has recently been engaging well with OT and vocational activities; his improvement has allowed his dose of clozapine to be reduced. Patient D was classified as markedly ill before beginning amisulpride, and now he is considered borderline mentally ill, with his main symptom being lack of insight. His side effects do not significantly interfere with function.
Patient E has an index offence of homicide, which was driven by delusional symptoms, and a long history of violence, with seven reports of assault prior to his index offense, despite being prescribed clozapine in the community. He also has a history of weapon use, and he posed grave and immediate risk to others in MSU. Since augmentation, he has been attending off-ward activities, including education, asking for a ward job, and attending all scheduled therapy sessions. He is being assessed for group cognitive behavioral therapy (CBT). He has made one threat, but there have been no violent events and he has moved to a lower-dependency unit. Patient E was one of the most severely ill patients in the hospital when he was first admitted. Since starting amisulpride, he has been much improved without side effects. He is still markedly ill, but is happy with his current medication and does not report any side effects.
Patient F has a history of violence prior to admission to the high-security hospital. At his previous MSU, he committed a series of assaults, including his index offense of wounding with intent. He was placed on the high-risk register due to his risk of harm to others. His behavior and mental state have been exemplary since admission; he has been able to be removed from the high-risk register, and has transferred to medium security. His illness is very much improved; he has gone from being markedly ill to only mildly ill while following augmentation therapy and has had no side effects.
Discussion
We report a case series of six forensic patients who suffer from treatment-resistant schizophrenia or schizoaffective disorder, with a history of extreme violence, who are being treated in a high-security hospital. These patients were treated with clozapine that was subsequently augmented with amisulpride because of a lack of clinical efficacy of clozapine alone.
All six of the patients showed clinical improvement in symptoms with the amisulpride augmentation regimen and also a reduction in their risk of violence to others. Five of the six patients had a reduction in number of violent/aggressive incidents. Three of the six patients were eligible to move to lower-dependency wards. Two of the patients who had a presentation of self-harming behavior showed a reduction in this. The dose of clozapine prescribed was reduced for two patients and increased for two patients. All patients showed an improvement in engagement in occupational, vocational, and/or psychological work. Metabolic parameters (where available) were largely unchanged, except for one patient who had an increase in BMI. Side effects were reported as unchanged or improved in five of the six patients. To our knowledge, this is the first report of this combination treatment having a positive effect on reducing aggressive behavior and risk of violence in schizophrenia patients.
Strategies for augmentation of clozapine
Our findings are largely in keeping with previous studies that have investigated augmentation of clozapine with amisulpride or sulpiride. Sulpiride is an atypical antipsychotic that is closely related to amisulpride. Small, randomized, controlled trials (RCTs), open studies, and retrospective studies have demonstrated this effect, but there have been no large RCTs in this area to date. These trials all demonstrated a reduction in positive and negative symptoms [23–25]. In a single-blinded RCT, amisulpride was found to be a superior augmenting agent to quetiapine [36], and in other studies, augmentation with amisulpride allowed the prescribed clozapine dose to be reduced [26,27,37]. Our findings were in keeping with studies that found that this treatment combination did not increase side effects [27,37].
There have also been promising results in studies using other pharmacological agents to augment the actions of clozapine. Ziprasidone, risperidone, and aripiprazole have some evidence base to suggest that they may be effective augmenters of clozapine [38,39,41]. A meta-analysis [40] of clozapine augmentation with a second antipsychotic from 14 randomized, placebo-controlled, double-blind studies that showed augmentation conferred a small benefit over placebo. Some of our patients were taking valproate concurrently with amisulpride and clozapine (initiated before amisulpride augmentation). Mood stabilizers have also been investigated as augmenting agents with clozapine, but the evidence is both limited and mixed [5,42].
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