Effectiveness of paliperidone depot injection in seriously violent men with comorbid schizophrenia and dissocial personality disorder in a UK high-security hospital

Abstract

Background:

High-security hospital patients are often complex in presentation and are characterized by treatment resistance, medication nonadherence and history of violence. Paliperidone is licensed both as an oral and depot antipsychotic medication in the treatment of schizophrenia. Clinical trials have shown that paliperidone depot is well tolerated with similar efficacy to risperidone depot but with additional practical advantages. Whilst data exist for the effectiveness of paliperidone palmitate (PP), there are no studies involving patients in forensic settings or those with comorbid personality disorder. Our aim was to evaluate the effectiveness of PP on violence, aggression and personality disorder symptoms.

Methods:

This project was a retrospective service evaluation involving 11 patients, carried out in a high-security hospital. A combination of patient records and interviews with the treating consultant psychiatrist were used to ascertain a Clinical Global Impression (CGI) score, the effect of PP on specific personality disorder symptom domains (cognitive-perceptual, impulsive-behavioural dyscontrol and affective dysregulation) and incidents of violence and aggression. Engagement with occupational and psychological therapies was also evaluated. Metabolic parameters were reviewed.

Results:

A total of 6 out of 11 patients continued on PP, most of whom had schizophrenia and dissocial personality disorder with histories of violence. All showed improvement in the CGI score with associated benefits in the three personality symptom domains. Overall, two patients demonstrated a reduction in the risk of violence. There was improvement in engagement with occupational therapy and psychological work. No significant effects on metabolic parameters were noted although hyperprolactinaemia, albeit asymptomatic, was consistently recorded.

Conclusions:

This pragmatic service evaluation of a small but complex patient group demonstrated, for the first time, that PP was effective in reducing violence as well as improving personality pathology across all dimensions: a finding which could have significant implications for management of such high-security patients.

Keywords

antipsychotic agents depot antipsychotic high-security paliperidone personality disorder schizophrenia violence

Introduction

Paliperidone (9-hydroxyrisperidone) is the major active metabolite of risperidone [Bishara, 2010]. It is effective in the treatment of schizophrenia [Pandina et al. 2011] and is licensed both as an oral and depot antipsychotic medication. In the largest [Pandina et al. 2010] of four short term, randomized double-blind studies evaluating effectiveness in the acute stages of illness, paliperidone palmitate (PP) was compared with placebo over 13 weeks. It was demonstrated that the mean change in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint improved significantly in all the PP dose groups (25, 100, 150 mg eq). These findings were supported by three smaller studies [Gopal et al. 2010; Kramer et al. 2009; Nasrallah et al. 2010].

Paliperidone has also been shown to delay relapse [Hough et al. 2010], significantly decrease hospitalizations [Kozma et al. 2011] and the average number of bed days per year [Taylor and Attard, 2013]. As well as being non-inferior to risperidone long-acting injectable (RIS-LAI) [Pandina et al. 2011], PP is relatively well tolerated [Pandina et al. 2011]. It has additional practical advantages over RIS-LAI, namely faster onset of action negating the need for oral supplementation in the first weeks of treatment, fewer monthly injections, a smaller needle, and a saving in nursing time because of provision in a prefilled syringe.

High-security hospital patients often have complex presentations that are marked by comorbidity, violence, poor concordance with oral medication and treatment resistance [Gibbon et al. 2011]. Although RIS-LAI and olanzapine pamoate have been demonstrated as showing a clinical benefit in these patients [Gibbon et al. 2011; Baruch et al. 2014], there is a scarcity of literature about the role of depot antipsychotic medication in this subgroup and there is no previously published work evaluating the effects of PP.

We report a service evaluation involving the use of PP depot in 11 patients within a high-security hospital in the UK. This project was retrospective in design involving review of the case records, and aimed at evaluating the clinical effectiveness of PP; specifically, its effect on personality disorder symptoms and violent behaviour.

Methods

All patients were inpatients at the high-security hospital Broadmoor, UK. There are three high-security hospitals in England and Wales, caring for a population of 56 million. High-security hospitals treat patients who have committed serious offences, have severe psychiatric conditions and therefore pose the highest level of risk to others, such that they cannot be managed in other levels of secure hospital environments.

Typically, in Broadmoor Hospital, the commonest diagnosis is schizophrenia followed by personality disorder. Patients are detained under the Mental Health Act and include patients transferred from less secure hospital units, prisons or those that receive a hospital treatment order at sentencing from court. The hospital has wards that are distinguished by the level of dependency or risk that the patient poses. This ranges from intensive care or high dependency to rehabilitation wards from where patients are discharged. Patients are discharged primarily to less secure hospitals or repatriated to prison once their treatment is complete.

All patients were diagnosed by the treating consultant psychiatrist as having paranoid schizophrenia and a dissocial personality disorder aside from two, who had diagnoses of schizoaffective disorder (Table 1). All were admitted with histories of serious violence along with psychotic symptoms. All clinical diagnoses were made using the criteria of the International Statistical Classification of Diseases and Related Health Problems, 10th revision [World Health Organization, 1992]. None of the patients had a history of learning disability, brain injury or epilepsy. Overall, one patient had a diagnosis of polysubstance dependence syndrome (currently in remission). Patients had an average age of 35.3 years.

Table 1.

Patient demographic and clinical details.

Patient	Age (years)	Diagnosis	Index offence	Duration of illness (years)	Duration in HSH(months)	Previous medication	Previous treatment with depot medication	Paliperidone dose (mg/month)	Duration of paliperidone treatment (months)	Concurrent medication	Treatment-resistant according to IPAP criteria
A	48	Paranoid schizophrenia, personality disorder; dissocial and schizoid traits	Murder	34	29	Clozapine Diazepam Haloperidol Mirtazapine Risperidone Sodium valproate Zopiclone	Risperidone Flupenthixol	150	25.75	Sodium valproate	Yes
B	36	Paranoid schizophrenia, personality disorder; dissocial, paranoid and borderline traits	Grievous bodily harm	20	62	Olanzapine Amisulpride Risperidone Semisodium valproate	Flupenthixol	150	33	Olanzapine Amisulpride	Yes
C	35	Paranoid schizophrenia, personality disorder; paranoid and dissocial	Wounding with intent to cause grievous bodily harm	9	23	Quetiapine Zopiclone	Flupenthixol	75	16.75	None	Yes
D	37	Paranoid schizophrenia, personality disorder; emotionally unstable borderline, paranoid, histrionic, dissocial	Murder	21	96	Olanzapine Quetiapine Risperidone	None	150	12.25	Sertraline Mirtazapine	Yes
E	30	Paranoid schizophrenia, dissocial personality disorder	Grievous bodily harm with intent	12	59	Olanzapine	Zuclopentixol (test dose) Risperidone Consta Flupenthixol decanoate	75	7	None	No
F	44	Schizoaffective disorder	Actual bodily harm × 2	19	27	Aripiprazole Diazepam Sodium valproate	Olanzapine	150	1st: 2.5 2nd: 5	During 2nd treatment period: Sodium valproate, ariprazole	Yes
G	33	Schizoaffective disorder, dissocial personality disorder, with histrionic personality traits	Affray, possession of offensive weapon	16	114	Aripiprazole Carbamazepine Diazepam Lithium citrate Quetiapine Risperidone Sodium valproate Valproate Semisodium	Flupentixol Risperidone Consta Zuclopentixol	150	10	Risperidone	Yes
H	38	Paranoid schizophrenia, dissocial personality disorder Polysubstance dependence syndrome	Rape	20	1st admission: 103 2nd admission: 112	Amisulpride Amitriptyline Chloral hydrate Chlorpromazine Clonazepam Diazepam Droperidol Haloperidol Lorazepam Lormetazepam Nitrazepam Pregabalin Promazine Risperidone Thiordazine Trifluperazine	Fluphenazine Haloperidol Zuclopentixol	150	10.5	None	Yes
I	27	Paranoid schizophrenia, dissocial personality disorder	Wounding with intent	6	1st admission 52 2nd admission 36	Aripiprazole Lithium citrate Lorazepam Olanzapine Risperidone Sodium valproate	Aripiprazole Zuclopentixol	75	10	None	yes
J	33	Paranoid schizophrenia, dissocial personality disorder	Manslaughter	18	107	Aripiprazole Chlorpromazine Diazepam Mianserin Olanzapine Prochlorperazine Quetiapine	Flupentixol Fluphenazine Zuclopentixol	150	47	Diazepam	yes
K	30	Paranoid schizophrenia, dissocial personality disorder	Actual bodily harm	16	99	Amisulpride Chlorpromazine Clozapine Diazepam Haloperidol Lithium carbonate Lorazepam Olanzapine Risperidone Sertraline Sodium valproate Zopiclone	Zuclopentixol	150	9	None	Yes

HSH, high-security hospital; IPAP, International Psychopharmacology Algorithm Project.

Patients were included in the evaluation if they had been on PP for a period of 2 months. They were identified using the hospital pharmacy database. Doses of PP for each patient were recorded and any changes in these doses and any concurrent medications were noted.

In total, 17 patients in the hospital were or had been prescribed PP. It was not possible to approach two patients as the treating consultant deemed the patient not to have the capacity to consent to participate in the project and one patient had not been on PP for the required amount of time (2 months). Therefore, the remaining 14 patients were approached individually for informed consent and 11 patients consented to participate and provided written informed consent. This project was approved as a service evaluation not requiring ethic committee approval by the hospital’s Audit committee.

The primary outcome measure was CGI [Guy, 1976]; specifically, severity of illness (CGI-S). CGI is a commonly used scale for measuring the effect of pharmacological intervention in various studies on personality disorders [Frankenburg and Zanarini, 1993; Binks et al. 2006]. CGI scores were ascertained before starting PP and during treatment with PP in the most recent 6 months.

The CGI-S score prior to starting PP was ascertained through review of data collected from the patients’ clinical notes. The clinical notes included Care Programme Approach documentation, Mental Health Act Review Tribunal reports, Historical, Clinical, Risk Management-20 forms [Webster et al. 1995] and the hospitals’ physical health centre records. Data were anonymized.

CGI-S scores post-starting PP (i.e. over the most recent 6 months) were ascertained through interview with the treating consultant psychiatrist. Outcome variables [Soloff, 1997; Ingenhoven et al. 2010] were also derived through interview with the treating consultant psychiatrist according to the following personality symptom domains: cognitive-perceptual, impulsive-behavioural dyscontrol and affective dysregulation. The psychiatrists were asked to rate the patients’ degree of improvement in the most recent 6 months as having ‘worsened’, ‘remained the same’, had ‘some improvement’ or ‘much improvement’. For those patients that had discontinued PP the psychiatrists were asked to rate degree of improvement at the time of stopping PP. For one patient whose consultant had left the hospital assessment pre- and post-PP was conducted by the principal author.

The cognitive-perceptual domain included symptoms of paranoia, suspiciousness and quasi psychotic symptoms; the impulsive-behavioural dyscontrol domain included impulsive behaviour, self-harm, agitation and aggression to person and property and the affective dysregulation domain contained emotional responses of low mood, anxiety, anger and mood lability.

Secondary outcome measures were incidents and episodes of violence and aggression and engagement with the multidisciplinary team, specifically occupational therapy and psychological therapy.

To gain a clinical impression of the patients’ risk of violence the hospital electronic incident recording system in combination with clinical records was reviewed. A patients’ risk of violence was assessed using a combination of the logged incidents as well as episodes of aggression documented in clinical notes which did not necessarily meet the hospital incident reporting system standards. This was ascertained for a 6-month period prior to starting PP and for the most recent 6 months.

The hospital’s incident reporting system is an electronic intranet system where staff members log every clinical incident for each patient. It has been used for a number of years to generate information about incident trends in the hospital and is reliable and comprehensive. Reports for each patient were generated and these were used to determine the number of incidents which had occurred in the 6 months prior to the start of PP and in the most recent 6 months.

The measure of aggression was subdivided into verbal aggression, aggression against property, aggression against the person and self-harm. In addition, there was a group that encompassed behaviour which did not fit in to the other categories which we termed threatening behaviour. Planned moves to wards of lower or higher dependency within the hospital were noted. Engagement with occupational therapy, vocational activities and psychological therapies were also recorded in the 6 months preceding commencing PP and in the most recent 6 months.

In addition, information about patients’ body mass index (BMI), cholesterol, glucose and prolactin levels before and after starting PP was collected. This was from the hospital physical health centre records.

Demographic data and information used to determine treatment resistance according to the International Psychopharmacology Algorithm Project (IPAP) criteria [IPAP, 2006] were obtained from clinical records.

Results

Of the 11 patients, PP had been discontinued in 6, however 1 of these patients had stopped but restarted PP and was included in the report. Therefore, six patients continued to receive PP; four patients were prescribed a dose of 150 mg every 4 weeks and two patients 75 mg every 4 weeks.

A number of patients were taking concurrent psychotropic medication. All medications had been started prior to PP except for mirtazapine (patient D) which had been started after initiation of PP. All patients had dose changes of their concurrent medication during treatment with PP.

Symptom improvement

All six patients who continued PP (patients A–F) showed improvement by a reduction in the CGI-S score of at least 1 point (Table 2). Overall, one of these patients demonstrated a reduction by 2 points and one patient by 4 points.

Table 2.

Primary outcome measures; CGI scale and personality symptom domains.

Patient	Pre-CGI; severity of illness	Post-CGI; severity of illness	Cognitive-perceptual	Impulsive-behavioural dyscontrol	Affective dysregulation				Paliperidone continued
	Pre-CGI; severity of illness	Post-CGI; severity of illness	Cognitive-perceptual	Impulsive-behavioural dyscontrol	Low mood	Anxiety	Anger	Mood lability	Paliperidone continued
A	5	4	↑↑	↑↑	↑	↑↑	↑↑	↑↑	Y
B	6	4	↑	↑	↔	↔	↔	↑	Y
C	5	4	↔	↑↑	↔	↔	↑↑	↑↑	Y
D	5	4	↑↑	↔	↑↑	↑	↔	↑	Y
E	4	3	↑	↑	↔	↔	↑	↔	Y
*Fa	–	5	↔	↔	↔	↔	↔	↔	N
b	5	1	↑	↑	↑	↑	↑	↑	Y
G	6	5	↔	↔	↔	↔	↔	↔	N
H	6	6	↔	↔	↔	↔	↔	↔	N
I	3	3	↑	↑↑	↑	↑	↑	↑	N
J	5	5	↑	↑	↑	↔	↑	↑	N
K	5	5	↔	↔	↔	↔	↔	↔	N

CGI, Clinical Global Improvement; PP, paliperidone palmitate.

Severity of illness: (1) Normal (2) Borderline mentally ill (3) Mildly ill (4) Moderately ill (5) Markedly ill (6) Severely ill. Personality symptom domains; ↑ = improved; ↑↑ = much improved; ↔ = no change. *Patient F was prescribed PP over two distinct time periods. a = first time period; b = second time period. Data were limited due to the patient being admitted on PP and hence the authors not having access to medical records prior to this.

Of the personality symptom domains, five of the six patients showed improvement in the cognitive-perceptual domain; three of these showed ‘much improvement’. A total of five of the six patients showed improvement in the impulsive-behavioural dyscontrol domain; two of these showed ‘much improvement’. All patients showed improvement in some aspect of affective dysregulation; three patients showed improved symptoms of low mood, three in anxiety, four demonstrated improved anger control and five showed an improvement in mood stability.

Of those that had discontinued PP (patients G–K) there was no improvement in CGI scores. However, there had been improvements reported in aspects of personality for some of these patients.

Improvement in aggression and violence

Of the patients that continued PP (patients A–F), two patients that demonstrated episodes of violence in the 6 months prior to starting PP showed a reduction in the number of episodes recorded compared with the most recent 6 months (Table 3).

Table 3.

Secondary outcome measures; violence indicators, engagement with the multidisciplinary team and change in dependency or security need.

Patient	Risk of violence	Verbal aggression	Aggression against property	Aggression against the person	Threatening behaviour	Improved engagement with occupational and/or psychological therapies	Move/planned move to lower dependency/security during paliperidone treatment	Paliperidonecontinued
A	↓	↓	↔ None	↓	↔ None	Yes	Yes	Y
B	↓	↓	↔ None	↑	↑	Yes	Yes	Y
C	↑	↑	↔ None	↔ None	↑	Yes	Yes	Y
D	↔	↔ None	↔ None	↔ None	↔ None	Yes	No	Y
E	↑	↑	↔ None	↑	↑	Yes	No	Y
*Fa	–	–	–	–	–	–	No	N
b	↔	None	None	None	None	Yes	Yes	Y
G	↑	↑	↑	↑	↑	No	No (move to high dependency)	N
H	↑	↓	↑	↑	↓	No	No	N
I	↑	↓	↑	↑	↓	Yes	No	N
J	↑	None	↑	None	↑	Yes	No	N
K	↔	↓	↔ None	↑	↔ None	Yes	No	N

PP, paliperidone palmitate.

↓ = decrease; ↑ = increase; ↔ = no change. *Patient F was prescribed PP over two distinct time periods. a = first time period b = second time period. Data were limited due to the patient being admitted on PP and hence the authors not having access to medical records prior to this.

Overall, two patients that had no incidents remained the same and two patients showed an increase in violence (Figure 1); patient C had an increase in verbal aggression and threatening behaviour (one incident in the 6 months pre-PP versus two incidents in the most recent 6 months) and patient E had an increase in aggression against the person (no incidents pre-PP versus one incident in the most recent 6 months) and threatening behaviour (no incidents pre-PP versus one incident in the most recent 6 months). There were no incidents of self-harm.

Figure 1.

Number of incidents and aggressive episodes before and after starting PP.

During the period of treatment with PP, three patients had progressed from a higher dependency ward and two of the six patients were being prepared for a move to a lower level of security (medium security).

Of those that discontinued PP (patients G–K), three patients showed an increase in risk. The subcategories which showed the most frequent increase were aggression against property and aggression against the person.

Engagement with the multidisciplinary team

In all cases where PP was continued there was improved engagement with the multidisciplinary team (Table 3). Improved engagement was also seen in patient I during treatment with PP as well as a move to a lower dependency ward. This patient had stopped PP due to pain at the injection site.

Metabolic parameters and side effects

There was no significant effect on fasting blood glucose or cholesterol levels, however, hyperprolactinaemia (albeit asymptomatic) was consistently recorded. There was a small decrease in fasting blood sugar results in four patients. There was a small decrease in total cholesterol: HDL (high density lipid) ratio in two patients. Prolactin levels increased in three patients by an average of 756 mU/l. BMI increased in three patients and decreased in four patients over the duration of PP treatment. The mean average increase in BMI was <1 point (0.49). Findings were limited due to absence of some data.

All patients reported a similar profile of side effects; most frequently were dry mouth, extrapyramidal side effects and blurred vision. A total of one patient reported excessive tiredness.

Patients that discontinued PP

Of the six patients that discontinued PP, the most common reasons for stopping were lack of efficacy (three patients) and pain at the injection site (two patients).

Patient F who restarted PP had stopped due to lack of efficacy. Between the two periods of PP prescription, patient F had been prescribed olanzapine depot and commenced on sodium valproate. Olanzapine was stopped and PP restarted whilst sodium valproate was continued. There was clinical improvement. It was noted that aripiprazole was prescribed for 4 weeks during the second treatment period of PP.

Of the patients that discontinued PP subsequent medications switched to were zuclopenthixol (patient G), haloperidol depot (patient H), oral aripiprazole later changed to depot (patient I), oral aripiprazole for 2 months followed by zuclopenthixol (patient J) and oral risperidone (patient K).

Discussion

We report a service evaluation of 11 patients, mostly with diagnoses of paranoid schizophrenia or schizoaffective disorder and dissocial personality disorder with histories of significant interpersonal violence who were treated with PP in the setting of a high-security hospital. All six patients showed clinical improvement during treatment with PP. Maximum improvement seen in the personality domains was in the severity of affective dysregulation symptoms, specifically lability of mood and anger control. Overall, two patients had reduction in violent incidents, in two there were no such incidents before or after starting PP, and in two there was an increase in incidents. All patients showed an improvement in engagement with the multidisciplinary team to varying degrees. Metabolic parameters were largely unchanged although prolactin levels increased.

For the purpose of this report we examined all patients who were prescribed PP in the hospital and after excluding patients who did not have capacity or did not consent, 11 patients were included in the report and outcomes for these patients are described. It is notable that all but one of the 11 patients were treatment-resistant. Additionally, five patients discontinued PP and three did so for lack of efficacy and two for pain at the injection site. Therefore, approximately half of the patients we report continued on PP, and all those who continued showed clinical benefits. It is notable that for one patient, improvement in clinical efficacy was seen following a combination of PP and a mood stabilizer.

In terms of clinical outcomes, we focussed on those that would be relevant for a forensic psychiatric patient such as reduction in incidents of aggression and reduction in risk. As all patients also had a diagnosis of dissocial personality disorder, we examined clinical response in domains of personality characteristics, which are additionally relevant to clinical improvement in a forensic hospital setting.

For those that continued PP, the medication was relatively well tolerated.

Pharmacodynamic rationale for treatment with paliperidone

Paliperidone is a dopamine D₂ and serotonin 5-HT_2A receptor antagonist. Like other atypical antipsychotics it has a high 5-HT_2A:D₂ affinity ratio. It also acts as an antagonist at α₁ and α₂ adrenergic and H₁ histaminergic receptors [Gopal et al. 2010].

Animal studies suggest that dopamine has considerable influence in mediating emotion, stress response, aggression and impulsivity [Harrison et al. 1997; Vukhac et al. 2001; Wade et al. 2000]. Additionally, several studies have demonstrated the association between abnormal dopamine metabolite (HVA) levels and impulsivity [Chotai et al. 1998]. These effects are particularly relevant to borderline and dissocial personality disorders which are characterized by emotional dysregulation and impulsivity [Friedel, 2004]. Dopamine dysfunction has been postulated as an underlying pathology in borderline personality disorder and this is supported by evidence that personality disorder symptoms can be treated by neuromodulators which improve dopamine dysfunction [Adams, 1979].

It has also been shown that serotonin (5HT) has a key role in the modulation of aggressive behaviour [Friedel, 2004; Adams, 1979; Berman et al. 1997; Brown, 1982; De Boer and Koolhaas, 2005; Gowin et al. 2010; Miczek et al. 2002; Moss et al. 1990], and several studies have identified an association between the serotonin metabolite (5-HIAA) in human cerebrospinal fluid and antisocial behaviour such as violence, homicide, arson and child abuse. The extent to which serotoninergic dysfunction influences aggression is dependent on a complex interplay between multiple environmental factors [Moss et al. 1990].

Through its complex action on both the dopaminergic and serotonergic system, it can be postulated that paliperidone induces anti-aggressive properties which can be of benefit in the treatment of personality disorders.

Existing literature

It is difficult to compare our results with current literature due to the scarcity of studies reporting on pharmacological treatment in this subgroup of patients.

We have considered the role of concurrent medication in view of two patients taking mood stabilizers, two patients taking an additional antipsychotic, one patient taking two antidepressants and one patient taking regular diazepam. All can contribute to improvement in symptom domains.

A meta-analysis [Ingenhoven et al. 2010] examined the actions of psychotropic medication on various symptom domains in severe personality disorder. It found that antipsychotics rather than mood stabilizers or antidepressants led to improvement in cognitive-perceptual symptoms, whereas, improvements in impulsive-behavioural dyscontrol and in affective dysregulation were found to respond to either antipsychotics, antidepressants or mood stabilizers. Therefore, the mechanism for improvement in the cognitive-perceptual domain may be due to improvement in potential dopamine dysfunction, whereas, impulsive behaviour dyscontrol and affective dysregulation domains are governed in addition by potential serotonin and noradrenergic dysfunction [Umukoro et al. 2012]. Our findings demonstrate improved functioning in all symptom domains, which may be attributed to the diverse spectrum of receptor actions by paliperidone, especially on dopaminergic and serotonergic systems.

Our patients were detained in a high-security hospital by virtue of posing the highest level of risk of violence towards others. It is important to note that there was a reduction in this risk as demonstrated by a reduction in incidents, movement to lower dependency wards and preparation for transfer to a lower level of security. Whilst this may be due to an anti-aggressive property of paliperidone, it may be secondary to improvement in cognitive-perceptual or impulsive-behavioural dyscontrol domains.

Important considerations

The retrospective nature of this case-series, small sample and lack of objective rating scales with regard to some aspects of data collection such as engagement with therapies are limitations that need to be appreciated before drawing any firm conclusions from our findings.

Studies conducted in a high-security hospital typically involve patients who are considered extreme not only in terms of their presentation and associated risks, but also in their management, which limits the ability of our results to be generalized. This evaluation had no control other than the individuals own prior records pre-starting PP. It also did not control for confounding variables such as other medications, psychological therapies and the therapeutic relationship between patient and the treating team.

However, this is a naturalistic service evaluation and has the advantage of allowing the authors to evaluate large volumes of data in a longitudinal perspective for all patients. This was afforded by all participants being inpatients in a setting with stringent and detailed recording of clinical information. Additionally, in such a setting, there are no confounding factors in the form of concurrent substance misuse or irregular/lack of adherence to medications. All patients reported in this case-series were fully concordant with PP treatment.

Cost−benefit and future recommendations

All the patients had been transferred to high-security hospital services from medium-security hospitals or from custodial settings due to unmanageable aggression and subsequent need for treatment. High-security hospital care is expensive in comparison with these alternatives and therefore, if proved beneficial, PP would be of an immense cost−benefit to the health service. Effective treatment with PP in these patients would reduce the duration of high-security hospital stay and encourage progression to a medium-security hospital or return to prison services, thereby mitigating the overall cost of treatment.

However, there is a considerable lack of evidence to support treatment with PP in the forensic setting. Additionally, research exploring pharmacotherapy in forensic patients is difficult to conduct and the subjects that are enrolled in randomized control trials are not representative of the most difficult-to-manage patients in secure units [Volavka and Citrome, 1999; Brown et al. 2014]. A previous study using a similar study design from our setting showed promising results for the depot olanzapine pamoate [Baruch et al. 2014], but further research in this area is warranted.

Conclusion

PP is an atypical antipsychotic which has been shown to improve symptoms in schizophrenia. We report our experience of PP treatment not only in patients with schizophrenia but also schizoaffective disorder and comorbid dissocial personality disorder, in the setting of a high-security hospital. We found that all patients who continued PP achieved clinical benefit. To the best of our knowledge, this is the first time that PP has been shown to be of benefit in reducing violence and aggression as well as improving personality pathology dimensions in patients with a comorbidity of dissocial personality disorder. A depot antipsychotic effective in reducing violence in addition to improving psychotic symptoms is a significant addition to the armamentarium of forensic psychiatrists for the future management of high-security forensic patients.

We are modest in our conclusions, however, and interpretations should be taken in the context of the nature of the evaluation and the limitations associated with it. Given the low number of patients, this service evaluation should be considered as exploratory. Further studies are required over a longer period of time to build up a robust pool of data on the efficacy of this medication and its role in reducing violent behaviour in patients with psychosis; especially schizophrenia.

Footnotes

Acknowledgements

We wish to thank John Wakelam Senior Pharmacist at Broadmoor Hospital, UK for assistance in accessing records.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

References

Adams

(1979) Brain mechanisms for offence, defence, and submission. Behav Brain Sci 2: 201–213.

Baruch

Das

Sharda

Basu

Bajorek

Ross

. (2014) An evaluation of the use of olanzapine pamoate depot injection in seriously violent men with schizophrenia in a UK high-security hospital. Ther Adv Psychopharmacol 4: 186–192.

Berman

Tracy

Coccaro

(1997) The serotonin hypothesis of aggression revisited. Clin Psychol Rev 17: 651–665.

Binks

Fenton

McCarthy

Lee

Adams

Duggan

(2006) Psychological therapies for people with borderline personality disorder. Cochrane Database Syst Rev CD005653.

Bishara

(2010) Once-monthly paliperidone injection for the treatment of schizophrenia. Neuropsychiatr Dis Treat 6: 561–572.

Bishara

Taylor

(2011) Paliperidone palmitate – a new long acting injection for schizophrenia. Br J Clin Pharm 3: 75–78.

Brown

Larkin

Sengupta

Romero-Ureclay

J.L.

Ross

C.C.

Gupta

. (2014) Clozapine: an effective treatment for seriously violent and psychopathic men with antisocial personality disorder in a UK high-security hospital. CNS Spectrums 19: 391–402.

Brown

(1982) Aggression, suicide, and serotonin: relationships of CSF amine metabolites. Am J Psychiatry 139: 741–746.

Chotai

Kullgren

Åsberg

(1998) CSF monoamine metabolites in relation to the diagnostic interview for borderline patients (DIB). Neuropsychobiology 38: 207–212.

10.

de Boer

Koolhaas

. (2005) 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis. Eur J Pharmacol 526: 125–139.

11.

Fleischhacker

Gopal

Lane

Gassmann-Mayer

Lim

Hough

. (2011) A randomized trial of paliperidone palmitate and risperidone long-acting injectable in schizophrenia. Int J Neuropsychopharmacol 22: 1–12.

12.

Frankenburg

Zanarini

(1993) Clozapine treatment of borderline patients: a preliminary study. Compr Psychiatry 34: 402–405.

13.

Friedel

(2004) Dopamine dysfunction in borderline personality disorder: a hypothesis. Neuropsychopharmacology 29: 1029–1039.

14.

Gibbon

Silva

Kaler

Qurashi

Das

Patrick

. (2011) Long-acting Injection (RLAI)-real world outcomes from the United Kingdom high-secure hospitals. Br J Forensic Pract 13: 264–269.

15.

Gopal

Hough

Lull

Gassmann-Mayer

Remmerie

. (2010) Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study. Int Clin Psychopharmacol 25: 247–256.

16.

Gopal

Vijapurkar

Lim

Morozova

Eerdekens

Hough

(2011) A 52-week open-label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia. J Psychopharmacol 25: 685–697.

17.

Gowin

Swann

Moeller

Lane

(2010) Zolmitriptan and human aggression: interaction with alcohol. Psychopharmacology (Berl) 210: 521–531.

18.

Guy

(1976) ECDEU assessment manual for psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration.

19.

Harrison

Everitt

Robbins

(1997) Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology (Berl) 133: 329–342.

20.

Hough

Gopal

Vijapurkar

Lim

Morozova

Eerdekens

(2010) Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind placebo-controlled study. Schizophr Res 116: 107–117.

21.

Ingenhoven

Lafay

Rinne

Duivenvoorden

(2010) Effectiveness of pharmacotherapy for severe personality disorders: meta-analyses of randomized controlled trials. J Clin Psychiatry 71: 14–25.

22.

IPAP (2006) Treatment resistant schizophrenia. The International Psychopharmacology Algorithm Project. Available at: http://www.ipap.org/pdf/schiz/IPAP_Schiz_treatment_resistant.pdf (accessed 5 November 2014).

23.

Kozma

Slaton

Fastenau

Hough

(2011) Changes in schizophrenia-related hospitalization and ER use among patients receiving paliperidone palmitate: results from a clinical trial with a 52-week open-label extension (OLE). Curr Med Res Opin 27: 1603–1611.

24.

Kramer

Litman

Hough

Lane

Lim

Liu

. (2009) Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study. Int J Neuropsychopharmacol 13: 635–647.

25.

Miczek

Fish

Joseph

De Almeida

(2002) Social and neural determinants of aggressive behaviour: pharmacotherapeutic targets at serotonin, dopamine and g-aminobutyric acid systems. Psychopharmacology (Berl) 163: 434–458.

26.

Moss

Yao

Panzak

(1990) Serotonergic responsivity and behavioral dimensions in antisocial personality disorder with substance abuse. Biol Psychiatry 28: 325–338.

27.

Nasrallah

Gopal

Gassmann-Mayer

Quiroz

Lim

Eerdekens

. (2010) A controlled-evidence based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia. Neuropsychopharmacology 35: 2072–2082.

28.

Pandina

Lane

Gopal

Gassmann-Mayer

Hough

Remmerie

(2011) A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Prog NeuroPsychopharmacol Biol Psychiatry 35: 218–226.

29.

Pandina

Lindenmayer

Lull

Lim

Gopal

Herben

. (2010) A randomised, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol 30: 235–244.

30.

Soloff

(1997) Algorithms for pharmacological treatment of personality dimensions: symptom-specific treatments for cognitive-perceptual, affective, and impulsive-behavioural dysregulation. Bull Menninger Clin 62: 195–214.

31.

Taylor

Attard

(2013) A naturalistic evaluation of the use of paliperidone palmitate at South London and Maudsley NHS Foundation Trust: interim results on bed stay and admission rates on the first 132 patients diagnosed with schizophrenia who were followed up for 12 months. In: Schizophrenia Research Forum, 17th Biennial Winter Workshop on Psychosis, 14–16 February 2013, Marrakesh.

32.

Umukoro

Aladeokin

Eduviere

(2012) Aggressive behavior: a comprehensive review of its neurochemical mechanisms and management. Aggress Violent Behav 18: 195–203.

33.

Volavka

Citrome

(1999) Atypical antipsychotics in the treatment of the persistently aggressive psychotic patient: methodological concerns. Schizophr Res 35(Suppl. 1): S23–S33.

34.

Vukhac

Sankoorika

Wang

(2001) Dopamine D2L receptor-and age-related reduction in offensive aggression. Neuroreport 12: 1035–1038.

35.

Wade

Wit

Richards

(2000) Effects of dopaminergic drugs on delayed reward as a measure of impulsive behaviour in rats. Psychopharmacology (Berl) 150: 90–101.

36.

Webster

Eaves

Douglas

Wintrup

(1995) The HCR-20 scheme: the assessment of dangerousness and risk. Vancouver, Canada: British Columbia Simon Fraser University and Forensic Psychiatric Services.

37.

World Health Organization (1992) The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva, Switzerland: World Health Organization.