Naltrexone efficacy in treating alcohol-use disorder in individuals with comorbid psychosis: a systematic review

Abstract

Background:

Psychotic illnesses, such as schizophrenia, are typically enduring and disabling conditions, impacting individual, family, and societal outcomes. Individuals with these face greater vulnerabilities in developing alcohol-use disorder (AUD). Furthermore, the nature of psychoses, often manifesting with paranoia, cognitive impairment, a lack of insight, sub-optimal treatment adherence, and stigma from others, means that they can pose unique treatment challenges when these two conditions comorbidly occur. These challenges mean that the standard literature on the effectiveness of the opioid antagonist naltrexone in AUD does not necessarily translate to this vulnerable population.

Methods:

Following PRISMA guidelines, we herein systematically reviewed the evidence for naltrexone in individuals with both psychosis and AUD. Overall, there is a paucity of research in this important area, with only nine reports meeting search criteria, only four of which were randomized control trials. Studies compared naltrexone with: placebo, another pharmaceutical agent, or upon changes to baseline drinking behaviour. One study evaluated the long-acting injectable formulation of this drug.

Results:

Most studies, including the methodologically more robust ones, supported naltrexone’s effectiveness over placebo in terms of reduction in drinking days and numbers of drinks consumed on such days in this cohort. Work comparing naltrexone to other pharmaceutical interventions showed approximate equivalence with disulfiram, and modest superiority over acamprosate.

Conclusions:

On this limited evidence base, this review endorses the use of naltrexone as both safe and effective in those with both psychotic illnesses and AUD. Several key issues remain to be elucidated. Critically, study designs meant that they were limited to individuals with good engagement with services, and levels of adherence were attained that are unlikely to be replicated in this cohort in real-world settings. Finally, effects of specific psychosis symptomatology, not least paranoia and insight, upon naltrexone use, and the reverse directional potential of ‘double dysphoria’ from an opioid antagonist remain largely unexplored.

Keywords

alcohol alcohol-use disorder comorbid psychosis dependency naltrexone schizophrenia

Introduction

Psychotic disorders have a lifetime prevalence of about 3%, with schizophrenia being the most common.¹ The overall annual financial burden of schizophrenia has been estimated at 63.7 billion dollars in the US² and 6.7 billion pounds in England,³ the majority of which are indirect costs due to societal losses of productivity.

These complex conditions are further complicated for many with comorbid substance misuse, of which alcohol is the most frequent.⁴ A recent meta-analysis reported an alcohol-use disorder (AUD) prevalence of 20% in individuals with schizophrenia.⁵ Individuals with psychoses may face additional risks for alcohol misuse due to increased social disadvantage, vulnerability,⁶ and self-medication to ease symptom distress,⁷ though research demonstrates that many experience an exacerbation of symptoms through alcohol use.^7–9 Alcohol use in this population is associated with more physical illness, medication nonadherence, earlier hospital readmission, greater rates of suicide, interpersonal and family problems, and homelessness,^10–16 though these works have varied in their use of alcohol dependency, harmful use, and AUD as relevant criteria. Furthermore, in terms of treatment, interventions with those with schizophrenia may face additional challenges such as cognitive impairment, paranoia and lack of insight, which could hinder an ability to actively engage in an intervention.^17,18

In the UK, the National Institute for Health and Care Excellence (NICE) guidelines recommend a stepped approach to treatment of AUD, starting with motivational interviewing, in order to build insight into the problems related to drinking, followed by a psychological intervention such as cognitive behavioural therapy; the addition of acamprosate or oral naltrexone is recommended for harmful drinkers who do not respond to psychological intervention alone.¹⁹ This integrated treatment approach is mirrored in the NICE guidelines for comorbid psychosis and substance use; the delineating factor between the two guidelines is the additional use of antipsychotic medications where appropriate. No drug has been specifically approved for use in populations with dual diagnoses, though having a concomitant psychotic illness is not a contraindication to use, except in the case of disulfiram.²⁰

Naltrexone, an opioid antagonist, initially used primarily for opioid addiction, has been shown to have promising effects in the treatment of AUD, and it is licensed for such use in the UK and in the US.^21–25 Further, the Combined Pharmacotherapies and Behavioural Interventions for Alcohol Dependence (COMBINE) study demonstrated that not only is naltrexone effective in reducing alcohol consumption, it is also superior to an alternative pharmacological treatment, acamprosate, and behavioural interventions.²⁶ While naltrexone’s mechanisms of action in AUD are not fully understood, it is postulated that it works by reducing craving, decreasing subjective pleasure from alcohol consumption, and stemming endorphin-mediated reinforcement effects.^27–30

Meta-analyses on the efficacy of naltrexone in alcohol dependent/abusing populations generally show a significant reduction in relapse and heavy drinking rates, though the evidence varies between trials, with some large robust studies failing to find a significant treatment effect.^31–34 Interestingly, though limited, there are data to show that clinicians may be more likely to utilize it in those with comorbid psychiatric conditions^35,36; the rationale for this may vary, though it might represent greater clinical contact and use of medication, and, speculatively, a more interventionist approach in a vulnerable cohort. However, these findings are not always consistent, and further research is necessary.

Given these unique population challenges, the aim of this systematic review is to assess and summarize the current available evidence regarding the treatment effect of naltrexone in individuals with comorbid psychosis spectrum and AUD.

Methods

Data acquisition

The aim was to identify and critically appraise all randomized controlled trials (RCTs) and non-RCTs available to review by August 2016, in which the effect of naltrexone on alcohol consumption was investigated in a population with comorbid psychosis spectrum disorder and an AUD. The PRISMA guidelines were utilized to gather studies, extract data, and synthesize information.³⁷

Search strategy

Electronic database and manual searches were performed to locate references. The following databases were searched: Global Health (1973 to week of 5 August 2016), International Pharmaceutical Abstracts (1970 to week of 5 August 2016), Journals @ Ovid Full Text (15 January 2016), Ovid MEDLINE (1946 to week of 5 August 2016), PsycARTICLES Full Text, PsycINFO (1806 to week of 5 August 2016), Embase Classic and Embase (1947 to week of 5 August 2016). The search criteria were ‘(naltrexone OR Revia OR Depade OR Vivitrol) AND (Schizophrenia OR Psychosis OR Psychotic) AND Alcohol’. Results were then de-duplicated.

Inclusion and exclusion criteria

Both RCTs and non-RCTs were included. Only studies with at least one participant group composed of dually diagnosed (a psychosis spectrum disorder and an AUD) individuals were included; animal studies were excluded. Studies were required to have at least one primary outcome of drinking behaviour post-naltrexone administration. Studies were restricted to the English language. Due to the scarcity of research with this specific population, poster presentations were included if sufficient information was available. Books, letters, comments, and editorials were excluded.

Data extraction

The following information was extracted from each study (where available): number of participants, participant age, sex, diagnosis, dosage of naltrexone, study design, and drinking behaviour outcome measures.

Results

The database search yielded 3879 reports. A further search through reference lists in these search results added three additional reports. After dismissal by title, 108 abstracts were reviewed. In total, nine reports were identified (five journal articles and four detailed poster presentation abstracts) that met inclusion and exclusion criteria, see Figure 1, with a total of 798 participants, all diagnosed with an AUD. Study characteristics are in Table 1. Of these participants, 273 were diagnosed with a psychotic disorder. When participants in all the studies are considered together, 39.97% were allocated to a treatment condition wherein they were prescribed solely naltrexone to treat their AUD; the remaining participants were allocated to various conditions such as placebo, other medication(s), and psychotherapy. The average age of participants, where provided, was 44.24. Overall, the studies demonstrate a gender bias, with approximately 87% of participants being male. Further participant details are listed in Table 2.

Figure 1.

Flow diagram demonstrating process of inclusion of studies for review.

Table 1.

Study characteristics.

Study	Design	Naltrexone dose	Comparison group	Concurrent intervention	Study period (weeks)	Primary alcohol outcomes
Batki et al.⁴⁵	Prospective open label	100 mg 2 × a week, 150 mg 1 × weekly	n/a	Antipsychotic medication	8	Drinking days Drinking to intoxication (heavy drinking) Number of standard drinks Number of drinks per drinking day
Batki et al.^{16 *}	Randomized controlled trial	100 mg 2 × a week, 150 mg 1 × weekly	Placebo	Motivational counselling	12	Drinking days Heavy drinking days Drinks per week
Batki et al.^{44 *}	Prospective open label	380 mg monthly injection	None	Motivational counselling, antipsychotic medication	12	Drinking days Heavy drinking days Drinks per week
Bratu and Sopterean^{42 *}	Prospective open label	50 mg	(1) Acamprosate Addiction counselling	Antipsychotic medication	24	Days of abstinence Heavy drinking days
Maxwell and Shinderman⁴⁶	Retrospective chart review	Not reported	n/a	Antipsychotic medication 32% of patients in outpatient treatment	8	Overall alcohol consumption
Petrakis et al.³⁸	Randomized controlled trial	50 mg	15 placebo	CBT drug relapse prevention strategies, antipsychotic medication	12	Drinking days Heavy drinking days Number of standard drinks
Petrakis et al.⁴¹	Randomized controlled trial (w/only disulfiram open label)	50 mg	(1) Placebo (2) Open-label disulfiram and blinded naltrexone (3) Open-label disulfiram and blinded placebo	Participants in substance-abuse treatment with intensive rehabilitation, antipsychotic medication	12	Days of abstinence Drinking days per week Heavy drinking days
Petrakis et al.³⁹	Randomized controlled trial	50 mg	(1) Disulfiram and placebo (2) Naltrexone and disulfiram (3) Placebo	Antipsychotic medication	12	Days of abstinence Drinking days per week Heavy drinking days
Vasile et al.^{43 *}	Prospective open label	50 mg	Disulfiram	Antipsychotic medication	24	Overall alcohol consumption

Denotes a poster presentation abstract. CBT, cognitive behavioural therapy; n/a, not applicable.

Table 2.

Demographics and clinical characteristics of participants.

Study	Age (years)	Sex males	Sex females	Total participants	Number of participants receiving naltrexone only	Participants with psychosis diagnosis	Other diagnoses included
Batki et al.⁴⁵	43	15	4	19	19	11 schizophrenia 7 schizoaffective 1 psychotic disorder NOS	–
Batki et al.¹⁶	42.5	64	26	90	45	45 schizophrenia 45 schizoaffective	–
Batki et al.⁴⁴	44	13	12	25	25	6 schizophrenia 11 schizoaffective	8 bipolar
Bratu and Sopterean⁴²	18–65	24	12	36	12	36 (schizophrenia)	–
Maxwell and Shinderman⁴⁶	Not reported	51	21	72	72	17 Schizophrenia 7 schizoaffective	37 MDD, 4 gender-identity disorder, 11 bipolar
Petrakis et al.³⁸	46	31	0	31	16	18 schizophrenia 13 schizoaffective	–
Petrakis et al.⁴¹	47	247	7	254	59	18 schizophrenia or schizoaffective	178 MDD, 109 PTSD, 50 cocaine abuse, 57 GAD, 49 bipolar
Petrakis et al.³⁹	46.98	244	7	251	63	11 schizophrenia 7 schizoaffective	150 MDD, 86 PTSD, 26 panic disorder, 20 GAD, 48 bipolar (exceeded count due to comorbidities)
Vasile et al.⁴³	40.2	9	11	20	8	20 (schizophrenia)	–

Abbreviations: NOS, not otherwise specified; MDD, major depressive disorder; PTSD, post-traumatic stress disorder; GAD, generalized anxiety disorder.

Drinking outcomes

Due to the varied designs adopted, three outcome groupings have been utilized. Naltrexone’s effects on drinking behaviour were compared: with placebo in four studies^38–41; with another pharmaceutical agent in four studies^39,41–43; and against baseline drinking behaviour in three studies, one of which utilized the long-acting injectable form of the medication.^44–46

Naltrexone versus placebo

All four studies^16,38,39,41 showed significant superiority of naltrexone over placebo, though the placebo groups did show improvement in comparison to baseline drinking behaviour. Further details may be found in Table 3. In the first placebo-controlled study on the topic³⁸ (n = 31; male = 31), by the 12-week intervention endpoint, individuals who received naltrexone (n = 16) drank, on average, 7.3 fewer days (p < 0.0001), 26.4 fewer drinks (p < 0.05), had 0.44 fewer heavy drinking days (p = 0.003), and reported more abstinent days (p = 0.04) than those receiving placebo (n = 15).³⁸ The findings of this pilot study led to a much larger, but equal-duration follow-up study by the same research group⁴¹, consisting of 254 (male = 247) military veterans with alcohol dependency and mental illness (not limited to psychosis). It adopted a more sophisticated design, with four study arms: placebo, naltrexone, disulfiram, and naltrexone plus disulfiram. The analysis thus looked not only at the efficacy of naltrexone versus placebo, but also of naltrexone versus disulfiram and monopharmacotherapy versus combination therapy. The findings of the pharmaceutical comparisons are presented in the next section. When comparing naltrexone efficacy against placebo, this larger trial found similar reductions in drinking days (p = 0.02).^39,41 In a post hoc analysis, Petrakis et al.³⁹ reviewed their 2005 study by investigating medication effects through grouping participants on the basis of psychosis spectrum disorders versus nonpsychotic disorders.³⁹ In this analysis, they found that when compared with individuals with nonpsychotic disorders, individuals with psychosis spectrum disorders relapsed more (p < 0.05), but experienced significantly more days of abstinence (p = 0.01) and fewer heavy drinking days (p = 0.02).³⁹ In a double-blind randomized controlled trial with 90 participants (male = 64), Batki et al.⁴⁰ directly administered oral naltrexone three times weekly with a dosing schedule of 100 mg on Mondays, 100 mg on Wednesdays, and 150 mg on Fridays. This study also found that heavy drinking was reduced at the 12-week endpoint of naltrexone treatment (p < 0.04). While not statistically significant (p < 0.08), they found a trend for a decrease in fewer standard drinks per week. However, they failed to replicate the finding of reduction in number of drinking days. In the three studies that measured this, there were no differences between naltrexone and placebo in terms of study retention and adherence to drug administration.^38,41 In the post hoc analysis that contained individuals with nonpsychotic disorders³⁹, there were also no differences in study retention or adherence between the clinical groups.³⁹

Table 3.

Naltrexone versus placebo.

Study	Self-reported days of abstinence	Self-reported heavy drinking days	Drinks	Drinking days	Drinks per drinking day
Batki et al.¹⁶	Not reported	Decreased,p < 0.04	Not reported	Decreased,p < 0.08	Not reported
Petrakis et al.³⁸	Not reported	Decreased,p = 0.003	Decrease of 26.4, p value not stated	Decreased,p < 0.0001	Not reported
Petrakis et al.⁴¹	Decreased,p = 0.04	No significant change	Not reported	Decreased,p = 0.02	Not reported due to high rates of abstinence
Petrakis et al.³⁹	Decreased,p = 0.04	Decreased,p = 0.02	Not reported	Decreased,p = 0.02	Not reported

Naltrexone versus other pharmacological treatment

Table 4 outlines the results of various pharamacological comparions. One study compared naltrexone with acamprosate. Bratu and Sopterean⁴² randomized 36 individuals with psychosis (male = 24) into three groups: naltrexone 50mg daily, acamprosate 999 mg daily, and counselling focused on addictive behaviour. Naltrexone yielded superior effect on the reduction of both heavy drinking days and maintenance of sobriety when compared with counselling targeting addictive behaviour (p < 0.01).⁴² Over the 24-week intervention, they found that while naltrexone had a significant effect on the maintenance of abstinence, acamprosate treatment resulted in a larger effect size, yielding an additional 23.6 sober days (p < 0.01).⁴² However, naltrexone was more effective in reducing the number of heavy drinking days (–5.7 days; p = 0.043). Furthermore, while insignificant (p = 0.122), the severity of alcohol dependence (as measured by the Inventory of Drug Taking Situations, alcohol-focused version) decreased most in the naltrexone group. In sum, naltrexone was effective in maintaining abstinence, though acamprosate yielded longer abstinence periods, and was superior to acamprosate in reducing the number of heavy drinking days.

Table 4.

Naltrexone versus other pharmacological treatment.

Study	Intervention	Self-reported days of abstinence	Self-reported heavy drinking days	Global alcohol dependence	Drinks per week	Drinking days per week
Bratu and Sopterean⁴²	Naltrexone versus acamprosate	+23.6 days,p < 0.01^*	−5.7 days,p = 0.043	Decreased, p = 0.122	Not measured	Not measured
Petrakis et al.³⁹	Disulfiram versus naltrexone	Decreased,p = 0.37	Decreased,p = 0.42	Not measured	Not reported	Not reported
	Disulfiram and naltrexone combined versus disulfiram or naltrexone	Decreased,p = 0.29	Decreased,p = 0.16	Not measured	Not reported	Not reported
Petrakis et al.⁴¹	Disulfiram versus naltrexone	Decreased,p = 0.68	Decreased,p = 0.65	Not measured	Not reported	Decreased, p not reported
	Disulfiram and naltrexone combined versus disulfiram or naltrexone	Decreased,p = 0.94	Decreased,p = 0.76	Not measured	Not measured	Decreased, p not reported
Vasile et al.⁴³	Disulfiram versus naltrexone	Not measured	Not measured	Decreased,p < 0.01 in both groups;group differences, p = 0.144	Not measured	Not measured

Denotes superiority of comparison drug.

Three studies compared naltrexone with disulfiram, with results showing approximate equivalence between them. Vasile et al.⁴³ utilized an open-label design to compare the efficacy of naltrexone with that of disulfiram in 20 participants with a 24-week intervention. Naltrexone demonstrated equal reduction of global alcohol symptomology and severity (p < 0.01). Furthermore, disulfiram had significantly more individuals discontinue treatment due to adverse events (p < 0.05), suggesting that naltrexone may be better tolerated than disulfiram.

In the aforementioned four-arm comparison study, Petrakis et al.⁴¹ evaluated the effects of placebo, open-label disulfiram and blinded placebo, blinded naltrexone and placebo, and open-label disulfiram and blinded naltrexone. Due to the potentially dangerous interaction of disulfiram and alcohol, as well as the temptation to sample alcohol to test a blind condition of disulfiram, the authors chose to dispense the disulfiram by open label. This study found that naltrexone significantly decreased drinking days per week (p = 0.02) and increased consecutive days of abstinence (p = 0.04) compared with placebo, though these decreases were not significantly different from those found with the other active arm, disulfiram. Post hoc analysis of this same study grouped participants according to presence of psychosis spectrum diagnoses³⁹ but again showed no differences between medications. Specifically, individuals with psychotic spectrum disorders fared worse; they experienced more relapse, more heavy drinking days, fewer days of consecutive abstinence, and fewer days of total abstinence (p < 0.05). While medications proved to be more efficacious than placebo, the combination of the two drugs did not yield a significant advantage over either medication alone in any clinical group.^39,41

Drinking behaviours at baseline versus postnaltrexone (no comparison condition)

Only three studies observed naltrexone outcomes by solely comparing drinking behaviour pre and post naltrexone (see Table 5). In the first study on this topic, a retrospective chart review, Maxwell and Shinderman⁴⁶ found that with the caveats of this method of analysis, naltrexone yielded an overall reduction in drinking, with 70.8% of participants (n = 31) reducing their drinking by more than 90%, and 11.2% reduced drinking by 75–90% over an 8-week period in an outpatient community mental health centre.

Table 5.

Naltrexone versus baseline.

Study	Self-reported days of abstinence	Self-reported heavy drinking days	Drinks per week	Drinking days per week	Drinks per drinking day	Global alcohol intake
Batki et al.⁴⁴	Not measured	Decreased, p < 0.02	Decreased, p < 0.02	Decreased, p < 0.02	Decreased, p < 0.02	Not measured
Batki et al.⁴⁵	Not measured	Decreased, p = 0.043	Decreased, p = 0.016	Decreased,p = 0.034	Decreased, p = 0.048	Not measured
Maxwell and Shinderman⁴⁶	Not measured	Not measured	Not measured	Not measured	Not measured	70.8% patients reduced by 90%, 11.2% reduced by 75–90%

An 8-week open-label pilot study (n = 19)⁴⁵ also compared drinking behaviours of individuals with schizophrenia and AUD at baseline with postnaltrexone administration. In this study, directly observed oral doses of 100 mg of naltrexone were given twice a week and 150 mg once a week, with no additional supports. This alternative dosing schedule did not produce differing results, with reductions in heavy drinking days (p = 0.043), drinks per week (p = 0.16), drinking days per week (p = 0.034), and drinks per drinking day (p = 0.048) observed.

Long-acting injection naltrexone

One study evaluated the feasibility and effects of the long-acting injectable form of naltrexone on baseline drinking behaviour over the course of 12 weeks.⁴⁴ When participants (n = 25; males = 13) received all three monthly depot injections of naltrexone (380 mg/injection), significant reductions were found in drinks per week (p < 0.02), drinking days per week (p < 0.02), heavy drinking days (p < 0.02), and drinks per drinking day (p < 0.03).⁴⁴

Outcomes on psychosis pathology and cravings

Across the three groupings, five of the studies reported on changes in psychopathology. Whilst an opioid antagonist would not be expected to have direct antipsychotic actions, any reduction in harmful alcohol consumption is postulated to lead to secondary changes in mental state. From the limited evidence available, any such effects on general psychopathology remain inconclusive. While some studies found naltrexone to not have a significant effect on general psychopathology,^38,39,42 two found that naltrexone significantly deceased psychopathology.^41,45 Similarly, studies found contradictory evidence for naltrexone’s effect on alcohol craving, with three studies finding significant decreases,^38,41,45 and two not finding this association.^39,40 Interestingly, Petrakis et al. found the decrease in craving when grouping together individuals with a mental health diagnosis,⁴¹ yet this significance dissipated when the analyses were conducted by grouping participants based on the presence of a psychotic disorder.³⁹ This may suggest that naltrexone has a differential effect on craving, based on the presence of psychotic symptoms. However, further research would be necessary to fully illuminate this relationship.

Discussion

In total, nine studies were located that investigated the effect of naltrexone on drinking behaviour in a comorbid schizophrenia and AUD population. The most favourable evidence for naltrexone’s efficacy was in the reduction of heavy drinking days,^{38–40,42,44,45} followed by maintenance of abstinence^39,41 and reduction in the number of drinking days.^38,44 Further evidence suggests that naltrexone may be effective in reduction of drinks per week⁴⁴ and the number of drinks per drinking day.⁴⁴

While studies indicate that the effect of disulfiram is approximately equivalent to that of naltrexone, fitting with the wider literature on the topic, naltrexone is shown to be better tolerated in patients suffering from comorbid alcohol use and psychotic disorders,^38,42,43 though mild side effects have been reported.⁴⁵ In the one study that tested for such an effect, combining these treatments did not offer any advantage, though it did produce more side effects than found in the administration of either drug alone.^39,41 Furthermore, it has been argued that because naltrexone does not produce an aversive reaction as disulfiram does, individuals may be more willing to try it due to less fear of punitive relapse consequences.⁴⁷

Interestingly, studies that offered a psychosocial intervention alongside naltrexone (concurrent interventions are listed in Table 1) did not yield further advantages over studies that prescribed naltrexone alone.^{38,40,41,44,46} While magnitude and longevity of gains remain to be discovered, even small changes in drinking behaviour may have a large subjective impact on the lives of those with comorbid psychosis and AUD, since these individuals suffer the same consequences of alcohol as their mentally healthy counterparts, but with less intake.⁴⁸

Two studies had contrary findings. While Batki and colleagues⁴⁰ did not find a significant decrease in drinking days, authors of the other three studies in the naltrexone versus placebo category found a significant effect in this measure.^38,39,41 However, Batki et al. did find a nonsignificant trend for fewer drinks per week in the naltrexone group. In contrast to a dosage of 50 mg used by the other three studies in this category, Batki and colleagues used a dosing schedule of 100 mg twice a week and 150 mg once a week. Since the trend found in other studies is present in the authors’ findings, it is conceivable that the dosing influenced the outcome. Indeed, the recommended dosage of naltrexone per general prescribing guidelines is 50 mg.^20,49 However, the authors note that the most salient part of their study was that dosing was directly observed, ensuring adherence on days that subjects attended, which was thus considerably better than many trials that had more inexact methods, such as pill count or self-report.

The second inconsistency is the finding by Petrakis et al.⁴¹ that naltrexone was ineffective for reduction in heavy drinking days. This is not only inconsistent with the studies comparing naltrexone with placebo, but to all studies in this review that measured heavy drinking, suggesting that this is an isolated finding to the participants enrolled in the study by Petrakis et al.⁴¹. This sample was composed of highly motivated individuals who were already enrolled in a treatment program and demonstrated high rates of abstinence. Evidence indicates that naltrexone may be most effective in conjunction with alcohol consumption, rather than sobriety.⁵⁰ High abstinence may explain the lack of significant effect on heavy drinking days in the sample studied by Petrakis et al.⁴¹.

Methodology, design, and limitations

The studies included in this review have several limitations. The majority of studies had participants stabilized on antipsychotic medications,^{38,39,41–46} putatively impacting dopaminergic reward systems, though it enhances the transferability of the findings.

Two studies administered naltrexone,^40,45 yielding high adherence and low attrition rates that may not be transferable to clinical practice. Interestingly, Batki and colleagues employed a model of adherence in an interim analysis of their 2009 study where they found alcohol reductions even in individuals who were nonadherent (taking less than 80% of the suggested dose of naltrexone).⁵¹ Long-acting ‘depot’ injection side-steps this issue, but the evidence base is currently limited.⁵²

Concurrent psychosocial ordinary care was not possible to control for in several works,^38,40,41,44 though studies with no such interventions still observed significant drinking reductions.^39,43,45,46

A total of 87% of the participants were male; women have been traditionally under-represented in this field⁵³ but appreciation for sex-specific differences has increased,^54,55 albeit that the general literature suggests men and women do not differ in their response to naltrexone.⁵⁶

Three studies utilized samples from the Veterans Administration in the USA,^39,41 with military personnel shown to often have differing personality traits from the general population,^57–60 and results were not stratified by ethnicity. Eastern-Asian and African-American individuals have been shown to respond differentially to naltrexone.^61,62 Therefore, the results may only be pertinent to the specific populations sampled, part of the wider challenge of stratified medicine; which interventions work in which subgroups.⁶³

Overall, the literature is notable for its small size, with several of the studies coming from a single research team. One study was a retrospective chart review,⁴⁶ four studies^42–45 were open-label trials, and three were randomized controlled trials.^38,40,41 The inclusion of a retrospective chart review yields weak evidence, as the intervention was not controlled, nor were specific drinking measures allowed to be taken. Open-label trials leave the possibilities of placebo effect and researcher biases open through unblinding. Several of these studies did not include a control group. In addition, the use of open-label designs may attract those who are more motivated to gain sobriety as patients are aware of receiving active medication. RCTs, while the ‘gold standard’, also suffer this same limitation by recruiting participants willing to receive a drug. As a consequence, external validity is compromised.⁶⁴

The variety of designs necessitated different statistical analyses to be employed to interpret the raw data. Analysis of variance,^39,41,45 analysis of covariance,⁴⁵ zero-inflated negative-binomial regression,^40,44 random regression analysis,^38,41 an unspecified effect size,⁴² and a qualitative scale⁴⁶ were all implemented in data analysis. Due to the lack of consistency across studies, a meta-analysis, which may provide ‘the best estimates of treatment effects’,⁶⁵ is neither currently feasible nor practical. The synthesis of findings found in this review, while qualitatively important, does not produce results about the magnitude of the pooled effects.

Lastly, inclusion of poster presentations does not allow for the critical analysis of methodology, as this is not discussed to similar depth as of that in journal articles. Not only is this lack of information a limitation intrinsically, but it also opens the possibility of further unknown disadvantages.

Future directions

While this review demonstrates safety and efficacy of naltrexone in a comorbid psychosis and AUD population, the small number of studies identified reflects a shortage of examination in this specific area; further research is necessary to overcome the present limitations and strengthen findings. In order to adequately evaluate the effect of naltrexone, future research should aim to adopt designs, outcomes, and statistical analyses that allow for direct comparison across studies. None of these studies have examined the durability of drinking behaviour reductions, with follow-up periods of a maximum of 24 weeks. Future research should investigate whether the effects produced by naltrexone are sustainable and lead to long-lasting change. This necessity is highlighted by findings that AUD-diagnosed individuals treated with naltrexone did not differ in drinking habits to the placebo-treated group at follow ups ranging from 6 to 12 months.^66,67 However, individuals with psychosis differ in significant ways to the general population, even further warranting additional study.

So-called ‘double dysphoria’ is another concern with this population. Individuals with psychosis are more prone to states of dysphoria, both due to the illness, but also due to social factors such as social isolation, financial difficulties and decreases in functioning. These factors lead individuals to attempt to reduce dysphoric states, commonly with illicit substances,⁶⁸ notably cannabis; a particular contemporary concern is the rise in use of synthetic cannabinoid receptor agonists, a class of novel psychoactive substances that appear particularly potent.^69–71 Due to naltrexone’s blockade of opioid receptors, there is concern about an exacerbation of dysphoria. While a recent meta-analysis indicates that dysphoria is not a serious side effect produced by naltrexone,⁷² this review did not include individuals with psychosis who have may have a higher dysphoric baseline prior to medication prescription. However, this review did include individuals with depression and demonstrated that the addition of an antidepressant yielded positive results. Further research should consider extending this line of research to populations with psychosis.

An additional factor to consider in this population is the concomitant necessity of antipsychotic medications. While the pharmacokinetic properties of naltrexone make an adverse interaction with antipsychotics unlikely, few studies have been conducted on this subject.⁷³ However, there have been reports of an adverse interaction between naltrexone and thiorizadine causing ‘intense lethargy’⁷⁴ warranting additional investigation, though it should be noted that these are primarily from case reports, involve an antipsychotic seldom prescribed in contemporary practice, and are now relatively old. Conversely, the majority of studies within this systematic review included patients that were stabilized on antipsychotic medications suggesting that interactions are unlikely. In fact, pilot research suggests that naltrexone may actually be a beneficial addition to antipsychotics in combatting the unwanted side effect of weight gain.⁷⁵

Despite a number of additional concerns associated with remediation of alcohol use in this population, effective interventions are vital to the safety of the individuals themselves and the public. A recent systematic review of schizophrenia and risk factors found that dually diagnosed patients are at an increased risk for suicide and suicidal behaviour.¹² Furthermore, while levels of crime committed by individuals with schizophrenia are approximately equal to the general population, dually diagnosed individuals are over four times more likely to be convicted of a violent crime.^76,77 Rural areas have a disproportionately higher rate of alcohol misuse and co-occurring disorders but fewer treatment resources, despite sizable populations.⁷⁸ When considered together, these findings highlight the need for empirically supported pharmacological interventions, as medications are easily accessible and relatively fast acting.

Robust results in this population may lead to the licensing of naltrexone explicitly for a comorbid psychosis and AUD population, leading to more access to this treatment and consequently, a better quality of life. In order for a regulatory body to grant approval for a target population, thousands of participants must typically undergo clinical trials to indicate an effect at the population level.^49,79 Future studies should therefore include much larger sample sizes. Not only should studies aim for considerable size, sex equality needs to be incorporated as present studies have almost exclusively explored the effect of naltrexone in men. Recent work has shown that ‘sweet liking’ preference predicts naltrexone effectiveness in individuals with AUD without psychosis,⁸⁰ the scientific rationale being that it is a marker for the functioning of the opioid system; this should be tested in future work on psychosis populations.

In conclusion, our findings support the use of naltrexone as safe and effective in those with AUD and psychosis, though the underlying evidence base is modest. Guidelines for AUD in the general population typically recommend psychosocial interventions before pharmacological ones, but this has added challenges in individuals with psychoses. On the one hand, medication might offer a ‘simpler’ choice than more complex interventions; on the other, illness insight, attitudes towards, and adherence with, medication can hinder pharmacological treatment. Clinicians should try offering informed choices mindful of these factors, the additional vulnerabilities those with psychoses have for developing AUD, and the extra challenges they may face in its treatment. Whilst currently generally unexplored in the scientific literature, the impact of psychopathology, including paranoid or delusional ideas, on a treatment regime should be considered, as should likely issues around adherence, whether unintentional through cognitive difficulties or as part of a wider pattern of noncompliance. Further, those with psychotic illnesses can suffer from antipsychotic-induced dysphoria, and an opioid antagonist risks exacerbating this. In summary, those with these comorbidities need intervention at least as much as anyone else, and the use of naltrexone can be supported, but clinicians should be mindful of unique potential pitfalls.

Footnotes

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.

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