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National Collaborating Centre for Mental Health (UK). Psychosis with Coexisting Substance Misuse: Assessment and Management in Adults and Young People. Leicester (UK): British Psychological Society; 2011. (NICE Clinical Guidelines, No. 120.)

8PHARMACOLOGICAL AND PHYSICAL INTERVENTIONS

8.1. INTRODUCTION

There are many pharmacological treatments for both psychotic disorders and substance misuse, but there is very little overlap between the treatments for each group of disorders. The pharmacological treatments for each of the substance-use disorders are generally specific ones for each substance of dependence, for example, disulfiram and acamprosate for alcohol dependence, and methadone for opioid addiction. In the treatment of psychoses, however, there is much greater overlap, with lithium salts and other mood stabilisers, antipsychotics of all types, and anticonvulsants being used; these medications show little commonality with the treatments for substance misuse. It might be expected that with a large number of drugs being used to treat each group of disorders, there could be important interactions between them, both pharmacodynamic and pharmacokinetic. In practice, there is insufficient data about such interactions. It might also be expected that polypharmacy would be a problem for these coexisting disorders but the data here are conflicting with no clear evidence of greater use of drug treatment in people with psychosis and coexisting substance misuse (Centorrino et al., 2008; Goldberg et al., 2009; Kreyenbuhl et al., 2007).

To date, few specific recommendations for pharmacological treatment of both groups of disorders have been made that are not covered by previous published NICE guidelines for substance misuse and the psychoses separately. The purpose of this chapter is to examine whether there is any evidence that pharmacological or physical treatment of each disorder should be modified as result of having a coexisting diagnosis.

8.1.1. Current practice

The pharmacological management of people with psychosis and substance misuse is primarily concerned with treating the individual disorders. Nevertheless, special attention needs to be paid to treatment adherence in this group, not least as the risk of adverse outcomes, including significant societal violence, is so much greater in this population (Kooyman et al., 2007).

8.2. EVIDENCE REVIEW

8.2.1. Introduction

A number of existing NICE guidelines have reviewed the evidence for pharmacological and physical interventions used to treat people with psychosis without substance misuse (that is, Bipolar Disorder [NCCMH, 2006] and Schizophrenia [NCCMH, 2010]), and for people with substance misuse without psychosis (that is, Alcohol-use Disorders: Diagnosis, Assessment and Management of Harmful Drinking and Alcohol Dependence [NCCMH, 2011] and Drug Misuse: Opioid Detoxification [NCCMH, 2008a]).

For the purposes of the current guideline, three main issues were addressed for people with psychosis and coexisting substance misuse:

  1. modification of the pharmacological treatment of psychosis as a result of substance misuse and the treatment provided (for example, methadone, buprenorphine, and so on)
  2. modification of the pharmacological or physical treatment of substance misuse as a result of the presence of psychosis and the treatment provided (for example, antipsychotic drugs, lithium, and so on)
  3. management of drug interactions or adverse effects from pharmacological interventions.

Where no evidence existed for a particular intervention in people with psychosis and coexisting substance misuse, the GDG used informal consensus to reach a conclusion about whether it was appropriate to cross-reference to existing NICE guidelines.

Interventions and licensing in the UK

Table 30 lists the interventions included in current NICE guidelines together with their licensed indications in the UK (those relevant to this guideline).

Table 30. Relevant interventions included in current NICE guidelines and current licence status of medication.

Table 30

Relevant interventions included in current NICE guidelines and current licence status of medication.

8.2.2. Clinical review protocol (pharmacological and physical interventions)

A summary of the review protocol, including the primary review question, information about the databases searched and the eligibility criteria used for this section of the guideline can be found in Table 31 (the full protocol can be found in Appendix 20). Initially a search for systematic reviews and existing guidelines that addressed the review question was conducted. Good-quality systematic reviews were then used as a source of evidence, and only a new systematic search for more recent primary-level studies was conducted for the guideline (further information about the search strategy can be found in Appendix 7).

Table 31. Databases searched and eligibility criteria for clinical evidence.

Table 31

Databases searched and eligibility criteria for clinical evidence.

If the evidence allowed, the following sub-question was asked for review questions 2.1.1 and 2.3.1: are there subgroups of people (for example, young people, people with a particular type of psychosis, people from BME groups) who may benefit from alternative strategies than those recommended for people with a single disorder?

8.2.3. Studies considered for review (pharmacological and physical interventions)

Thirteen clinical evidence reviews and guidelines met the eligibility criteria for this section of the guideline (Buchanan et al., 2009 [Schizophrenia Patient Outcomes Research Team, PORT, psychopharmacological treatment recommendations and summary statements]; Casas et al., 2008; Center for Substance Abuse Treatment, 2005a [Treatment Improvement Protocol series 42]; Center for Substance Abuse Treatment, 2005b [Treatment Improvement Protocol series 43]; Center for Substance Abuse Treatment, 2006 [Treatment Improvement Protocol series 45]; Green et al., 2008; Hjorthoj et al., 2009; Mills et al., 2009 [Australian guideline]; San et al., 2007; Smelson et al., 2008; Tiet & Mausbach, 2007; Vornik & Brown, 2006; Wobrock & Soyka, 2008). All were published in peer-reviewed journals between 2006 and 2009. In addition, a number of reviews were excluded as they had either been superseded by more recent reviews (for example, Brunette et al., 2005; Goldstein et al., 2006; Green, 2005), or are currently under review (that is, Lingford-Hughes et al., 2004).

In addition, a search was conducted for RCT evidence that may have been published too recently to be included in existing reviews. From this, four RCTs were found (Brown et al., 2009; Kemp et al., 2009; Nejtek et al., 2008; Van Nimwegen et al., 2008). A summary of study characteristics is given in Table 32 and the results are described in the text below. Additionally, a secondary analysis from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project was reviewed (Swartz et al., 2006).

Table 32. Summary information table for RCTs of pharmacological interventions.

Table 32

Summary information table for RCTs of pharmacological interventions.

All of the studies, evidence reviews and guidelines were of pharmacological interventions; no evidence was found for physical or complementary treatments for psychosis and coexisting substance misuse.

8.2.4. Evidence from existing reviews and guidelines for pharmacological interventions for people with schizophrenia and coexisting substance misuse

Eleven recent existing reviews and/or guidelines included evidence for the pharmacological treatment of people with schizophrenia (or related disorders) and coexisting substance misuse (Buchanan et al., 2009 [Schizophrenia Patient Outcomes Research Team, PORT]; Center for Substance Abuse Treatment, 2005a [Treatment Improvement Protocol series 42]; Center for Substance Abuse Treatment, 2005b [Treatment Improvement Protocol series 43]; Center for Substance Abuse Treatment, 2006 [Treatment Improvement Protocol series 45]; Green et al., 2008; Hjorthoj et al., 2009; Mills et al., 2009 [Australian guideline]; San et al., 2007; Smelson et al., 2008; Tiet & Mausbach, 2007; Wobrock & Soyka, 2008). They review a range of evidence, from case studies to RCTs.

Buchanan and colleagues (2009) updated the PORT psychopharmacological treatment recommendations last published in 2004 (Lehman et al., 2004). The authors conducted a systematic review of evidence sourced from quarterly searches of MEDLINE (January 2002 to March 2008) to supplement searches undertaken for their previous guideline. No other electronic database was used. The guideline covers pharmacological treatments for schizophrenia, with a subsection on the treatment of coexisting substance misuse. It mostly focuses on double-blind RCTs. It included studies where at least 50% of participants had a schizophrenia spectrum disorder diagnosis and where study drugs had US Food and Drug Administration (FDA) approval. Studies involving people with schizophrenia and coexisting cocaine misuse or dependence included two double-blind RCTs comparing olanzapine with haloperidol, and one double-blind RCT comparing olanzapine with risperidone. Also included was one double-blind RCT comparing naltrexone with placebo in people with schizophrenia and coexisting alcohol-use disorders. Finally, the authors mention a sub-analysis of a larger RCT that examined naltrexone, disulfiram, and naltrexone plus disulfiram compared with placebo in people with psychosis and coexisting substance misuse. The GDG concluded that based on the research examined there was insufficient evidence to support a specific recommendation for a pharmacological intervention to treat people with schizophrenia and coexisting substance misuse.

Green and colleagues (2008) conducted a narrative review of evidence, but did not describe their methodology for identifying relevant research. The authors focused on antipsychotic drugs for the treatment of schizophrenia and coexisting substance misuse, but also covered medications for substance-use disorders. They reported a range of evidence (mostly low-level such as case reports and open-label non-comparative studies) suggesting that atypical antipsychotics may be helpful in reducing substance misuse in people with coexisting schizophrenia and substance misuse. The evidence reviewed covered a range of drugs of misuse, including alcohol, cocaine and marijuana. They found the most consistent evidence (from non-randomised studies) suggesting that clozapine may reduce substance use. There was ‘less substantial’ evidence for quetiapine and aripiprazole, while that for olanzapine and risperidone was unclear, with some studies showing benefit and others not. Overall they concluded that RCT evidence is required before firmer conclusions can be drawn.

With regard to evidence for drugs specifically used to treat substance misuse, Green and colleagues (2008) found preliminary evidence to support the use of naltrexone and disulfiram in people with coexisting schizophrenia and alcohol dependence. They found no relevant studies of acamprosate. They report case studies indicating the potential benefit of valproic acid in people with schizophrenia and coexisting alcohol misuse or dependence.

However, Green and colleagues (2008) conclude that ‘despite numerous suggestive reports, the questions of whether and to what degree antipsychotic medications and other medications for substance use disorders are effective in reducing substance use among people with [schizophrenia and] co-occurring disorders are not yet answered.’

Hjorthoj and colleagues (2009) conducted a systematic review focusing on the treatment of cannabis-use disorder in schizophrenia spectrum disorders, covering all types of intervention including psychosocial. The evidence was sourced from searches of four electronic databases up to September 2008. The authors focused on studies that provided outcomes for cannabis use separately from outcomes for other substance misuse, although they also looked at studies reporting cannabis use as part of a grouped outcome. With regard to pharmacological interventions for reducing cannabis use, they found evidence from non-randomised studies of benefit from using clozapine and quetiapine.

The Australian Government Department of Health and Ageing funded the National Drug and Alcohol Research Centre to develop a guideline (Mills et al., 2009) covering the management of people with mental disorders with coexisting alcohol and other drug misuse. The guideline, designed for alcohol and other drug workers, was based on a comprehensive review of the available evidence together with the experience of an expert panel. However, details of the methodology used to undertake the review work were not provided. For people with psychosis, Mills and colleagues (2009) found evidence that clozapine may be useful, but that evidence of benefit for second-generation antipsychotics was not yet clear. The authors also suggest that pharmacological interventions may be more effective than psychosocial interventions, because negative symptoms associated with psychosis may restrict involvement with and outcomes from psychosocial interventions. In addition, this group of people may have greater tolerance to medication regimes.

Mills and colleagues (2009) conclude that treatments that work for mental health disorders without coexisting substance misuse will also work for those with a coexisting disorder. They raise the issue of adherence and also the importance of an awareness of possible interactions and side effects.

San and colleagues (2007) produced a systematic review of treatment with antipsychotic drugs for people with schizophrenia and coexisting substance misuse. The evidence was sourced from searches of three electronic databases up to November 2006. The authors found three RCTs comparing olanzapine with haloperidol, plus other non-RCT evidence. From this they concluded that there was preliminary evidence that, compared with haloperidol, olanzapine is more effective in reducing cravings while retaining antipsychotic action, and that clozapine showed similar potential. They also concluded that older antipsychotics (first-generation) were not as appropriate in this population compared with newer drugs (second-generation) since they were more likely to increase extrapyramidal symptoms. Based on case reports, open and retrospective studies, they found that newer antipsychotics may be of use, although the evidence is generally weak. The authors point out the limitations of the evidence base, including small sample sizes, short follow-up periods, and high dropout rates, as well as the paucity of RCTs and blinded studies.

Smelson and colleagues (2008) conducted a review of FDA-approved medications for people with schizophrenia with coexisting substance misuse. There are no details of the methods used, including how evidence was sourced. However, they provide reasonably comprehensive tables of evidence found (compared with other reviews). They cover medication for the treatment of both schizophrenia (antipsychotics) and substance misuse. They conclude that there is very little evidence to support specific treatment recommendations and, therefore, that clinicians should base treatment decisions on what suits the service user in terms of efficacy and side effects. They found the most evidence suggesting benefit for clozapine, olanzapine and risperidone, although this evidence is not strong. They suggest that second-generation antipsychotics may be better for controlling drug craving in people with cocaine dependence. The authors make the point that non-adherence is a bigger threat to effective treatment rather than poor efficacy and, therefore, advocate that clinicians should consider depot medication. The authors found evidence to support the use of disulfiram and naltrexone.

Tiet and Mausbach (2007) report a systematic review of studies of treatment for people with mental disorders, including schizophrenia and bipolar disorder, with coexisting substance misuse. Studies were sourced from a search of two electronic databases. The search date is unclear, but is probably no later than 2006. The authors estimated effect sizes using Cohen's d but they do not give CIs. It is unclear whether, or how, they applied diagnostic criteria when assessing studies. The authors concluded that treatments that are effective in reducing psychiatric symptoms in those with a mental disorder without coexisting substance misuse, also work with coexisting substance misuse, and those treatments that are effective for improving substance misuse also work in those with a mental disorder. Specifically, they found that naltrexone may reduce coexisting alcohol-related disorders. They found no evidence of enhanced efficacy with higher doses.

The Treatment Improvement Protocol (TIP) series 42, 43 and 45 published by the Center for Substance Abuse Treatment (2005a, 2005b and 2006) are based on systematic reviews and reviews of published meta-analyses together with the views of an expert consensus panel for the treatment of substance abuse in people with coexisting disorders (TIP series 42), pharmacological treatment of opioid addiction (TIP series 43) and detoxification and substance misuse treatment (TIP series 45). The methods for evidence review are not available, but the guidelines were drafted by expert panels.

TIP series 42 (Center for Substance Abuse Treatment, 2005a) does not focus on specific pharmacological treatments, but on general management and care by clinicians, and special considerations (such as for pregnant women). It is not considered further here.

TIP series 43 (Center for Substance Abuse Treatment, 2005b), which focuses specifically on opioid addiction, recommends stabilisation of addiction symptoms with methadone, and using newer antipsychotics as either initial or second-line treatment. This is based on the supposed lower side-effect profile and increased effectiveness of many newer antipsychotics compared with older medications.

TIP series 45 (Center for Substance Abuse Treatment, 2006), which focuses on detoxification, recommends avoiding abrupt withdrawal of existing medication because of the risk of withdrawal symptoms or precipitating a psychiatric episode. It recommends maintenance on existing medications, unless the person has been misusing the medication or the psychiatric symptoms were caused by the medication. It also recommends giving consideration to withdrawal of medications that lower seizure threshold during acute alcohol withdrawal, or at least using a loading dose or schedule taper of a benzodiazepine. The authors point out the importance of balancing risks and benefits of medication for people with mental disorders and coexisting substance misuse. These include the tension between the tendency for some medications to ‘impair cognition and blunt feelings’, which may hinder people from addressing problems in their lives that they need to change in order to abstain from misused substances successfully. However, untreated mental disorders ‘can be powerful relapse triggers, especially for people with a long-standing pattern of relying on alcohol or other drugs to manage their symptoms’. With regard to psychotic disorders, TIP series 45 has no specific recommendations for treatment in the presence of coexisting substance abuse apart from usual care.

Wobrock and Soyka (2008) conducted a systematic review of pharmacological treatment of people with schizophrenia or psychosis and coexisting substance misuse based on searches of five electronic databases searched to November 2007. They report a range of evidence including other reviews, RCTs and case studies. With regard to first-generation antipsychotics, Wobrock and Soyka (2008) found that ‘most studies reported that service users with the psychosis and coexisting substance misuse showed a generally poorer response to treatment’. Whether the authors were using studies with both substance misuse and substance non-misuse populations, or whether they were comparing studies with substance misuse populations with studies with non-misusing populations is unclear. They include a range of substances including alcohol. They found some evidence that switching to flupenthixol improves outcomes in alcohol or cocaine misuse.

With regard to second-generation antipsychotics, Wobrock and Soyka (2008) found little high-quality evidence, but concluded making a theoretical case for the use of second-generation antipsychotics based on limited evidence that second-generation antipsychotics, particularly aripiprazole, clozapine, olanzapine, quetiapine and risperidone, may be more effective than older antipsychotics for both psychotic symptoms and for reducing craving and drug consumption. They found some evidence for the use of naltrexone in controlling alcohol misuse, as well as for the use of disulfiram, but did not consider this to be appropriate because of the risk of inducing psychosis.

Summary of evidence from reviews and guidelines for pharmacological interventions for people with schizophrenia and coexisting substance misuse

Although some of the reviews and guidelines described above either did not search widely for relevant studies, or did not describe the source of the evidence reviewed, they all came to the conclusion that there is poor evidence for the effectiveness of pharmacological interventions for people with schizophrenia and coexisting substance misuse. Some authors concluded that no specific drugs can be recommended and that treatment should follow that used for schizophrenia alone, while others suggest that the limited evidence for several second-generation antipsychotics, including clozapine, quetiapine, risperidone and olanzapine, should be interpreted as an indication for use of these drugs. All call for better-quality research to be undertaken.

8.2.5. Evidence from new RCTs for pharmacological interventions for people with schizophrenia and coexisting substance misuse

One additional RCT (Van Nimwegen et al., 2008) and a secondary analysis from an earlier RCT (Swartz et al., 2006) were found that were not included in the published reviews and guidelines.

The Van Nimwegen and colleagues' (2008) trial was a 6-week double-blind RCT comparing olanzapine with risperidone in people with schizophrenia, schizoaffective disorder or schizophreniform disorder with coexisting cannabis use. Participants were a subsample (N = 41) of 138 service users or outpatients from four mental health centres aged 18 to 30. The authors reported no differences between the study drugs in terms of cannabis use or cravings.

The Swartz and colleagues' (2006) study was a secondary analysis of a large pragmatic trial that included 1,432 participants (643 substance users and 789 non-users). People with schizophrenia were recruited at 57 US sites and randomly assigned to olanzapine, perphenazine, quetiapine, risperidone or ziprasidone for up to 18 months. Among those using substances, there were no significant differences between treatment groups in time to all-cause discontinuation. The authors also report that people using substances and non-users were generally similar in terms of improvement of symptoms of psychosis and side effects. An analysis of the effect of treatment on substance misuse outcomes has not yet been published.

Summary of evidence from new RCTs

There is no new evidence showing increased effectiveness of any particular antipsychotic in reducing substance misuse in people with coexisting schizophrenia and substance misuse.

8.2.6. Evidence from existing reviews and guidelines for pharmacological interventions for people with bipolar disorder and coexisting substance misuse

Two reviews focus solely on the treatment of people with bipolar disorder and coexisting substance misuse (Casas et al., 2008; Vornik & Brown, 2006). In addition, three reviews and guidelines discussed above also cover bipolar disorder (Mills et al., 2009; Tiet & Mausbach, 2007; Center for Substance Abuse Treatment, 2006 [TIP series 45]).

Casas and colleagues (2008) developed a guideline based on a systematic review of published evidence together with expert consensus and surveys of expert practice. Evidence was sourced from a search of MEDLINE (to 2005). How the evidence was assessed, or what outcomes were used, is unclear. Similarly the diagnostic criteria used to include or exclude studies are unclear. Nevertheless, recommendations are made for the treatment of different episode types. With regard to mania, Casas and colleagues (2008) recommend that treatment for ‘concomitant substance use disorder … should be initiated at the same time [as treatment for mania] without giving priority to one over the other. However, if substance abuse presents as an acute intoxication or abstinence syndrome, then the treatment of the manic episode must be adapted.’ They recommend second-generation antipsychotics, as well as carbamazepine and valproate, but not antidepressants. For rapid cycling bipolar disorder, Casas and colleagues (2008) recommend that treatment should be adapted if substance misuse presents as acute intoxication or abstinence syndrome, using the same drugs recommended for use in a manic episode; otherwise treat as for mania. The authors found that lithium was shown to be effective in young people with coexisting substance misuse, and that valproate was helpful in reducing alcohol consumption. They found no RCT evidence for carbamazepine, gabapentin, lamotrigine or benzodiazepines.

With regard to bipolar disorder, Mills and colleagues (2009) found evidence to suggest that alcohol-use outcomes improved with the use of valproate; that carbamazepine and lithium may help to reduce substance misuse; and that quetiapine and lamotrigine may also be of value in people with cocaine dependence.

In addition to the findings described above, Tiet and Mausbach (2007) found that the combination of valproate and lithium may reduce coexisting alcohol use in bipolar disorder.

TIP series 45 (Center for Substance Abuse Treatment, 2006) looked at drugs commonly prescribed for bipolar disorder in the context of people with substance misuse. With regard to lithium, the authors concluded that ‘lithium has no conclusively positive effect on rates of abstinence in either depressed or nondepressed patients.’ They also state that ‘anticonvulsant mood stabilizers, such as divalproex sodium and carbamazepine, can be effective in controlling mania and, some evidence suggests, in coexisting addictive conditions as well. Carbamazepine is known to be as effective as some benzodiazepines in inpatient treatment of alcohol withdrawal and, because of its anticonvulsant properties, it may be a good choice for treating those service users at high risk of withdrawal seizures.’

Vornik and Brown (2006) reviewed pharmacological interventions for bipolar disorder and coexisting substance misuse. There is no description of how evidence was sourced or of any criteria by which evidence was assessed, which makes it difficult to assess the overall quality of the conclusions drawn. The authors report some evidence from RCTs for the effectiveness of mood stabilisers, including carbamazepine for reducing depressive symptoms in bipolar disorder (depressed phase) and coexisting cocaine misuse; major depressive disorder and coexisting substance use; and valproate in reducing alcohol use. They report non-randomised evidence for lamotrigine in reducing psychiatric symptoms and cocaine use. They also found evidence for the effectiveness of antipsychotics, including quetiapine (open-label, randomised) and aripiprazole (open-label, non-randomised), for reducing psychiatric symptoms and drug craving.

Summary of evidence from reviews and guidelines

As with schizophrenia, not all the reviews searched more than one electronic database or gave full details of their methodology, which makes it hard to judge their quality. However, the reviews and guidelines largely came to similar conclusions, other than concerning the use of lithium. Some used the Geller and colleagues' (1998) trial in young people (see Chapter 9) as evidence for lithium's effectiveness (for example, Casas et al., 2008), but others found no particular effect (for example, TIP series 45). With regard to other drugs used as mood stabilisers, most reviewers found evidence for the use of carbamazepine, valproate for improving alcohol-related outcomes, and antipsychotics. One found low-level evidence for the use of lamotrigine.

8.2.7. Evidence from new RCTs for pharmacological interventions for people with bipolar disorder and coexisting substance misuse

Three relevant RCTs were found that were not included in the published reviews and guidelines (Brown et al., 2009, Kemp et al., 2009, Nejtek et al., 2008).

Brown and colleagues (2009) reported results from a 12-week placebo-controlled double-blind RCT of naltrexone plus CBT in 50 people with bipolar disorder I or II (currently depressed or mixed phase) with coexisting alcohol dependence. All participants continued to take their usual medication throughout the trial. The authors report that although the decline in alcohol consumption was numerically greater in the naltrexone group, there was no significant difference between groups on the primary outcome (percentage of drinking days) or any secondary outcome.

Kemp and colleagues (2009) reported results from a 6-month, double-blind, maintenance trial of lithium monotherapy versus the combination of lithium and divalproex in people with coexisting rapid-cycling bipolar disorder and substance misuse and/or dependence. Of 149 participants enrolled into an open-label acute stabilisation phase, 31 were randomised to the maintenance phase. The authors report no statistically significant advantage in using combination therapy in terms of the primary outcome measure (time to relapse; defined as treatment for a mood disorder) or any secondary outcome.

Nejtek and colleagues (2008) report results from a 20-week, double-blind RCT comparing risperidone with quetiapine in people with bipolar disorder I or II and coexisting stimulant dependence. Of 96 participants who consented and were randomly assigned, 80 attended at least one follow-up visit. The results suggested little difference between study medication in terms of drug use or craving, or mood.

Summary of evidence from new RCTs

When tested in an RCT, there was insufficient evidence to reach a conclusion about the effectiveness of using naltrexone or a combination of lithium with divalproex to improve alcohol-related outcomes in people with bipolar disorder and coexisting alcohol dependence. In terms of antipsychotic medication, evidence from one trial suggests little difference between risperidone and quetiapine, but a lack of placebo control makes it difficult to determine if these medications may be effective.

8.2.8. Clinical evidence for the management of drug interactions or adverse events from pharmacological interventions for people with psychosis and coexisting substance misuse

None of the reviews specifically focuses on interactions between treatment medication and substances of misuse, or on adverse events that are specific to, or especially elevated in, people with psychosis and coexisting substance misuse compared with those with psychosis alone.

Adverse events associated with most psychotropic drugs are well documented. For antipsychotics, these include extrapyramidal symptoms (notably with first-generation drugs), weight gain, and increased glucose and lipid levels, leading to increased risk of diabetes (notably with second-generation drugs). Clozapine, which is used in several of the trials discussed above, tends to be associated with more reports of side effects than other antipsychotic medication. However, as Green and colleagues (2008) state, interactions between psychotropic medications and drugs of misuse are rare. These authors also point out that some newer medication can be sedating, which can be problematic with some drugs of misuse. In addition, Farren and colleagues (2000) reported near syncopal episode following cocaine use in a service user treated with clozapine.

Meanwhile, pharmacological treatments for alcohol misuse, such as naltrexone and acamprosate, are not contraindicated in schizophrenia, and disulfiram also seems to be well tolerated, although it has been suggested that symptoms of psychosis and liver toxicity should be closely monitored (Green et al., 2008).

TIP series 43 (Center for Substance Abuse Treatment, 2005b) covers problems with treatments for opioid dependence, such as methadone and buprenorphine. These drugs can precipitate withdrawal in people also taking drugs to treat HIV infection, such as nelfinavir, efavirenz, and nevirapine. There is a similar problem with these opioid treatments and carbamazepine, phenytoin and phenobarbital.

With antidepressants, some SSRIs that inhibit the isoenzymes that metabolise methadone (particularly, CYP3A4, CYP1A and CYP2D6) could lead to increased serum methadone levels. Fluvoxamine is the most likely to cause excessive serum methadone levels due to inhibition of CYP1A2 and has been implicated in over-sedation and respiratory depression when combined with methadone. Also, there is some indication that methadone increases serum levels of tricyclic antidepressants, so lower doses may be needed. Rifampin, carbamazepine, phenobarbital and some HIV infection medications may induce liver enzymes that alter the transformation of methadone. So clinicians may need to adjust the dose of methadone accordingly.

TIP series 45 (Center for Substance Abuse Treatment, 2006) warns that benzodiazepines, which are known to be addictive, are particularly so in those already addicted to other substances. Because of their reduced side-effect profile and lower risk of dangerous drug interactions, SSRIs may be considered as the antidepressants of choice for those with substance misuse and coexisting psychiatric conditions. However, the potential for different SSRIs to cause drug interactions should be considered in individual cases.

8.2.9. Clinical evidence summary (pharmacological interventions)

There is limited evidence from well conducted RCTs for the relative effectiveness of pharmacological treatments for people with psychosis and coexisting substance misuse, either for psychosis or aimed at improving substance misuse. There is also little data on interactions between drugs given as medication and drugs of misuse. See Table 33 for a summary for each medication.

Table 33. Relevant interventions included in current NICE guidelines and summary of evidence of effectiveness.

Table 33

Relevant interventions included in current NICE guidelines and summary of evidence of effectiveness.

8.2.10. Health economic evidence (pharmacological and physical interventions)

No studies assessing the cost effectiveness of pharmacological and physical interventions for people with psychosis and coexisting substance misuse were identified by the systematic search of the economic literature undertaken for this guideline. Details on the methods used for the systematic search of the economic literature are described in Appendix 9.

8.3. FROM EVIDENCE TO RECOMMENDATIONS

There is little robust evidence to guide the use of specific pharmacological treatments for people with psychosis and coexisting substance misuse in the UK. On the basis of the evidence reviewed, it is not possible to identify specific drugs that should be considered as agents of first choice.

The GDG felt that the use of depot formulations may be expected to increase the opportunity to identify episodes of non-adherence to prescribed treatment. While this may be an important consideration in individual cases there is, overall, insufficient evidence to recommend depot preparations as routine first-line treatment.

Clozapine is frequently cited as having a particular role in this population, although there is no RCT evidence to support this view. In addition, its use may increase the risk of adverse effects, and due to the possibility of a syncopal episode, the GDG felt that particular care should be exercised where the drug of misuse is cocaine.

In general though, as no good-quality evidence was found relating to the modification of interventions recommended for people with a single diagnosis, the GDG concluded that people with psychosis and coexisting substance misuse should be offered the same range of evidence-based interventions recommended for people with a single diagnosis. In addition, the GDG felt it important to make a number of recommendations for good practice concerning the initiation and use of medication.

There was no evidence that addressed the sub-question regarding subgroups of people (see Section 8.2.2 for further information about the sub-question). In addition, the GDG noted that valuable information about the potential benefits of pharmacological and psychosocial interventions for people with psychosis and substance misuse could be obtained from trials of treatments for people with either of the two different types of problems. However, to date, most trials conducted among people with psychosis have excluded those who have coexisting substance misuse and nearly all trials among people with substance misuse have excluded those with coexisting psychosis. In some instances, it may be necessary to exclude people with coexisting problems from future studies. However, very often, this important and prevalent group of service users has been excluded from intervention trials with no clear reason being offered. Therefore, future research should not routinely exclude people with psychosis and coexisting substance misuse.

8.4. RECOMMENDATIONS

8.4.1. Clinical practice recommendations

Secondary care mental health services

Treatment
8.4.1.1.

Before starting treatment for adults and young people with psychosis and coexisting substance misuse, review:

  • the diagnosis of psychosis and of the coexisting substance misuse, especially if either diagnosis has been made during a crisis or emergency presentation and
  • the effectiveness of previous and current treatments and their acceptability to the person; discontinue ineffective treatments.31
8.4.1.2.

Ensure that adults and young people with psychosis and coexisting substance misuse are offered evidence-based treatments for both conditions (see 8.4.1.3 and 8.4.1.4).31

8.4.1.3.

For the treatment of psychosis, see ‘Bipolar disorder: the management of bipolar disorder in adults, children and adolescents, in primary and secondary care’ (NICE, 2006) or the guideline on schizophrenia (NICE, 2009a).31

8.4.1.4.

For the treatment of substance misuse, see:

  • ‘Alcohol-use disorders: diagnosis and clinical management of alcohol-related physical complications’ (NICE, 2010a) and the guideline on alcohol dependence and harmful alcohol use (NICE, 2011) and/or
  • ‘Drug misuse: psychosocial interventions’ (NICE, 2007b) and the guideline on opioid detoxification (NICE, 2007a).31
8.4.1.5.

Use antipsychotics according to the guideline on schizophrenia (NICE, 2009a) or bipolar disorder (NICE, 2006) because there is no evidence for any differential benefit for one antipsychotic over another for people with psychosis and coexisting substance misuse.

8.4.1.6.

Use depot/long-acting injectable antipsychotics according to the guideline on schizophrenia (NICE, 2009a) in managing covert non-adherence with treatment for psychosis and not as a specific treatment for psychosis and coexisting substance misuse.

8.4.1.7.

When prescribing medication for adults and young people with psychosis and coexisting substance misuse:

  • take into account the level and type of substance misuse, especially of alcohol, as this may alter the metabolism of prescribed medication, decrease its effectiveness and/or increase the risk of side effects
  • warn the person about potential interactions between substances of misuse and prescribed medication
  • discuss the problems and potential dangers of using non-prescribed substances and alcohol to counteract the effects or side effects of prescribed medication.

8.4.2. Research recommendations

8.4.2.1.

Are interventions for psychosis or substance misuse clinically and cost effective when compared with standard care for people with psychosis and coexisting substance misuse?31

8.4.2.2.

Is clozapine clinically and cost effective when compared with other pharmacological interventions for people with psychosis and coexisting substance misuse? (For further details see Appendix 12.)

This recommendation also appears in Chapter 7 (Section 7.4) where the psychological/psychosocial data is presented.

Footnotes

31

This recommendation also appears in Chapter 7 (Section 7.4) where the psychological/psychosocial data is presented.

Copyright © 2011, The British Psychological Society & The Royal College of Psychiatrists.

All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Enquiries in this regard should be directed to the British Psychological Society.

Cover of Psychosis with Coexisting Substance Misuse
Psychosis with Coexisting Substance Misuse: Assessment and Management in Adults and Young People.
NICE Clinical Guidelines, No. 120.
National Collaborating Centre for Mental Health (UK).
Leicester (UK): British Psychological Society; 2011.

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