For people with SMD who use tobacco, are pharmacological (including nicotine replacement therapy, bupropion, varenicline) and/or nonpharmacological interventions effective to support tobacco cessation?

Background

People with SMD are twice as likely to use tobacco as the general population (around 61% of people with SMD smoke compared to 33% in the general population), to smoke more on average, and are less likely to quit smoking (Centers for Disease Control and Prevention, 2015). People with SMD have been reported to die 15–20 years earlier on average than people in the general population and this is often due to preventable tobacco-related health conditions for example due to heart disease, cancer, and lung disease, which can all be caused by smoking (Trainor and Leavey, 2017). Nicotine has also been shown to have mood-altering effects that can temporarily mask the negative symptoms of mental disorder, putting people with mental disorder at higher risk for cigarette use and nicotine addiction, and tobacco smoke can interact with and inhibit the effectiveness of certain medications taken for mental health conditions and substance abuse (https://www.cdc.gov/tobacco/disparities/mental-illness-substance-use/index.html).

In regard to interventions that have been recommended in the general population for tobacco cessation, bupropion, varenicline and nicotine replacement therapy (NRT) have all been recommended (e.g. mhGAP Intervention Guide, The National Institute for Health and Care Excellence (NICE)), and NICE has also recommended these pharmacological interventions for tobacco cessation for people with mental disorders (NICE guidelines CG178, CG185, CG91. PH48).

Recommendations and Considerations

In the context of tobacco cessation programmes:

Supporting Evidence and Rationale

Behavioural treatment alone for tobacco smoking cessation has a low abstinence rate in SMD of about 4% which is why combination behavioural treatment and pharmacotherapy is recommended for the population with SMD. At present there is insufficient evidence to indicate whether specialised smoking cessation interventions (vs. standard smoking cessation) and contingent reinforcement i.e. a positive reinforcement technique to increase desired behaviours, in this case tobacco cessation (vs. care as usual) are beneficial for the cessation of smoking in people with SMD. Varenicline’s efficacy has been shown to be the highest of the pharmaco-therapy choices for persons with SMD including when compared to bupropion (Anthenelli et al., 2016). Evidence for efficacy of bupropion comes from several studies included in the Cochrane review such as the EAGLES trial (Tsoi, 2013); evidence for efficacy of nicotine patch vs. placebo can be seen in the EAGLES trial. While there are no known interactions between NRT or varenicline and medicines used for SMD, there are multiple interactions between bupropion and medicines used for SMD, specifically involving elevated seizure risk and enzymatic inhibition/induction. There is some evidence that people taking buproprion, and varenicline may have increased risk of neuropsychiatric symptoms.

Although the evidence specifically for people with SMD is limited with few studies of small size, WHO has comprehensive tools for tobacco cessation in the general population and the GDG agreed that there was no suggestion of inconsistency with the evidence for tobacco cessation interventions in the general population and in people with SMD. The GDG agreed that the benefits of the interventions outweighed the harms while recognising that prescribers should take into account potential interactions between buproprion with psychotropic medications as well as possible contra-indications of the use of bupropion and varenicline in people with SMD. In view of the low quality evidence, the GDG made conditional recommendations for tobacco cessation interventions in people with SMD.

3.2.1. For people with SMD who are overweight or obese, are non-pharmacological and/or pharmacological interventions and/or pharmacological management strategies effective to support weight reduction?

3.2.2. For people with SMD who are at risk of becoming overweight or obese, are non-pharmacological interventions effective to support prevention of weight gain?

Background

Persons with SMD are 50% more likely to be obese than the general population; different studies have reported obesity rates of around 50% amongst women with SMD, and between around 30 to 40% for men with SMD (Dickerson et al., 2006). People with SMD commonly have poor diets, and tend to consume more sugar and saturated fats than the general population. In addition, they are less likely to exercise, have a high prevalence of low physical activity, and spend over 12 hours on average in sedentary activities everyday (Janney, 2013). Also, increased appetite and metabolic effects of some psychotropic medicines can result in weight gain. Being overweight or obese may be associated with higher rates of mortality and is related to other cardiovascular risk outcomes. Interventions in the general population have been described in the Prevention and control of noncommunicable diseases: Guidelines for primary health care in low-resource settings (2012) (http://www.who.int/nmh/publications/phc2012/en/).

Recommendations and Considerations

Supporting Evidence and Rationale

Evidence was extracted from one systematic review with regards to lifestyle interventions for the prevention of weight gain amongst people with SMD who are at risk of becoming overweight/obese, though most of the studies in the review included participants who were already overweight (i.e. BMI over 25) on average. For this reason, the recommendations for the two PICO questions (3.2.1 and 3.2.2) were combined into one when formulating the recommendations.

For non-pharmacological interventions for weight management amongst people with SMD who were already overweight or obese, evidence was extracted from two systematic reviews for short-term lifestyle interventions (Gierisch et al., 2013; Naslund et al., 2017), and from one systematic review for long-term lifestyle interventions (Naslund et al., 2017). With regards to anti-psychotic switching from olanzapine, evidence was extracted from one systematic review. Several systematic reviews have reported on the use of metformin for weight management amongst people with SMD who were already overweight or obese; evidence was considered from two systematic reviews when formulating the recommendations (Mizuno et al., 2014; de Silva et al., 2016).

The systematic reviews revealed very low to low quality evidence from randomized controlled trials for all of these interventions. With regards to all of the included lifestyle interventions, statistically significant effects were reported in favour of all of these. The most consistent evidence was for metformin, as – even though the quality of evidence was very low to low – the six systematic reviews from which evidence was extracted showed positive effects in terms of weight change when compared to placebo. The drug interaction review showed moderate interaction between metformin and some psychotropic medicines (fluoxetine, risperidone and clozapine) for which monitoring of blood glucose and dose adjustment may be needed. Other pharmacological interventions for which statistically significant weight change effects were found in the systematic reviews (Gierisch et al., 2013; Mizuno et al., 2014) were aripiprazole, reboxetine, sibutramine and topiramate, though the evidence base for these are only emerging and results need to be treated with caution. Sibutramine in particular has been withdrawn from use in several countries due to cardiac risks and so cannot be recommended. There is also some evidence in favour of switching from olanzapine to aripiprazole for the management of weight.

The GDG concluded that the behavioural lifestyle interventions recommended in the WHO guidelines for the general population should be followed in people with SMD since there is some evidence from the general population that advising people to give preference to low glycaemic index foods, follow a balanced diet and advice on exercise may have a beneficial effect on glycaemic control. Although the evidence in the general population is of low quality, these simple interventions are deemed as low-cost, feasible and with a negligible risk of adverse events. The GDG made a strong recommendation for non-pharmacological behavioural/lifestyle interventions, as they concluded that the benefits outweighed the harms including benefits of the intervention on other noncommunicable disease outcomes. WHO general population guidelines (WHO PEN) also make a strong recommendation for these interventions in the general population. With regards to pharmacological interventions, the GDG made a strong recommendation for initiating a psychotropic medication with lower propensity for weight gain. The recommendation for switching antipsychotic medication was rated by the GDG as conditional since the quality of the evidence was low and switching antipsychotics because of weight gain should be offset against the risk of relapse of the mental disorder, as well as any potential side effects associated with the newly introduced medication.

For people with SMD and substance (drug and/or alcohol) use disorder, are pharmacological and/or non-pharmacological interventions for substance use disorder effective to support reduction in substance use-related outcomes?

Background

Comorbid substance use disorders are the most prevalent psychiatric conditions associated with SMD. The pooled prevalence for comorbid substance use disorders in SMD has been noted to range up to 42% (for alcohol use disorders), 69% (for cannabis use in schizophrenia), and just over 50% (for affective disorder amongst those on a methadone maintenance programme) (McLoughlin et al., 2014) (Di Florio, Craddock and van den Bree, 2014). The relationship between substance use disorders and SMD is likely bidirectional and their co-occurrence has been associated with a number of adverse outcomes, including: relapse of the mental disorder and longer hospital admissions, more positive symptoms in people with schizophrenia, and an increased risk of fatal and non-fatal overdoses and suicide.

There have been several Cochrane systematic reviews conducted on interventions for people with substance use disorder (in the general population), which have provided evidence on the effectiveness of the following interventions: Psychosocial interventions, such as combined motivational enhancement therapy (MET) and cognitive behaviour therapy (CBT) with abstinence-based incentives in cannabis use disorder (Gates et al., 2016); methadone in people with opioid dependence (Mattick et al., 2014). WHO mhGAP Intervention Guide provides recommendations for the management of substance use disorders. We have considered these pharmacological and/or non-pharmacological interventions for people with co-morbid SMD and substance use disorder.

Recommendations and Considerations

Supporting Evidence and Rationale

Evidence of pharmacological interventions for mental disorders comorbid with substance use disorders was extracted from two systematic reviews which focused on antipsychotic prescribing (Wilson and Bhattacharyya, 2016; Temmingh et al., 2018) and one systematic review which focused on antidepressant prescribing in depression comorbid with alcohol use (Agabio et al., 2018). Evidence on psychological interventions for these populations were extracted from two systematic reviews (Hunt et al., 2014; Boniface, 2018).

Detailed reviews revealed very low to low quality evidence from randomized controlled trials, which did not support the superiority of any of the pharmacological interventions against each other. Potential side effects from pharmacological therapies were noted as moderate and will need to be considered when determining the choice of pharmacotherapy. Methadone and buprenorphine, medicines used for treatment of substance use disorders, have major interactions with commonly prescribed psychotropic medications including increased risk of for CNS depression (sedation, confusion, decreased respiratory drive), QT prolongation on ECG, and serotonergic effects (confusion, neuromuscular excitability, and dysautonomia) (Annex 6).

There was no evidence to support superiority of any of the psychosocial interventions against each other in populations with comorbid SMD and substance use disorder. None of the reviewed trials for psychosocial therapies have been conducted in LMIC settings. The absence of high quality evidence does not mean that these treatments do not work but that at present the evidence is of insufficient quality to support the use of one form of non-pharmacological or psychosocial intervention over another in these special populations. One reason for the lack of evidence may be that people with comorbidities are commonly excluded from research (Dennis et al., 2015).

The resource requirements for offering interventions (both pharmacological and psychological) are currently unclear with only one study identified which estimated the cost of providing CBT plus motivational interviewing compared to care-as-usual in a well-resourced setting (USA).

There is good indirect evidence that certain interventions work for alcohol and substance use disorders in the general population, which have been detailed in the current mhGAP 2.0 guidelines, as well as in other guidelines such as those for Opioid Agonist Maintenance Treatment (OAMT) for relapse prevention. The GDG agreed that although the quality of evidence was very low for most psychological interventions in populations with co-morbid SMD and substance use disorders, the psychological interventions which are currently recommended in the MHGAP 2.0 guidelines for the general population (in particular- CBT plus motivational interviewing, motivational interviewing and contingency management) may also be effective in people with SMD. Furthermore, undesirable side effects from nonpharmacological treatments were noted to be trivial. Noting the risk of drug interactions between medicines used for treatment of opioid use disorders and SMD, the GDG agreed that the interactions are outweighed by the risk of other harms of untreated opioid use disorders in people with SMD and rather than withholding opioid replacement therapy, cautious medication management is advised.

Given the low quality of evidence and that all the evidence identified for the treatment of substance use disorders comorbid with SMD came from well-resourced/high-income settings, the GDG made conditional recommendations.

3.4.1. For people with SMD and pre-existing cardiovascular disease, what pharmacological and/or non-pharmacological interventions are effective to support reduction of cardiovascular disease outcomes?

3.4.2. For people with SMD and cardiovascular risk factors (a. high blood pressure; b. high lipid levels), what pharmacological and/or non-pharmacological interventions are effective to support reduction of cardiovascular risk factors?

Background

Cardiovascular disease is considered as one of the main potentially avoidable contributors to excess mortality amongst people with SMD. Overall, people with SMD have an approximately 1.5 to 3 times higher risk of cardiovascular morbidity and mortality compared to the general population (Laursen, 2011). There is a complex interplay between several non-communicable diseases, such as diabetes, hypertension and cardiovascular disease, and the presence of SMD. People with SMD are more likely to engage in lifestyle behaviours that contribute to increased cardiovascular risk including tobacco use, harmful use of alcohol, unhealthy diets, and physical inactivity. The iatrogenic effects of medicines used to treat SMDs are linked with increased risk of cardiometabolic diseases. The use of antipsychotic medications has been associated with obesity, insulin resistance, diabetes, myocardial infarctions, atrial fibrillation, stroke, and death.

Pharmacological and non-pharmacological interventions for the general population have been described in the Package of Essential Noncommunicable (PEN) Disease Interventions for Primary Health Care in Low-Resource Settings (WHO, 2010).

Recommendations and Considerations

Supporting Evidence and Rationale

For people with SMD and pre-existing cardiovascular disease, two systematic reviews were included that reported on anti-depressants as compared to care as usual (Maslej et al., 2017; Nieuwsma et al., 2017); one systematic review was included that reported on psychosocial interventions (Ski et al., 2016); and one systematic review each for exercise therapy (Verschueren et al., 2018) and collaborative care (Tully and Baumeister, 2015).

For people with SMD and cardiovascular risk (e.g. high blood pressure or cholesterol), regarding the use of pharmacological interventions, two systematic reviews were used to extract evidence on the use of metformin versus placebo (Mizuno et al., 2014; de Silva et al., 2016), and two on the use of aripiprazole versus placebo (Gierisch et al, 2013; Mizuno et al, 2014), in the management of either blood pressure or cholesterol, or the frequency of adverse effects. Two systematic reviews were included that reported on nonpharmacological interventions as compared to care as usual (Gierisch et al, 2013; Teasdale et al, 2017). None of these systematic reviews included cardiovascular disease incidence as an outcome which is one of the critical outcomes for this PICO question. All of the systematic reviews and meta-analyses for comorbid cardiovascular disease focused on interventions for people with depression. No reviews assessed interventions in populations with other SMD (e.g. schizophrenia, bipolar disorder) with comorbid cardiovascular disease. The evidence and recommendations are therefore indirect for populations with SMD and comorbid cardiovascular disease.

No sufficiently high-quality systematic reviews could be identified that reported on either pharmacological or nonpharmacological interventions compared to another treatment, either for SMD and pre-existing cardiovascular disease or cardiovascular risk.

The systematic reviews revealed either very low or low quality evidence from randomized controlled trials for all of these interventions; the only exception to this was for psychosocial interventions for people with SMD and preexisting cardiovascular disease, for which some of the evidence was graded as moderate quality. The only included intervention for which statistically significant effects were reported for people with SMD and pre-existing cardiovascular disease was collaborative care, which may show a relative and absolute reduction in major adverse cardiac events in the short to medium-term (less than 12 months), though it is less clear whether this is the case in the longer-term (over 12 months).

Major drug-drug interactions were found between several psychotropic medications and commonly prescribed medications for cardiac conditions, hypertension and cholesterol control. Some examples of these are: the risk of hypotension or beta-blocker toxicity (including hypotension, bradycardia, and heart block/prolonged PR interval) with beta blockers and the risk of hypotension with diuretics (Annex 6).

Given the evidence was limited for people with SMD, the GDG used evidence from general populations and thought it to be applicable because they would benefit people with SMD too. However, the GDG agreed that it is important to exercise caution in the initiation of psychotropic medication due to the heightened risk of cardiovascular disease and potential drug interactions. There is currently insufficient evidence for behvioural lifestyle interventions for people with SMD and cardiovascular disease and risk, conditional recommendations have been made for these interventions as the GDG agreed that there the benefits outweighed the risks including benefits of the intervention on other non-communicable disease outcomes.

For people with SMD and diabetes mellitus, what pharmacological and/or nonpharmacological interventions are effective to improve glycaemic control?

Background

There is high co-morbidity between SMD and diabetes mellitus. People with SMD are at an increased risk of diabetes (around double for schizophrenia and bipolar disorder, and 1.5 times the risk for depression), and people with diabetes are at a heightened risk of SMD (around double for depression), with a higher risk in low- and middle-income countries (Vancampfort et al., 2016). However, this often goes undetected, and people with comorbid SMD and diabetes have an increased risk of mortality. There is an association with diabetes with some anti-psychotics, anti-depressants and lithium, as well as with health-related behaviours (such as physical activity and diet), other environmental factors, and gender (elevated risk in women).

This section covers evidence regarding pharmacological and/or non-pharmacological interventions for people with SMD and diabetes mellitus. The inclusion of interventions was guided by the research evidence available for people with diabetes and SMD.

Recommendations and Considerations

Supporting Evidence and Rationale

With regards to pharmacological interventions for people with SMD and diabetes, one (the same) systematic review was used to extract evidence for diabetes medication, weight loss medications, anti-psychotic switching, and weight loss and diabetes medications combined.

The systematic reviews revealed very low quality evidence from randomized controlled trials for all of these interventions. There was some evidence to suggest anti-psychotic switching had beneficial effects. The drug-drug interaction review showed moderate interactions between some psychotropic medicines and anti-diabetic medicines (increased or decreased potency of the anti-diabetic medicine) that requires blood glucose monitoring and dose adjustment of anti-diabetic medicines.

With regards to non-pharmacological interventions, evidence from one systematic review each was considered for behavioural interventions (Taylor et al., 2017) and cognitive behaviour therapy (Li et al., 2017), and one systematic review for self-management interventions (McBain et al., 2016). There was some evidence that cognitive behaviour therapy for treatment of depression shows positive effects on blood glucose amongst people with diabetes and comorbid depression (probably by eliminating the negative effects of depression on diabetes). There is insufficient evidence available for the management of diabetes amongst people with SMD for all other reviewed interventions.

Since all of the evidence was rated as very low in quality, and there was insufficient evidence available for most of the reviewed interventions, the GDG concluded that the WHO guidelines for the general population in low-resource settings should be followed as a first step as the underlying pathophysiological mechanisms would be similar in people with SMD. Nevertheless, the GDG made additional best practice statements for the initiation of psychotropic medication and potential drug-drug interactions, to counter the risks of taking these medications. A strong recommendation has also been made for behavioural lifestyle interventions despite very low quality evidence as the GDG agreed that the benefits outweighed the harms and as there is a strong recommendation for this by WHO for the general population (WHO PEN). The GDG also concluded that there are benefits of the intervention on other noncommunicable disease outcomes. The GDG made a conditional recommendation for cognitive behaviour therapy because of very low quality evidence and the possible lack of generalizability to all people with SMD.

For people with SMD and HIV/AIDS, what pharmacological (i.e. antiretroviral drugs, psychopharmacology) and nonpharmacological interventions are effective to support reduction in HIV-related outcomes?

Background

The association between mental health disorders and HIV/AIDS is complex and bi-directional - they frequently co-occur: mental disorders can be precursors to HIV/AIDS, consequences of HIV infection, or the result of interactive effects. They also have similar consequences in terms of their public health, social, and economic impacts.

International evidence has found that populations with SMD have higher rates of HIV infection. Among persons with SMD, the median prevalence of HIV in the US is 1.8 % (range: 0.1%–5.0%) with a high rate among inpatient populations (3.8%), whereas the overall US adult population estimated prevalence of HIV is 0.5% (Janssen et al., 2015). HIV rates may be even higher in certain vulnerable populations, such as those who have SMD and are also homeless (Susser, Valencia and Conover, 1993). People with SMD and HIV experience a complex set of medical, psychological and social complications that need to be tackled through integrated care. The interventions included pharmacological interventions for SMD and HIV as well as non-pharmacological interventions such as psychosocial support.

Recommendations and Considerations

[List of abbreviations: DTG: dolutegravir; EFV efavirenz]

Supporting Evidence and Rationale

There is limited RCT evidence for pharmacological treatment in people with SMD and HIV/AIDS. One systematic review that was included in the evidence profile assessed the efficacy of antidepressant therapy for treatment of depression in people with HIV/AIDS (Eshun-Wilson, 2018). The evidence was of very low quality and the results inconclusive. The drug interaction review reveals multiple interactions between efavirenz and psychotropic medicines, specifically involving the risk of QT interval prolongation, CNS depression and /or enzyme induction (Annex 6). No reviews were identified for non-pharmacological treatments including adherence management specifically in people with SMD and comorbid HIV/AIDS.

These recommendations are based on indirect evidence of HIV treatment in the general population that are provided in existing WHO guidelines that strongly recommend ARV and adherence management to support ARV adherence in people with HIV/AIDS with or without SMD. The GDG concluded that the balance between desirable and undesirable effects favor the intervention leading to strong recommendations while noting the need to consider drug interactions. They also concluded that there was no important uncertainty about or variability in how much people value the main outcomes and that the interventions would increase health equity. The GDG agreed that people with SMD would need additional support for adherence as the presence of SMD and its associated symptoms can have a detrimental impact on adherence to ARV and progression of AIDS.

For people with SMD and infectious diseases (Tuberculosis, Hepatitis B/C), what pharmacological and nonpharmacological (social, psychological) interventions are effective for treatment of infectious diseases (i.e. tuberculosis, hepatitis B, hepatitis C)?

Background

People with SMD are at greater risk than the general population for exposure to infectious diseases, including tuberculosis (TB) and chronic hepatitis (Rosenberg et al., 2010). Infectious diseases appear to contribute to an increased risk of death in persons with SMD, with a 4- to 8-fold risk of death due to infection compared to the general population.

Tuberculosis and SMD share common risk factors including homelessness, HIV positive serology, alcohol/substance abuse and migrant status leading to frequent co-morbidity. There are widespread discriminatory attitudes and behaviours towards patients with TB and SMD in the community which affects health-related quality of life. In people with SMD and TB, there may be a negative impact on health behaviours such as medication adherence leading to greater morbidity, mortality, amplification of drug-resistance, transmission and all the associated social costs of these outcomes (Alene et al., 2018).

The WHO End TB strategy calls to provide TB care through an integrated approach in collaboration with other public health programmes including mental health services such as tailoring TB care delivery models to the specific needs of populations with mental health problems.

There is also a high prevalence of hepatitis B and C in people with SMD. There is evidence that hepatitis C infection itself may be directly associated with psychiatric symptoms, independent of pre-existing psychiatric disorders. Stigmatization and the fact that people have to cope with a chronic infectious disorder increase the risk of depression. As is seen with TB, mental health problems during antiviral treatment have a strong impact on quality of life, may reduce treatment compliance and are risk factors for treatment failure.

For people with SMD and TB or hepatitis B/C, pharmacological and non-pharmacological interventions need to be considered as in the general population.

Recommendations and Considerations

Supporting Evidence and Rationale

No reviews were identified for interventions in people with SMD and comorbid TB, Hepatitis B/C. A recent systematic review reported that programmes that included educational, psychological, and/or material support were associated with better TB outcomes, and can now be considered best practice (Alipanah et al., 2018). Some trial evidence shows effectiveness of treatment of pulmonary TB in people with SMD (Mishin et al 2008) and of a brief intervention to deliver best practice services for infectious diseases to people with mental disorders in increasing participation and acceptance of core services, including testing for hepatitis B/C; immunization for hepatitis A and B; increased hepatitis knowledge reduction of substance use (Rosenberg et al., 2010).

The drug-drug interaction review showed that major interactions exist between medicines used for TB, hepatitis B/C and psychotropic medicines (Annex 6). These require close clinical monitoring and dose adjustments and in some cases use of alternate psychotropic medicines with less potential for interaction.

These recommendations are based on indirect evidence of TB/Hepatitis treatment in the general population that are provided in existing WHO guidelines as the GDG concluded that the same pathophysiological mechanisms for these conditions would apply to people with SMD. The GDG provided strong recommendations as they agreed that the benefits of the interventions outweighed the harms while noting the need to consider drug interactions. The GDG also agreed that there was no important uncertainty about or variability in how much people value the main outcomes and that the interventions would increase health equity. The GDG agreed that people with SMD would need additional support for adherence to TB treatments and provided a strong recommendation for this intervention drawing from existing general population guidelines.