Description of the condition
Weight gain and schizophrenia
The World Health Organization (WHO) defines overweight and obesity as an 'abnormal or excessive fat accumulation that may impair health'. A person who has a body mass index (BMI) of over 25 is overweight and those with a BMI of over 30 are obese (WHO 2013). Weight gain and obesity are common problems for people with schizophrenia, a problem that has been exacerbated more recently with the increased use of second generation antipsychotics, many of which are associated with the risk of weight gain and metabolic disturbance (Allison 1999; Casey 2004; De Hert 2011; Homel 2002). The prevalence of obesity in people with schizophrenia has been reported to be anywhere from 1.5 to 4 times higher than the general population (ADA/APA 2004; Coodin 2001; Gurpegui 2012; Silverstone 1988). For people with schizophrenia, there is a marked increase in standardised mortality ratios for both natural and unnatural causes of death and much of this increment may be attributed to the increased prevalence of coronary heart disease risk (Cohn 2004; Goff 2005; Henderson 2005; Mackin 2005; Saari 2005), and related obesity in this population (Coodin 2001; Daumit 2003; Susce 2005). The significance and recognition of this prevalence and its impact on premature mortality and morbidity has led to the development of consensus statements on its management (ADA/APA 2004; De Nayer 2005). Despite this, evidence from a systematic review suggests that the all-cause standardised mortality ratio between persons with schizophrenia and general population has risen steadily since the 1970s (Saha 2007).
Antipsychotic medication and weight gain in schizophrenia
It is difficult to identify the relative contributions of disease-specific factors such as genetics, the side effects of medications, and lifestyle factors such as diet and physical inactivity on the prevalence of obesity in schizophrenia. In the seminal meta-analysis highlighting atypical-antipsychotic related weight gain, every antipsychotic medication except ziprasidone and molindone were associated with some degree of weight increase after just 10 weeks of treatment (Allison 1999). The effects were greatest with olanzapine and clozapine which increased body weight by approximately 4 to 4.5 kilograms, followed by risperidone (mean weight gain 2 kg). Notably, these data were assembled from chronic populations characterised by many years of exposure to medications and illness-related effects. What has become clearer is that factors related to illness chronicity likely result in an underestimation of the impact of antipsychotics on weight gain, and an overestimation of differences between agents. Collectively, data involving both short-term and long-term evidence comparing olanzapine or risperidone in chronic patients to those experiencing a first episode, demonstrate a three to four times larger magnitude of weight gain in those early on in the illness (Alvarez-Jimenez 2008). Furthermore, no antipsychotic medication appears to be devoid of weight gain risk in patients with little prior antipsychotic exposure. For example, one 12-week cohort study enrolling antipsychotic-naive youth assigned to aripiprazole, quetiapine or olanzapine, demonstrated substantial weight gain not only with olanzapine (average 8.5 kg), but also with risperidone, quetipaine as well as aripiprazole (average 4.4 kg; Correll 2009). Interestingly, data in previously medication unexposed individuals also suggests that agents classified as being metabolically neutral may exhibit a more delayed onset of weight gain, with treatments differing by pattern, and not always the final amount of weight increase (Findling 2010; Perez-Iglesias 2008; Zipursky 2005). Taken together, these emerging data highlight the susceptibility, particularly of first episode patients, to antipsychotic-related weight gain. This highlights the case for early effective strategies to decrease metabolic risk accrual which may occur early in the treatment of the illness.
Mechanisms of weight gain in schizophrenia
To date, there is no consensus on what pharmacological factors may be involved in this weight gain particularly regarding the newer antipsychotics. As reviewed elsewhere (Ananth 2004; Jin 2008; Reynolds 2010), a range of potential weight-inducing mechanisms such as dopaminergic blockage; increased appetite due to the interaction of antipsychotic medication with dopamine, serotonin, and histamine neuronal receptors; increased leptin; and increases in systemic levels of various cytokines and soluble cytokine receptors could be implicated. Whether gender influences antipsychotic-related weight gain susceptibility remains a topic of debate; while there are clinical data suggesting that women may be more susceptible to atypical antipsychotic-associated weight gain (Aichhorn 2007; Gebhardt 2009), others have failed to demonstrate this (Basson 2001; Ratzoni 2002). The weight gain story may be further complicated through genetic and/or epigenetic mechanisms, which may modulate risk. In this regard, among others, dopamine, serotonin, and leptin gene polymorphisms have emerged as genetic candidates for antipsychotic-related cardiometabolic side effects (Correll 2011). In addition, it is important to note that obesity was commonly reported before antipsychotics were widely introduced (Baptista 2002). Compared to the general population, people with schizophrenia also have a poor diet (Dipasquale 2013; McCreadie 1998; Strassnig 2003a) and a physically inactive lifestyle (Brown 1999; Cohn 2004; Daumit 2005) and these lifestyle factors will contribute to weight gain. However, pharmacological intervention strategies may still treat or minimise weight gain associated with poor lifestyle.
Health effects of obesity
Obesity doubles the risk of all-cause mortality, coronary heart disease, stroke and type 2 diabetes, increases the risk of some cancers, musculoskeletal problems and loss of function, and carries negative psychological consequences (DoH 2004). Being an obese or overweight adult is associated with increases in early mortality and large decreases in life expectancy, and these decreases are similar to those seen with smoking (Peeters 2003). The burden of obesity in schizophrenia will be at least comparable in terms of premature mortality and morbidity, and is likely to have important deleterious effects on mortality and health (Fontaine 2001).
Growing evidence in non-psychiatric populations also suggests that obesity can be associated with structural brain changes, brain perfusion changes and cognitive deficits (Jagust 2007; Sellbom 2012), with observations supporting some similarities to those noted in schizophrenia (Reichenberg 2007).The clinical implications of being overweight or obese on cognitive function in addition to the deficits observed in schizophrenia, remains a relatively unexplored area of research. Preliminary evidence has linked cognitive impairment in schizophrenia to metabolic dysfunction (Friedman 2010; Lindenmayer 2012), which might in turn might suggest that interventions to reduce obesity and cardiometabolic risk could have dual salutary benefits on cardiovascular outcomes and illness-related functional disability.
Quality of life is further reduced for people with schizophrenia with a high BMI (Faulkner 2007a; Kurzthaler 2001; Strassnig 2003b) and those gaining weight (Allison 2003). Furthermore, Weiden et al. (Weiden 2004) reported a significant, positive association between obesity, subjective distress from weight gain and medication non-compliance in a sample of people with schizophrenia. People with schizophrenia face the combined challenges of living with the illness, and for many, additional obesity and related illnesses. This combination is a major public health problem (Wirshing 2004) and carries considerable human cost. Recognition of this has led to growing concern with how best to intervene (Birt 2003; Catapana 2004; Green 2000; Le Fevre 2001; Osborn 2001).
Description of the intervention
Treatment of obesity in the general population
The treatment of obesity consists of non-pharmacological and pharmacological interventions. Guidelines state that non-pharmacological interventions should always be used before, and then in conjunction with the latter (Faulkner 2006; Lau 2007; Snow 2005). In terms of non-pharmacological interventions, strategies can combine diet, exercise and psychological/behavioural components, and will be reviewed in a concurrent Cochrane review (Faulkner 2013). Bariatric surgery could be considered as a treatment option for patients with a BMI of 40 kg/m2 or greater, and who have failed an adequate lifestyle modification programme (with or without adjunctive pharmacological therapy) (see Hamoui 2004 in the context of schizophrenia).
Approved anti-obesity medications can be divided into three broad categories (Padwal 2003). The first includes inhibitors of intestinal fat absorption (e.g., orlistat). The second acts to suppress appetite, increase satiety, or increase thermogenesis by modifying central nervous system neurotransmission of norepinephrine, dopamine and serotonin (e.g., sibutramine). A third acts as an inhibitor of the endocannabinoid system (e.g., rimonabant). A Cochrane review (Padwal 2003) of long-term interventions reported that compared with placebo, orlistat reduced weight by 2.9 kg (95% confidence interval (CI) 2.5 to 3.2 kg), sibutramine by 4.2 kg (95% CI 3.6 to 4.7 kg), and rimonabant by 4.7 kg (95% CI 4.1 to 5.3 kg). Patients on active drug therapy were significantly more likely to achieve 5% and 10% weight loss thresholds. Another meta-analysis of anti-obesity agents found that average weight losses compared with placebo were modest and never exceeded 4 kg for any one agent (Haddock 2002). In 2012, the FDA approved two new anti-obesity drugs - lorcaserin which is a selective agonist of 5-hydroxytryptamine receptor 2C (5-HT2C) and phentermine–topiramate controlled-release (CR) (Rueda-Clausen 2013).
Overall, existing evidence suggests that even effective treatments for adult obesity only produce modest weight loss (approximately 2-5 kg) compared to no treatment or usual care. Given such modest weight loss in studies in the adult population, it might be expected that interventions may be difficult for people with schizophrenia given the range of social and cognitive difficulties associated with the illness. Another implication is that the best treatment of obesity is its prevention. However, modest weight loss is a worthwhile outcome of interventions. There is evidence that loss of body weight by as little as 5% to 10% may reduce some of the health risks associated with adult obesity (Wilding 1997). Furthermore, sustained changes in health behaviours as a result of such interventions, e.g., increased levels of physical activity, may reduce risk of mortality and morbidity independent of any weight loss (Wei 1999). Increasing levels of physical activity are also associated with a range of mental health benefits in this population (Faulkner 1999).
How the intervention might work
Pharmacological interventions may operate on a range of potential mechanisms such as suppressing appetite, increasing satiety, or increasing thermogenesis by modifying central nervous system neurotransmission of norepinephrine, dopamine and serotonin.
Why it is important to do this review
We believe there is a sufficient volume of material to split the previous Cochrane review (Faulkner 2007) into separate reviews focusing on behavioural and pharmacological interventions independently. There are at least seven systematic reviews examining either behavioural interventions (Caemmerer 2012; Loh 2006; Werneke 2003), pharmacological interventions (Maayan 2010; Werneke 2002), or both (Faulkner 2003; Faulkner 2007). This Cochrane review updates and extends these recent reviews by focusing on evidence from randomised controlled trials. We are interested in identifying and including all randomised controlled trials of pharmacological agents to reduce or prevent excess weight, regardless of aetiology, in all people with schizophrenia or schizophrenia-like illnesses.