Metabolic Dysregulation and Weight Gain

15


Metabolic Dysregulation and Weight Gain


Dyslipidemias


General Recommendations


Patients who develop dyslipidemias while taking SGAs or some antidepressants may warrant cotherapy with lipid-lowering agents prescribed in conjunction with the primary care physician or cardiologist. Decisions must be made on a case-by-case basis about the relative merits of switching from an existing SGA to an alternative agent with potentially lesser risk for lipid dysregulation versus treating abnormal lipids with statins, depending on assessment of atherosclerotic cardiac disease risk versus the magnitude of benefit with an existing psychotropic agent, and the likelihood that a replacement drug would yield at least comparable efficacy. Melatonin agonists have shown preliminary evidence of lowering total serum cholesterol levels among atypical antipsychotic recipients.




Abnormal elevations of total serum cholesterol and serum triglycerides have been linked directly with most SGAs and represent a key aspect of metabolic syndrome. The mechanisms by which SGAs may cause dyslipidemias, other than as a secondary consequence of obesity caused by increased caloric intake, remain elusive. In addition, abdominal obesity and hypercholesterolemia have been associated with some SSRIs—notably, sertraline, fluoxetine, and fluvoxamine—but not with citalopram, whereas weight gain with paroxetine appears to be independent of new-onset dyslipidemias (Raeder et al. 2006).


The CATIE study (Lieberman et al. 2005) in chronic schizophrenia found the greatest rises in serum cholesterol with olanzapine and the greatest reductions from baseline with ziprasidone (Table 15–1).


Several studies have reported a lower incidence of hypertriglyceridemia and elevations in serum leptin levels in patients with schizophrenia during treatment with quetiapine, and a minimal change during risperidone therapy, as compared with during therapy with clozapine or olanzapine (Atmaca et al. 2003).


Hypertriglyceridemia is generally thought to pose a less direct atherosclerotic risk than other lipid parameters (e.g., high LDL cholesterol or low HDL cholesterol), and it carries an increased risk mainly for pancreatitis or cholelithiasis. Hypertriglyceridemia also has been identified as a risk factor for the development of hyperglycemia and eventual non-insulin-dependent diabetes mellitus (NIDDM) (Tirosh et al. 2008), although hypertriglyceridemia is thought to be a covariate (rather than a cause) of NIDDM that becomes evident before the emergence of frank diabetes. Nevertheless, moderate or greater hypertriglyceridemia alters lipoprotein metabolism and still represents an independent risk factor for coronary artery disease, especially in women (McBride 2007). By convention, normal triglycerides are generally defined as <150 mg/dL, borderline-high triglycerides as 150–199 mg/dL, high triglycerides as 200–499 mg/dL, and very high triglycerides as ≥ 500 mg/dL.


The components of metabolic syndrome, summarized in Table 15–2, collectively increase the risk for coronary heart disease, regardless of LDL cholesterol levels. Metabolic syndrome is defined by the presence of three or more of these risk factors. To further aid medication risk-benefit decisions, clinicians should calculate a given patient’s 10-year risk for ASCVD using the so-called Pooled Cohort Equations (see www.cvriskcalculator.com/) based on age, gender, race, total cholesterol, HDL cholesterol, diabetes status, smoking status, and blood pressure. Pooled Cohort Equations have come to replace the FRS, which does not account for diabetes or race. The so-called Reynolds risk score is a similar measure that adds C-reactive protein level and parental history of premature MI to the calculated risk score. Current guidelines from the American College of Cardiology and the American Heart Association (ACC/AHA; Stone et al. 2014) advise physicians to base their decisions about statin initiation (and dosing intensity) according to Pooled Cohort Equation scores when 10-year risk for an MI equals or exceeds 7.5% (and in some cases even ≥5%). Previously, decisions about initiating statins were driven more narrowly by LDL-cholesterol scores per se rather than by global ASCVD risk.


































































TABLE 15–1.Changes in lipid parameters during U.S. Food and Drug Administration registration trials or randomized studies of second-generation antipsychotics


Agent


Changes in total cholesterol


Changes in serum triglycerides


Aripiprazole


Randomized trials in schizophrenia; median change in total cholesterol across five acute placebo-controlled studies (n=860)=+1.0 mg/dL (Marder et al. 2003). LDL declined by 5.1 mg/dL over 26 weeks (Pigott et al. 2003). Acute or long-term schizophrenia FDA trials: no differences from placebo.


In 6-week adjunctive trials for major depression: 5% increase from baseline. In 26-week randomized trial in schizophrenia: –37.2 mg/dL (Pigott et al. 2003).


Asenapine


Acute bipolar or schizophrenia trials: mean changes from +1.1 to +0.4 mg/dL; 1-year open extension trial in schizophrenia: –6.0 mg/dL.


Acute bipolar or schizophrenia trials: mean changes from –3.5 to +3.8 mg/dL; 1-year open extension trial in schizophrenia: –9.8 mg/dL.


Brexpiprazole


Major depression adjunctive therapy and schizophrenia acute trials: no differences from placebo; in long-term open-label phases, 9% of major depression and 6% of schizophrenia patients had categorical shifts in total cholesterol from “normal” to “high.”


Categorical shifts from “normal” to “high” occurred in 5%–13% of major depression patients across dosages over 6 weeks during acute adjunctive therapy and up to 17% of patients during long-term open-label treatment; and in 8%–10% of schizophrenia patients during 6-week acute trials as well as 13% during long-term open label treatment.


Cariprazine


Acute schizophrenia and bipolar mania trials: no significant differences from placebo in categorical shifts from “normal” to “high.”


Acute schizophrenia and bipolar mania trials: no significant differences from placebo in categorical shifts from “normal” to “high.”


Iloperidone


Acute schizophrenia trials: net 0 mg/dL change (Weiden et al. 2008).


–26.5 mg/dL (Weiden et al. 2008).


Lurasidone


Manufacturer’s short-term trials in schizophrenia: across dosages, –8.2 mg/dL.


Manufacturer’s longer-term studies: at 24 weeks, –4.2 mg/dL; at 36 weeks, –1.9 mg/dL; at 52 weeks: –3.6 mg/dL.


Monotherapy in bipolar depression: +1.2 mg/dL (dosing 20–60 mg/day) or –4.6 mg/dL (dosing 80–120 mg/day) over 6 weeks (Loebel et al. 2014a).


Adjunctive therapy in bipolar depression: –3.0 mg/dL over 6 weeks (Loebel et al. 2014b).


Manufacturer’s collective short-term trials in schizophrenia: across dosages, –9.3 mg/dL.


Manufacturer’s longer-term studies: at 24 weeks, –13.6 mg/dL; at 36 weeks, –3.5 mg/dL; at 52 weeks, –6.5 mg/dL.


Monotherapy in bipolar depression: +5.6 mg/dL (dosing 20–60 mg/day) or +0.4 mg/dL (dosing 80–120 mg/day) over 6 weeks (Loebel et al. 2014a).


Adjunctive therapy in bipolar depression: +9.0 mg/dL over 6 weeks (Loebel et al. 2014b).


Olanzapine


+21.1 mg/dL over 24 weeks (Newcomer et al. 2009).


+9.4±2.4 mg/dL in CATIE (Lieberman et al. 2005).


+30.9 mg/dL over 24 weeks (Newcomer et al. 2009).


+40.5±8.9 mg/dL in CATIE (Lieberman et al. 2005).


Paliperidone


<0.1 mg/dL across three 6-week trials in schizophrenia (Meltzer et al. 2008).


<0.1 mg/dL across three 6-week trials in schizophrenia (Meltzer et al. 2008).


Pimavanserin


Not reported


Not reported


Quetiapine


+13.1 mg/dL over 24 weeks (Newcomer et al. 2009).


+6.6±2.4 mg/dL in CATIE (Lieberman et al. 2005).


+21.2±9.2 mg/dL in CATIE (Lieberman et al. 2005).


Risperidone


–1.3±2.4 mg/dL in CATIE (Lieberman et al. 2005).


–2.4±9.1 mg/dL in CATIE (Lieberman et al. 2005).


Ziprasidone


–8.2±3.2 mg/dL in CATIE (Lieberman et al. 2005); median change of –14.5 mg/dL from baseline in acute industry trials for psychosis.


–16.5±12.2 mg/dL in CATIE (Lieberman et al. 2005); median change of –37.0 mg/dL from baseline in acute industry trials for psychosis.


Note. CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness; FDA=U.S. Food and Drug Administration; LDL=low-density lipoprotein.



Longitudinal studies indicate that risk factors for the development of diabetes or prediabetes during treatment with an SGA include HDL concentrations <28 mg/dL, age >58 if HDL is ≥28 mg/dL, serum glucose levels ≥92 mg/dL, posttreatment rises in triglyceride values ≥145 mg/dL (for diabetes) or ≥59 mg/dL (for prediabetes), and rapid weight gain (within 2 weeks) of ≥6.1 kg in conjunction with a triglyceride increase of ≥145 mg/dL (Reaven et al. 2009). On the basis of the nontrivial risks for coronary heart disease caused by iatrogenic dyslipidemias, many psychiatrists often favor replacing an SGA that is suspected of causing dyslipidemia or metabolic dysregulation with a different SGA of presumed lower risk, or possibly even an FGA, regardless of possible differences in psychotropic efficacy. However, the risk-benefit analysis of this proposition is not always straightforward. A significant dyslipidemia certainly presents a compelling rationale for considering a switch to alternative agents. The main uncertainties in doing so involve whether the substituted new agent indeed possesses more benign metabolic effects for a given patient, and has at least comparable efficacy to sustain the benefit of a previous agent. Unless there are no viable alternatives to a known effective SGA with substantial cardiovascular adverse effects, patients with significant cardiovascular risk factors generally should receive psychotropic agents with minimal metabolic or cardiovascular adverse effects (e.g., aripiprazole, ziprasidone, asenapine, iloperidone, lurasidone, or FGAs with minimal glycemic or lipid-altering effects).


On the other hand, circumstances may arise in which the benefit of a particular agent is so dramatic and unique (e.g., in the case of patients with schizophrenia in whom clozapine exerts unequivocally greater efficacy than other antipsychotics) that active treatment of an iatrogenic dyslipidemia may be advisable. In the case of clozapine, metabolic dysregulation has been linked with serum norclozapine but not serum clozapine levels—a finding that led to a preliminary randomized study of adjunctive fluvoxamine (50 mg/day) or placebo added to clozapine (≤250 mg/day with fluvoxamine or ≤600 mg/day with placebo), yielding greater reductions in weight, serum glucose, and triglycerides (but not cholesterol) with fluvoxamine cotherapy (Lu et al. 2004). Such a strategy demands careful monitoring of other adverse effects (e.g., lowered seizure threshold, anticholinergic effects), signs of toxicity, and clozapine levels, due to the potential for marked increases in serum clozapine levels.













































TABLE 15–2.Risk determinants for metabolic syndromea


Risk factor


Defining level


Central obesityb


Waist circumference


 Men


≥90 cm in South Asians, Chinese, or Japanese; ≥94 cm in Europids


 Women


≥80 cm


plus any two of the following factors:


Triglycerides


≥150 mg/dL


HDL cholesterol


 


 Men


<40 mg/dL


 Women


<50 mg/dL


Blood pressure


≥130/≥85 mm Hg


Fasting glucose


≥100 mg/dL


Note. HDL=high-density lipoprotein.


aBased on the International Diabetes Foundation Consensus Worldwide Definition of the Metabolic Syndrome. Brussels, Belgium, IDF Communications, 2006, pp. 1–24.


bCan be assumed if BMI>30 kg/m2.


To date, surprisingly little study has been done on efforts to treat hypercholesterolemia or hypertriglyceridemia using lipid-lowering drugs in patients who have developed dyslipidemias secondary to SGA therapy. Landry et al. (2008) retrospectively examined outcomes in 18 clozapine-treated schizophrenia patients with hyperlipidemia who were followed for a mean of 4.4 years while taking lipid-lowering medications (either pravastatin, atorvastatin, fenofibrate, gemfibrozil, or lovastatin). Mean triglyceride and total cholesterol levels declined significantly from baseline. Similarly, a 28-day open trial of omega-3 fatty acids (~10 g/day of fish oil, containing 1.8 g/day of eicosapentaenoic acid and 1.2 g/day of docosahexaenoic acid) among 28 clozapine recipients was associated with a significant (22%) reduction in LDL and a 22% reduction in triglycerides (Cantiano et al. 2006). These dosages are higher than the more customary 2–4 g/day of omega-3 fatty acids sometimes recommended by primary care physicians for hyperlipidemia. Notably, however, the clinical end-point data do not robustly demonstrate the efficacy of omega-3 fatty acids to reduce the risk for coronary heart disease, and they are not considered first-line therapies for diagnosed hyperlipidemia.


The first level of intervention for weight gain and dyslipidemias continues to be lifestyle modification (i.e., aerobic exercise lasting about 4 hours/week, dietary changes that include the minimization of simple sugars such as fructose, and elimination of smoking). The 2013 ACC/AHA guideline (Stone et al. 2014) advises that statin therapy may benefit patients with the following characteristics:




  • Clinical presence of atherosclerotic cardiovascular disease (ASCVD)



  • Low-density lipoprotein cholesterol (LDL-C)>190 mg/dL



  • Diabetic patients ages 40–75 with LDL-C of 70–189 mg/dL and without signs of clinical ASCVD



  • Nondiabetic patients ages 40–75 with an estimated 10-year risk (e.g., Pooled Cohort Equations score)>7.5%


Statins vary in the extent to which they reduce LDL, and the magnitude of desired LDL reduction may depend on the presence and extent of other cardiac risk factors. Dosages may vary depending on the presence of additional factors (e.g., comorbid hypothyroidism), and all statins may require monitoring of liver enzymes and the clinical emergence of myalgias (which could reflect rhabdomyolysis).


Psychiatrists need to be aware of the risks and benefits of psychotropic drugs that may cause dyslipidemias, weight gain, or glycemic dysregulation, and they should collaborate proactively with primary care physicians when the observed psychiatric benefits are substantial and not easily re-created by an alternative medication. To that end, psychiatrists should be conversant with the use of available lipid-lowering agents, their specific indications (e.g., including dosing variations and the extent to which statins can reduce triglycerides as well as LDL), and relative safety profiles (Table 15–3). It is important to note that the 2014 ACC/AHA guideline favors statins (and their optimized dosages when necessary) as first-line lipid-lowering strategies rather than other cholesterol-lowering agents such as fibrates (e.g., gemfibrozil, clofibrate) or niacin, since controlled data are lacking for the use of nonstatins in lowering ASCVD mortality.


Additionally, preliminary controlled trial data suggest a possible lipid-lowering benefit from daily melatonin 3 mg/day or the melatonin agonist ramelteon 8 mg/day (Wang et al. 2016). Use of adjunctive lisdexamfetamine for bipolar depression also has been associated with reductions in total cholesterol, fasting LDL, and triglycerides (McElroy et al. 2015). Use of these agents, when psychiatrically appropriate, may thus have an added benefit of at least partly countering hypercholesterolemia, although neither would be a strategy aimed to reduce ASCVD and its associated risk for mortality.



























































































TABLE 15–3.Lipid-lowering medications


Agent


Indication or usual clinical profile


Dosing range, mg/day


Common adverse effects


Laboratory monitoring


Statins (HMG-CoA reductase inhibitors)


First-line therapies, usually recommended for LDL ≥ 190 mg/dL or LDL≥160 mg/dL and positive family history of premature coronary artery disease or ≥2 coronary risk factors present in adolescents.



Myalgias; rare risk for rhabdomyolysis or diabetes mellitus


Serum ALT monitoring is recommended at baseline and periodically thereafter.


Atorvastatin



10–80




Fluvastatin



20–80




Lovastatin



20–80




Pravastatin



20–40




Rosuvastatin


The most potent statin; FDA approved for men > age 50 or women > age 60 with normal LDL but elevated CRP and one other risk factor for coronary artery disease (e.g., smoking, low HDL, family history).


5–40




Simvastatin


Lowers LDL by >30%; appropriate in diabetes or known heart disease as well as primary or secondary prevention indications.


20–80




Omega-3 fatty acids


Reduce triglycerides (FDA approved for triglycerides >500 mg/dL) and may increase HDL; have not been shown to reduce LDL or to lower risk for myocardial infarction or cardiovascular mortality.


≥1,000


Fishy aftertaste, GI upset, eructation, potential risk for increased bleeding time


None


Lovazaa


Hypertriglyceridemia.




None


Combination regimens



Atorvastatin/amlodipine


Combination treatment for hypercholesterolemia and hypertension.


2.5/10–10/80


Constipation, diarrhea, nausea, headaches, dizziness, flushing, fatigue, weakness


As per statins


Ezetimibe/simvastatin


Decreases total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and non-HDL cholesterol; increases HDL.


10/10–10/80


Headache, arthralgias, GI upset


As per statins


Note. ALT=alanine aminotransferase; CRP=C-reactive protein; ER=extended release; FDA=U.S. Food and Drug Administration; GI=gastrointestinal; HDL=high-density lipoprotein; HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A; LDL=low-density lipoprotein; VLDL=very-low-density lipoprotein.


aA 1-g capsule contains 47% eicosapentaenoic acid and 38% docosahexaenoic acid.



Glycemic Dysregulation and Diabetes Mellitus


General Recommendations


Patients taking SGAs should have fasting blood glucose assessments before or upon the initiation of therapy, after 12 weeks of treatment, and annually thereafter while continuing an SGA. Measurement of hemoglobin A1C also may be informative regarding patterns of hyperglycemia and assessment of diabetes or risk for the development of diabetes. The introduction of oral hypoglycemic agents such as metformin may be useful to counter weight gain and possible insulin resistance caused by psychotropic agents. Progression of insulin resistance or glycemic dysregulation may warrant discontinuation of a presumptive causal agent, particularly in the setting of other risk factors for coronary artery disease—unless a particular psychiatric agent appears to exert a unique benefit that outweighs metabolic risk, in which case active management of glycemic dysregulation to permit continued pharmacotherapy may be warranted.



Impaired glucose homeostasis is a known risk with SGAs and a number of other psychotropic compounds. Pharmaceutical manufacturers are quick to point out that individuals with serious mental illnesses such as bipolar disorder and schizophrenia have an inherently increased risk for the eventual development of diabetes and cardiovascular disease, independent of pharmacotherapies. Such observations, however, provide clinicians with little perspective on the independent contributions of specific psychotropic agents to a given patient’s cumulative metabolic risk.


Above and beyond the increased vulnerability to diabetes caused by bipolar disorder or schizophrenia, SGAs can to varying degrees disrupt glucose metabolism by causing insulin resistance. For example, short-term (8-day) exposure of olanzapine in healthy men has been shown to impair insulin-mediated glucose metabolism, as well as to impede insulin-induced declines of free fatty acids and triglycerides (Vidarsdottir et al. 2010)—a finding at variance with earlier industry-sponsored reports that claimed to find no adverse effects on glucose disposal rate or insulin sensitivity among healthy volunteers after 3 weeks of exposure to olanzapine or risperidone (Sowell et al. 2003). Preclinical studies also indicate that the acute infusion of olanzapine in animals leads to rapid increases in blood sugar and marked reductions of plasma insulin and C-peptide in response to glucose challenge (Chintoh et al. 2008). In patients with schizophrenia treated over 24 months with an SGA, significant reductions from baseline in insulin sensitivity have been shown with olanzapine (~19%) or risperidone (~16%) but not with quetiapine (Newcomer et al. 2009). At least in schizophrenia, antipsychotic polypharmacy does not appear to increase the risk for metabolic syndrome over and above the risk incurred by use of a single SGA.


The reporting of changes in fasting blood glucose levels from short-term randomized trials is far less informative than long-term data, given that impaired glucose tolerance is a phenomenon that arises over the course of months to years, rather than weeks to months. In addition, pharmaceutical manufacturers of SGAs sometimes imply that their own reported fasting glucose rates may be overstated because some study participants may not reliably be tested under fasting conditions. By contrast, obviously, clinicians and patients are more concerned with manufacturers’ underestimation rather than overestimation of metabolic parameters.


The American Diabetes Association (2010) identifies diabetes mellitus on a continuum based on degrees of hyperglycemia and impaired glucose tolerance, as summarized in Table 15–4.



Current recommendations from the American Diabetes Association and the American Psychiatric Association for patients taking an SGA include monitoring of fasting glucose and blood pressure at baseline, at 12 weeks, and annually thereafter. Metabolic monitoring for SGA recipients also includes weight or BMI measurement at baseline and at 4, 8, and 12 weeks, followed by quarterly assessments, waist circumference measurement at baseline and annually thereafter, and fasting lipid profiles at baseline, 12 weeks, and every 5 years thereafter (American Diabetes Association et al. 2004).


Insulin resistance refers to the body’s inability to transport and use glucose from the vascular to the intracellular compartment. One theory to account for hyperglycemia associated with SGAs involves their apparent capacity to increase insulin resistance. An elevated ratio of serum triglycerides to HDL cholesterol (specifically, >3.8) is predictive of coronary disease and is sometimes taken as a rough proxy for insulin resistance (although the relationship appears less robust among blacks than whites). Insulin resistance and pancreatic beta-cell function also can be quantified using the homeostatic model assessment of insulin resistance (HOMA-IR) defined by the following equation:




















































TABLE 15–4.Operational definitions of diabetes mellitus


Category


Operational definition


Increased risk for diabetes


Fasting blood glucose of 100–125 mg/dL


 


or


 


2-hour blood glucose of 140–199 mg/dL during a 75-g oral glucose tolerance test


 


or


 


Hemoglobin A1C of 5.7%–6.4%


Diabetes mellitus


Hemoglobin A1C≥6.5%


 


or


 


Fasting (≥8 hours) blood glucose≥126 mg/dL


 


or


 


2-hour blood glucose≥200 mg/dL during 75-g oral glucose tolerance test


 


or


 


Random blood glucose>200 mg/dL


Source.American Diabetes Association 2010.


image


HOMA-IR values≥2.6 are sometimes viewed as a threshold cutoff to define insulin resistance (Ascaso et al. 2003).


Table 15–5 reports incidence rates for changes in blood glucose levels identified in randomized clinical trials of SGAs.


Since 2003, manufacturers’ package inserts for all SGAs have carried a class warning from the FDA regarding their potential to increase blood sugar. Hyperglycemia may arise after short-term exposure to SGAs and may occur independently of weight gain (which separately can contribute to peripheral insulin resistance). Both clozapine and olanzapine inhibit glucose-induced insulin release from pancreatic beta cells (Chintoh et al. 2009), posing an independent cause of iatrogenic hyperglycemia.


In addition to the risk factors for metabolic syndrome previously identified above in Table 15–5, a personal or family history of non-insulin-dependent diabetes (e.g., gestational diabetes) increases the risk specifically for hyperglycemia or the eventual development of diabetes. Racial/ethnic differences also may contribute to differential effects on metabolic dysregulation. For example, the risk for metabolic syndrome during treatment with aripiprazole appears higher in black or Hispanic subjects than in white subjects, whereas no such racial/ethnic differences have been observed in the case of olanzapine (Meyer et al. 2009) even though weight gain may be significantly greater during olanzapine treatment among black versus white patients with primary psychotic disorders (Stauffer et al. 2010).




















































TABLE 15–5.Changes in blood sugar reported in FDA registration and other representative randomized trials of second-generation antipsychotics


Agent


Observations


Aripiprazole


In a 26-week randomized trial in schizophrenia, +0.13 mg/dL from baseline (Pigott et al. 2003); mean of 4.1 mg/dL less than seen with olanzapine across three schizophrenia trials (N=1,487) (Rummel-Kluge et al. 2010).


Asenapine


In 3-week registration trials for bipolar mania and 6-week registration trials for schizophrenia, mean change from baseline=–0.6 mg/dL and +3.2 mg/dL, respectively. In 52-week open extension data in schizophrenia, mean change from baseline=+2.4 mg/dL.


Brexpiprazole


In 6-week schizophrenia or major depression adjunctive trials, no significant differences from placebo in categorical changes from “normal” (<100 mg/dL) to “high” (≥126 mg/dL) fasting glucose; in long-term open trials, 9% of major depression patients and 10% of schizophrenia patients had categorical shifts from “normal” or “borderline” to “high.”


Cariprazine


Across pooled 3-week registration trials in bipolar I mania (N=1,065), changes from baseline in fasting glucose levels were only nominally higher with cariprazine (3–6 mg/day=6.6 mg/dL; 9–12 mg/day=7.2 mg/dL) than placebo (1.7 mg/dL) (Earley et al. 2017b). In 48-week open-label extension data in schizophrenia, categorical shifts from normal (<100 mg/dL) to high (≥126 mg/dL) fasting glucose levels were comparable across cariprazine doses (2.6%–4.5%) to those seen with placebo (3.8%) (Nasrallah et al. 2017).


Iloperidone


Mean serum glucose: +7.2 mg/dL to +16.2 mg/dL (dose dependent and greater than seen with placebo) (Weiden et al. 2008).


Lurasidone


Fasting glucose levels across dosages from manufacturer’s pooled short-term trials in schizophrenia=+1.3 mg/dL.


From open-label extension data: at 24 weeks: +1.6 mg/dL; at 36 weeks: +0.3 mg/dL; at 52 weeks: +1.2 mg/dL.


In bipolar depression monotherapy or adjunctive therapy trials: –0.8 mg/dL to +0.9 mg/dL (Loebel et al. 2014a, 2014b).


Olanzapine


In CATIE, mean change in fasting glucose= +15.0 mg/dL (Lieberman et al. 2005).


Paliperidone


Mean change from baseline in serum glucose level=+0.1 mg/dL across three pooled 6-week randomized trials in schizophrenia (Meltzer et al. 2008).


Pimavanserin


Not reported.


Quetiapine


Incidence of fasting glucose≥126 mg/dL=2%–12% across indications in FDA randomized trials. In CATIE, mean change in fasting glucose=+6.8 mg/dL (Lieberman et al. 2005); mean of 9.3 mg/dL less than olanzapine across four schizophrenia trials (N=986) (Rummel-Kluge et al. 2010).


Risperidone


In CATIE, mean change in fasting glucose= +6.7 mg/dL (Lieberman et al. 2005); mean of 5.9 mg/dL less than olanzapine across nine schizophrenia trials (N=986) (Rummel-Kluge et al. 2010).


Ziprasidone


In CATIE, mean change in fasting glucose= +2.3 mg/dL (Lieberman et al. 2005); mean of 8.35 mg/dL less than olanzapine across four schizophrenia trials (N=1,420) (Rummel-Kluge et al. 2010).


Note. CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness; FDA=U.S. Food and Drug Administration.



Although no absolute contraindication exists for the use of SGAs among individuals with known type 2 diabetes, minimal literature is available on the safety and efficacy of using such agents in this population. The CATIE study (Lieberman et al. 2005) included about 10% of subjects with known type 2 diabetes at baseline, but all were treated with oral hypoglycemics or additional antidiabetic regimens, which would have confounded post hoc analyses regarding differential effects of antipsychotics on blood glucose levels. No prospective randomized studies of SGAs have been undertaken specifically among individuals with preexisting type 2 diabetes; consequently, decisions about the relative risks versus benefits of SGAs for diabetic patients must be individualized on the basis of the magnitude and extent of metabolic dysregulation and cardiovascular risk versus the severity of psychopathology and availability of other effective, metabolically neutral pharmacotherapies.


Certain antidepressants, including SSRIs, venlafaxine, and TCAs, have also been implicated in the development of impaired glucose homeostasis and diabetes, particularly during long-term treatment in patients under age 44. In patients with diabetic neuropathic pain, for example, duloxetine significantly increased fasting glucose (by 12.5 mg/dL over 52 weeks) and hemoglobin A1C (by 0.5%) versus placebo. A nested case-control study of 165,958 patients with major depression in the United Kingdom found that over a period of at least 2 years’ exposure, recipients of an SSRI or TCA had an approximate twofold increased risk for new-onset diabetes mellitus compared with matched comparison subjects who did not take an antidepressant (Andersohn et al. 2009); among studied agents, the highest rates were seen with amitriptyline (risk ratio=9.05) or venlafaxine (risk ratio=3.01), and the lowest rates were seen with fluvoxamine (risk ratio=1.75). The risk for developing type 2 diabetes with an SSRI was lower in patients whose exposure was shorter and in whom dosages were lower. In this study, glycemic dysregulation was thought to arise secondarily to weight gain rather than other mechanisms (e.g., time spent depressed).



The oral hypoglycemic agent metformin is perhaps the most extensively studied of adjunctive pharmacotherapies used for patients who gain significant weight or develop increased metabolic risk due to psychotropic drugs, most notably SGAs. Metformin belongs to a drug class known as biguanides; two other biguanides, buformin (never approved by the FDA) and phenformin, have been withdrawn from most worldwide markets due to high risks for lactic acidosis. By comparison, the risk for either significant hypoglycemia or lactic acidosis among type 2 diabetics taking metformin appears extremely low (i.e., 6 cases in total identified among 50,048 subjects in one nested case-control study, yielding a crude incident rate of 3.3 cases per 100,000 person-years); in fact, recognized cases of lactic acidosis during metformin therapy for diabetes typically appear linked to the presence of other risk factors for lactic acidosis, such as congestive heart failure, acute renal failure, or sepsis (Bodmer et al. 2008). Metformin does not directly stimulate insulin secretion, and this likely accounts for its low risk for causing hypoglycemia.


A meta-analysis by Ehret et al. (2010) showed that although metformin added to SGAs did not significantly lower the risk for the eventual development of type 2 diabetes, it was associated with significant reductions in weight, body mass index, and waist circumference. Metformin’s presumptive mechanism for weight loss appears related to helping overcome insulin resistance caused by antipsychotics and decreasing hepatic glucose production. Studies have not, as yet, examined whether metformin could help counteract weight gain caused by psychotropic drugs other than SGAs, although to the extent that its mechanism of action appears linked with counteracting drug-induced insulin resistance, it might not be expected to cause weight loss unless the proximal cause of weight gain involved increased insulin resistance.


A number of other agents have been developed in recent years that function as oral hypoglycemics or insulin-sensitizing drugs relevant to patients with, or at risk for, diabetes. These drugs vary in the extent to which they have been found to promote weight loss, and most have not been formally studied to counteract iatrogenic metabolic dysregulation specifically caused by psychotropic medications. Such agents include three main classes:




  • Thiazolidinediones (also known as glitazones or peroxisome proliferator-activated receptor gamma [PPARγ] agonists), including pioglitazone and rosiglitazone, decrease insulin resistance and reduce leptin levels (potentially increasing appetite, posing greater likelihood of weight gain than loss); they may shift fat distribution from visceral to subcutaneous adipose tissue, thereby improving insulin sensitivity.



  • Selective dipeptidyl peptidase–4 inhibitors (DPP-4 inhibitors, also known as gliptins), such as alogliptin, linagliptin, saxagliptin, and sitagliptin, increase levels of incretins (metabolic hormones that augment insulin release to enhance lowering of postprandial blood sugar). DPP-4 inhibitors as a class may cause severe joint pain. There is unresolved controversy about whether they may also increase the risk for pancreatitis and pancreatic cancer, based mainly on data in rodents.



  • Glycogen-like peptide–1 (GLP-1) agonists, such as luraglutide and dulaglutide, which mimic the action of incretins to lower blood sugar, slow gastric emptying and increase insulin release from pancreatic beta cells. Some SGAs appear to increase glucagon levels and suppress GLP-1 activity in preclinical studies.


A summary of findings regarding oral hypoglycemics and their potential value for managing obesity and metabolic dysregulation is provided in Table 15–6.


Weight Gain


General Recommendations


Interventions focused on diet and exercise appear to have the greatest overall efficacy in helping to counteract psychotropic-induced weight gain, particularly in patients with poor nutritional habits and sedentary lifestyles. Pharmacological strategies that have demonstrated clinically meaningful weight loss include metformin (for atypical antipsychotics), topiramate, zonisamide, amantadine, lamotrigine, and either switches to or augmentation with aripiprazole or ziprasidone. Psychostimulants or phentermine may be useful when appropriate. Adjunctive orlistat has shown modest benefit in men with psychotropic-induced weight gain. Liraglutide may promote weight loss particularly among patients with at-risk status for diabetes.



Iatrogenic obesity and overweight are among the most common and difficult-to-treat problems that confront prescribers of almost all classes of psychotropic medications and represent a leading cause of medication cessation. Differences may exist across types of medicines regarding probable mechanisms of weight gain, time course to weight gain, and risk factors, although particular risk factors for weight gain with a specific psychotropic agent have not been well described in the literature. Many agents that cause significant weight gain (e.g., lithium, divalproex) do so only after extended periods of treatment, and this limits the extent to which short-term randomized controlled trials of FDA registration studies are able to detect long-term risk. Risks also may differ with a given compound across varying disease states (e.g., schizophrenia vs. bipolar disorder; major depression vs. anxiety disorders), within a given disease state (e.g., atypical depression vs. agitated or melancholic depression), in the presence or absence of common comorbidities (e.g., alcohol abuse), or when used as a monotherapy versus in conjunction with other agents.














































































TABLE 15–6.Oral hypoglycemics and other insulin-sensitizing agents relevant to managing metabolic dysregulation


Drug class


Dosing range/route


Relevant findings


Oral hypoglycemics/biguanides



Metformin


500–2,550 mg po qDay


A meta-analysis of 12 studies involving 743 antipsychotic-treated schizophrenia or schizoaffective disorder patients revealed a mean weight change of –3.27 kg (95% CI=–4.66 to –1.89 kg), significantly reduced BMI, and improved insulin resistance (de Silva et al. 2016). May also decrease blood lipids.


Thiazolidinediones



Pioglitazone


15–30 mg po qDay


Improves fasting glucose levels, insulin resistance, and HDL levels in antipsychotic-treated schizophrenia patients with dyslipidemias or glycemic dysregulation, but weight loss has not been demonstrated (Smith et al. 2013).


Rosiglitazone


4–8 mg po qDay


Preliminary trials suggest improved glucose utilization and trends toward improved insulin sensitivity in clozapine-treated schizophrenia patients (Henderson et al. 2009b) and improved glycemic control but no weight reduction in olanzapine-treated schizophrenia patients (Baptista et al. 2009).


DPP-4 inhibitors



Alogliptin


25 mg po qDay


No data in psychotropic-induced weight gain or metabolic dysregulation. In NIDDM patients, improves glycemic control, but there is no evidence of weight loss. May increase the risk of heart failure.


Linagliptin


5 mg po qDay


No data in psychotropic-induced weight gain or metabolic dysregulation. In NIDDM patients, improves glycemic control, but there is no evidence of weight loss.


Saxagliptin


2.5–5 mg po qDay


No data in psychotropic-induced weight gain or metabolic dysregulation. In NIDDM patients, improves glycemic control, but there is no evidence of weight loss. May increase the risk of heart failure.


Sitagliptin


100 mg po qDay


No data in psychotropic-induced weight gain or metabolic dysregulation. In NIDDM patients, improves glycemic control, but there is no evidence of weight loss. Rare cases of renal failure and pancreatitis in humans have been reported.


GLP-1 agonists



Albiglutide


30–50 mg SC once weekly


Modest weight loss in overweight adults with diabetes.


Liraglutide


Begun at 0.6 mg/day SC, increased by 0.6 mg/day each week to target dose of 1.8 mg/day SC


In prediabetic and overweight/obese clozapine- or olanzapine-treated schizophrenia spectrum patients, significantly better glucose tolerance, greater weight loss (–5.3 kg), and reductions in waist circumference (–4.1 cm), visceral fat (–250.19 grams), and LDL cholesterol levels (–15.4 mg/dL) after 16 weeks (Larsen et al. 2017); may also reduce insulin resistance and weight gain in olanzapine-treated obese rats.


Lixisenatide


10 μg/day SC × 14 days, then 20 μg/day SC


In otherwise healthy adults with NIDDM, may improve glycemic control as well as promote weight loss (–2.96 to +0.3 kg in acute trials; Trujillo and Goldman 2017). No data as yet for managing psychotropic-induced weight gain or metabolic dysregulation.


Dulaglutide


0.75 mg–1.5 mg SC once weekly


Weak but significant correlation between improvements in HbA1C and weight loss over 26 weeks in otherwise healthy adults with NIDDM (weight loss range=–0.87 kg to –3.18 kg; Umpierrez et al. 2016). No data as of yet for managing psychotropic-induced weight gain or metabolic dysregulation.


Exenatide


2 mg SC once weekly


No difference from placebo in weight loss over 3 months in obese antipsychotic-treated schizophrenia patients (Ishøy et al. 2017).


Note. BMI=body mass index; DPP-4=dipeptidyl peptidase–4; GLP-1=glycogen-like peptide–1; HbA1C=hemoglobin A1C; NIDDM=non-insulin-dependent diabetes mellitus; po=by mouth; SC=subcutaneously.



As a rule of thumb, ideal body weight for men is 47.7 kg for the first 5 feet and an additional 2.7 kg for each inch above 5 feet; in women, ideal body weight is 45 kg at 5 feet with 2.3 kg added per inch above 5 feet. Medically, clinicians should assure the absence of other causes of weight gain before assuming it is the result of psychotropic medications. Careful assessment includes the following considerations:




  • Differentiating weight gain caused by adipose tissue versus fluid retention (rapid and substantial weight gain should prompt examination for edema)



  • Assuring the absence of hypothyroidism



  • Assessing dietary habits, including alcohol



  • Differentiating hyperphagia due to depression or anxiety from appetite stimulation caused by medications



  • Identifying all medications, both psychiatric and nonpsychiatric, that may predispose to weight gain (Table 15–7)



  • Identifying any nonprescribed nutritional supplements, such as high-dose vitamins, minerals, and antioxidants, that potentially could interfere with treatment



Industry-sponsored clinical trials typically define substantial weight gain by convention as increases of ≥7% from baseline weight, but this metric can be clinically uninformative if it is not normalized by baseline weight or BMI (i.e., less weight gain is needed to fulfill this criterion in subjects with low initial weight). In adults, but not children, absolute weight gain offers a more robust and clinically useful statistic. In addition, although weight gain has been reported in some industry clinical trials as being more likely among subjects with low rather than high pretreatment BMI, this distinction has not been borne out in naturalistic studies.


Second-Generation Antipsychotics


Representative rates of weight gain with SGAs as reported in clinical trials, stratified by psychiatric disorders, are summarized in Table 15–8.
































































TABLE 15–7.Weight changes associated with common medications


Minimal or no weight gain


Moderate or variable weight gain


Substantial weight gain


ACE inhibitors


Aripiprazole


Clozapine


Asenapine


Brexpiprazole


Mirtazapine


Atomoxetine


Divalproex


Olanzapine


Beta-blockers


Duloxetine


Quetiapine


Bupropion


Gabapentin


Risperidone


Buspirone


Lithium


 


Carbamazepine


MAOIs


 


Desvenlafaxine


Pregabalin


 


Fluoxetine


H2 blockers


Iloperidone


SSRIs other than fluoxetine or vilazodone


 


Lamotrigine


Tricyclic antidepressants


 


Levomilnacipran


Venlafaxine


 


Lurasidone


Naltrexone


Psychostimulants


Topiramate


Transdermal selegiline


Vilazodone


Vortioxetine


Ziprasidone


Note. ACE=angiotensin-converting enzyme; MAOI=monoamine oxidase inhibitor; SSRI=selective serotonin reuptake inhibitors.


Appetite Stimulation


In the case of SGAs, it is thought that weight gain, to varying degrees, may occur from appetite stimulation caused by blockade of histamine H1 receptors and antagonism of serotonin type 2C (5-HT2C) receptors, which together disrupt hypothalamic satiety control. SGAs may induce lipogenic genes (Kristiana et al. 2010) and activate protein kinase C-beta, which in turn may foster the differentiation and proliferation of preadipocytes (Pavan et al. 2010). Other proposed mechanisms of weight gain include decreased thermogenesis and decreased energy expenditure. Weight gain associated with some SGAs also has been associated with changes in levels of the appetite-stimulating peptide hormone ghrelin and the appetite-suppressing hormones leptin and adiponectin. However, the relationships between changes in these hormones and appetite increases induced by SGAs are not straightforward. Several studies have identified increases in serum leptin after administration of some SGAs—notably, clozapine (Atmaca et al. 2003) and olanzapine (Atmaca et al. 2003; Hosojima et al. 2006), with a lesser effect from risperidone (Atmaca et al. 2003). Serum ghrelin levels have been shown to decrease during treatment with olanzapine in some studies (Hosojima et al. 2006; B. J. Kim et al. 2008), whereas adiponectin levels appear unaffected during the first few weeks after initiation of an SGA (Hosojima et al. 2006). Still other investigators have found elevated ghrelin levels with relatively unchanged leptin levels in connection with weight gain related to clozapine, olanzapine, or risperidone (Esen-Danaci et al. 2008). In all likelihood, leptin levels rise as a result of (rather than cause) the increased fat stores induced by some SGAs, and persistent hunger fails to override the leptin signal that would otherwise promote satiety.






































































































































































































TABLE 15–8.Representative rates of weight gain with SGAs as reported in FDA registration trials and other randomized studiesa





Short-term


Long-term


Drug


Disorder


NNHb


Mean weight changes


Incidence of clinically significant weight ↑c


Mean weight changes


Incidence of clinically significant weight ↑b


Aripiprazole


Schizophrenia


21


+0.7 kg across 4- to 6-week trials


8%


+0.3 kg over 28 weeks (oral)


–0.2 kg over 52 weeks (long-acting injectible) (Kane et al. 2012)


16% (oral) (Kane et al. 2009)


6.4% (long-acting injectible) (Kane et al. 2012)


 


Bipolar disorder


ND


+0.1 kg across 3-week trials


2%


+0.4 kg across three randomized trials


20% (McIntyre 2010)


 


Major depression


22


+1.7 kg across two randomized 6-week trials (Fava et al. 2009)


5.2%




Asenapine


Schizophrenia


35


+1.1 kg


4.9%


+0.7 kg over 26 weeks of randomized monotherapy (Kane et al. 2010)


8.0% (Kane et al. 2011)


 


Bipolar disorder


19


+1.3 kg


5.8%




Brexpiprazole


Major depressive disorder


52


+1.3 kg to +1.6 kg across doses in acute adjunctive trials


2%–5%


+2.9 kg at 26 weeks; +3.1 kg at 52 weeks


30%


 


Schizophrenia


17


+1.0 to +1.2 kg across doses in acute trials


10%–11%


+1.3 kg at 26 weeks; +2.0 kg at 52 weeks


20%


 


Bipolar mania


ND


+0.5 to +0.6 kg across doses in 3-week trials


3%


+0.9 kg over 16-week open-label trial (Ketter et al. 2018)


9.3% after 16 weeks (Ketter et al. 2018)


Cariprazine


Bipolar depression


ND


+0.6 to +1.1 kg across doses (no clear dose relationship) in 8-week randomized trial (Durgam et al. 2016)


2%–7% across doses (no clear dose relationship)


No data


No data


 


Schizophrenia


34


+0.8 to +1.0 kg across doses in 6-week trials


8%–17%


+1.2 kg at 12 weeks; +1.7 kg at 24 weeks; +2.5 kg at 48 weeks



 


Schizophrenia


ND


+1.1 kg (dose-related across four acute trials (Earley et al. 2017a)


9.2%


+1.58 kg over 48 weeks (Nasrallah et al. 2017)


27% (Nasrallah et al. 2017)


Clozapine


Schizophrenia


NR


+4.5 kg (meta-analysis of acute trials; Allison et al. 1999)



+7.7 kg; 75% gained ≥ 4.5 kg over 6 months (Lamberti et al. 1992); +11.7 kg over 8 years (Bai et al. 2006)



Iloperidone


Schizophrenia


10


+1.5 kg to +2.1 kg (Weiden et al. 2008)


12%–18%




Lurasidone


Schizophrenia


67


+0.5 kg to +0.9 kg (Meltzer et al. 2011)


5.6%


–0.4 kg to –0.7 kg (24- to 52-week open-label extension data)



 


Bipolar depression


58


Monotherapy: +0.6 kg (20–60 mg/day) or 0.0 kg (80–120 mg/day) (Loebel et al. 2014a)


Adjunctive therapy: +0.2 kg (Loebel et al. 2014b)


2.4% (monotherapy)


3.1% (adjunctive therapy)


–0.2 kg (24-week open-label extension data)



Olanzapine


All indications


3–6


Across 13 acute placebo-controlled FDA registration trials, mean change of +2.6 kg; +4.2 kg in meta-analysis of acute trials (Allison et al. 1999)


22%


+4.3 to +13.2 kg over 6 months to 2.5 years (Kinon et al. 2001; Lieberman et al. 2005; Newcomer et al. 2009; Vanina et al. 2002); +5.6 kg over 48 weeks in FDA registration trials


30% (Lieberman et al. 2005) to 75% (Perez-Iglesias et al. 2008)


Paliperidone


Schizophrenia


35


+0.6 to +1.1 kg across three 6-week acute trials


6%–9%


+1.4 kg across 24 weeks; +2.6 kg at 52 weeks in open-label extension trials


32% (52-week open-label extension data)


Quetiapine


Schizophrenia


6


+2.0 kg


23%


+0.5 kg to +3.7 kg (up to 18 months) (Lieberman et al. 2005; Newcomer et al. 2009)


16% (Lieberman et al. 2005)


Bipolar disorder


8–20


+1.7 kg (mania)


+1.0 kg to +1.6 kg (depression; Calabrese et al. 2005)


21%


8.5%–9%


In maintenance trials, +3.1 kg as monotherapy in first 36 weeks, then +0.5 kg as adjunct to lithium or divalproex in weeks 37–104 (Suppes et al. 2009)


11.5% as adjunct to lithium or divalproex over 104 weeks (Suppes et al. 2009)


Risperidone


All indications


18


+2.1 kg (meta-analysis of acute trials; Allison et al. 1999)


18% (acute schizophrenia trials); 2.5% (bipolar mania trials)


+0.4 kg to +9.5 kg (up to 18 months) (Lieberman et al. 2005; Newcomer et al. 2009; Perez-Iglesias et al. 2008; Vanina et al. 2002)


14% (Lieberman et al. 2005) to 71% (Perez-Iglesias et al. 2008)


Ziprasidone


All indications


16–58


Stratifies by BMI: baseline BMI<23: 1.4-kg gain; BMI>27: 1.3-kg loss


10%


–0.7±0.5 kg (CATIE; Lieberman et al. 2005)


7% (Lieberman et al. 2005)


Note. —=no data; BMI=body mass index; CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness; FDA=U.S. Food and Drug Administration; ND=no different from (or less than reported with) placebo; NR=not reported.


aData based on FDA registration trial data as reported in manufacturers’ package insert information, unless otherwise noted.


bNNH for significant weight gain as reported by Citrome (2009a, 2010, 2011a, 2014, 2015).


cClinically significant weight gain” defined as ≥7% increase of initial weight.



Predictors of Weight Gain


The literature is surprisingly sparse in identifying robust predictors of weight gain caused by SGAs, with few exceptions. Substantial weight gain appears more likely to occur during treatment with olanzapine in patients who are younger, are nonwhite, have a low BMI, have a non-rapid-cycling course of bipolar illness, and have psychotic features (Lipkovich et al. 2006). Weight gain seems to correlate with clinical response (which may be an artifact of the amount and duration of exposure to therapy), as well as rises in blood pressure, total serum cholesterol, and nonfasting blood glucose levels (Hennen et al. 2004). In short-term (~6-week) trials of olanzapine or risperidone in patients with schizophrenia, predictors of weight gain included younger age, male gender, nonwhite race, and favorable clinical response (Basson et al. 2001). Longer-term randomized trials (≥39 weeks) of olanzapine in schizophrenia identified low baseline BMI as a robust predictor of weight gain (Kinon et al. 2001). Other reported predictors of weight gain with olanzapine, risperidone, or clozapine include female gender, parents’ BMI, younger age, and nonsmoking status (Gebhardt et al. 2009). In bipolar disorder, lower cognitive function (notably, attention, verbal memory, working memory, and global cognition) appear to be associated with weight gain during pharmacotherapy, independent of other clinical predictors (Bond et al. 2017).



Time Course and Magnitude of Weight Gain


The time course and magnitude of weight gain with SGAs can vary. In the case of olanzapine in the treatment of schizophrenia, weight gain appears to persist for up to 39 weeks before eventually plateauing (see Kinon et al. 2001). During a 1-year follow-up of 351 psychiatric patients taking a variety of antipsychotics, antidepressants, and mood stabilizers associated with weight gain, an increase from baseline weight of >5% after one month was highly predictive of more serious subsequent weight gain (≥15% after 3 months) (Vandenberghe et al. 2015). While most SGAs carry some liability for weight gain, they may vary considerably in magnitude and extent. In the CATIE chronic schizophrenia trial (Lieberman et al. 2005), for example, premature study termination due to weight gain or metabolic effects was significantly more likely among subjects taking olanzapine (9%) than all other agents (1%–4%).


Zydis Formulations


Anecdotal observations and reports from small case series have suggested that the Zydis orally dissolving formulation of olanzapine may cause less weight gain than the conventional formulation (for review, see Karagianis et al. 2008). At least one rather speculative mechanism has been proposed to account theoretically for this possibility, involving the faster absorption of orally dissolving olanzapine when administered sublingually (Markowitz et al. 2006), which in turn may lead to decreased ghrelin signaling, possibly because of the lesser quantity of olanzapine coming into proximity with ghrelin-containing cells in the fundus of the stomach (Chawla and Luxton-Andrew 2008).


A preliminary 6-week randomized comparison of orally dissolving olanzapine versus standard olanzapine in 38 first-onset psychosis patients found significantly less weight gain occurring in those taking the orally dissolving formulation (Arranz et al. 2007), although a larger and more definitive industry-sponsored 16-week multisite randomized trial, involving 149 bipolar or primary psychotic disorder patients who had gained at least 5 kg with standard olanzapine tablets, found no significant differences between conventional olanzapine and the Zydis formulation in any parameters related to weight gain (Karagianis et al. 2009).


Long-Acting Injectable SGA Formulations


Metabolic changes, including potential weight gain, during treatment with long-acting injectable (LAI) formulations of SGAs, are generally comparable to those observed during short- and long-term use of oral SGA formulations. Changes in weight as reported from clinical trials with SGA LAIs are presented in Table 15–9.


Lithium, Anticonvulsants, and Antidepressants


Tables 15–10 and 15–11 summarize information from controlled trials, including FDA registration trials, regarding the incidence and correlates of weight gain during treatment with lithium or anticonvulsants and with antidepressants, respectively.


Mechanisms for iatrogenic weight gain with lithium or anticonvulsants are less well understood than appears to be the case with SGAs or antidepressants. Notably, however, divalproex may increase body mass via raising serum leptin levels (Verrotti et al. 1999) as well as by reducing thermogenesis and increasing long-chain fatty acids through competitive binding to serum albumin (Vanina et al. 2002). Lithium-induced weight gain (unrelated to peripheral edema or hypothyroidism) has been suggested to result from thirst-related increased consumption of high-sugar beverages and increased body stores of carbohydrates and lipids (Vanina et al. 2002). Lithium also may decrease plasma adiponectin levels, in turn contributing to weight gain. Compared with olanzapine, weight gain with lithium or divalproex may follow a more gradual trajectory and result in less total weight gain than seen with certain SGAs.


Studies that report weight gain with anticonvulsants other than divalproex (e.g., gabapentin; DeToledo et al. 1997) typically have focused on high doses in epilepsy populations rather than in psychiatric patients. Extended-release carbamazepine and lamotrigine each appear to be weight-neutral during long-term treatment for bipolar disorder (Ketter et al. 2004; Sachs et al. 2006a). In fact, lamotrigine has been associated with weight loss in obese nonpsychiatric patients as well as obese patients with bipolar disorder (see Table 15–2).


Data from FDA registration studies have important limitations regarding inferences for patients treated in routine clinical practice: 1) trials are generally brief, providing no information on weight gain with long-term use; 2) most trials involve monotherapy, whereas many patients with mood or anxiety disorders take combinations of drugs with additive or synergistic risks for weight gain; and 3) subjects enrolled in FDA registration trials often are already overweight and lack risk factors for weight gain that pertain to the general population. These include the absence of unstable medical problems (e.g., diabetes, nonalcoholic steatohepatitis or nonalcoholic fatty liver disease; see the section “Hepatic Impairment and Transaminitis” in Chapter 12, “Gastrointestinal System”); an absence of concurrent psychiatric disorders (e.g., eating disorders) or substance use disorders (notably, alcoholism) that may influence body weight and nutritional intake; and minimal if any contribution from cotherapies that may pose additive weight gain, such as anticholinergic drugs or sedative-hypnotics. A further consideration regarding iatrogenic weight gain in both research trials and routine treatment for mood disorders involves the distinction between the restoration of lost appetite attributable to the treatment of depression versus the stimulation of appetite and weight gain above and beyond changes caused by treating depression.





















































































TABLE 15–9.Weight changes with long-acting injectable second-generation antipsychotic formulations


Agent


Study


Total weight change


Proportion with >7% weight gain


Aripiprazole extended-release injectable suspension


Schizophrenia (12-week placebo-controlled trial) (Kane et al. 2014)


+3.5 kg


21.5%


 


Schizophrenia (52-week placebo-controlled trial) (Kane et al. 2012)


+0.1 kg during acute stabilization; –0.2 kg at end of maintenance phase


5.4% during acute stabilization; 6.4% at end of maintenance phase


 


Bipolar disorder (52-week placebo-controlled trial) (Calabrese et al. 2017)


+1.3 kg


18%


Paliperidone palmitate


Schizophrenia (Four 9-13-week placebo-controlled trials (manufacturer’s product information)


+0.4 to +1.4 kg across dosages and trials


6.0%–13.1% across dosages and trials


 


Schizophrenia (24-week placebo-controlled trial) (Hough et al. 2010)


+1.9 kg


23%


 


Schizophrenia (53-week open label trial) (manufacturer’s product information)


+2.4 kg at week 29;


+4.3 kg at week 53


Not reported


 


Schizoaffective disorder (25-week open label trial) (manufacturer’s product information)


+2.2 kg


18.4%


Risperidone long-acting injectable


Schizophrenia (12-week placebo-controlled trial) (manufacturer’s product information)


+0.5 kg to +1.2 kg


8%–10%


 


Schizophrenia (50-week open label trial) (manufacturer’s product information)


+2.1 kg (week 24); +2.8 kg (week 50)


Not reported


 


Bipolar I disorder (12-week open label, then 18-week placebo-controlled trial) (Vieta et al. 2012)


24% reported “weight increase”


14%


Olanzapine long-acting injectable


Schizophrenia (8-week placebo-controlled trial) (Lauriello et al. 2008)


+3.2 to +4.8 kg across doses


23.6%–35.4% across doses


 


Schizophrenia (24-week placebo-controlled trial) (Kane et al. 2010)


+0.67 to +1.70 kg across doses


8%–24% across doses


 


Schizophrenia (6-year open label) (Anand et al. 2015)


+2.19 kg


40.8%


 









































TABLE 15–10.Representative rates of weight change with lithium or anticonvulsants reported in FDA registration trials and other randomized studies


Agent


Weight change and time course


Notable risk factors


Lithium


Up to 66% of patients gained an average of 10 kg over 2–10 years (Vanina et al. 2002); 13% of bipolar I patients had weight gain with monotherapy over 1 year (Bowden et al. 2000). In a 1-year comparison of lithium with lamotrigine or placebo for bipolar relapse prevention, mean weight changes with lithium monotherapy were +6.1 kg among initially obese subjects and +1.1 kg in initially nonobese subjects (Bowden et al. 2006a).


Obesity at baseline; mechanism of weight gain may be related to lithium-induced decreases in serum leptin levels (Atmaca et al. 2002) or direct serotonergic effects; no clear dose relationship.


Carbamazepine


Weight gain is not identified as an adverse effect in FDA registration trials, although isolated case reports of weight gain have been described in the epilepsy literature.


None known.


Divalproex


21% of bipolar I patients had weight gain during divalproex maintenance treatment over 1 year (Bowden et al. 2000).


Serum valproate levels >125 ng/mL (Bowden et al. 2000).


Gabapentin


2% of patients had weight gain in trials for postherpetic neuralgia; 3% of patients had weight gain in add-on therapy trials for epilepsy.


None known.


Lamotrigine


In trials for bipolar disorder, weight gain was reported in 1%–5%. Mean weight change at 52 weeks was –4.2 kg among initially obese patients and –0.5 kg among nonobese patients (Bowden et al. 2006a).


None known.


Oxcarbazepine


1%–2% incidence of any weight gain during trials of adjunctive therapy for epilepsy. Postmarketing case reports also identify weight loss.


None known.


Note. FDA=U.S. Food and Drug Administration.


























































































TABLE 15–11.Representative rates of weight changes across antidepressants reported in clinical trials


Agent


Weight changes in FDA registration trials


Additional studies and observations


Bupropion


Major depression


Bupropion IR: 9% gained weight over 3–6 weeks; 28% had weight loss of >2.3 kg.


Bupropion SR: 2%–3% gained >2.3 kg in 4–6 weeks (300 or 400 mg/day); 14% (300 mg/day) to 19% (400 mg/day) had weight loss >2.3 kg.


Seasonal affective disorder: Bupropion XL: 11% gained >2.3 kg; 23% lost >2.3 kg.


Mean weight loss identified in meta-analysis was 2.8 kg (95% CI, 1.1–4.5 kg) over 6–12 months (Li et al. 2005).


Citalopram


Major depression: Mean weight change was –0.5 kg over 4–6 weeks.


Meta-analysis suggests greater weight loss than gain (Li et al. 2005).


Desvenlafaxine


Major depression: 1%–2% of subjects reported weight loss across dosages (50–400 mg/day). Mean weight change ranged from –0.4 to –1.1 kg in acute trials at dosages up to 400 mg/day. Mean weights did not differ significantly from those with placebo by the end of a 6-month placebo-controlled extension phase for acute responders.


None.


Duloxetine


Major depression: Weight loss in 2% (cf. <1% with placebo).


Major depression and GAD: Mean weight change over 10 weeks of –0.5 kg (cf. +0.2 kg with placebo).


All other indications: Mean weight change over 26 weeks was –0.6 kg (cf. +0.2 kg with placebo).


Major depression: A 7-week open trial (N=128) yielded a mean weight loss of –1.2 kg, which then normalized by 20 weeks and subsequently increased to a gain of +2.4 kg at 1 year and 3.1 kg after 2 years (Wohlreich et al. 2007).


Major depression: Mean +2.4-kg weight gain over 1 year (N=1,279) (Raskin et al. 2003).


Escitalopram


Major depression: No difference from placebo in weight change.


In three 8-month placebo-controlled trials for GAD, mean weight gain was +1.4 kg (Davidson et al. 2005).


Fluoxetine


Major depression: Decreased appetite in 11% and weight loss in 1.4%.


OCD: Decreased appetite in 17%, weight loss in 2%.


Bulimia nervosa: Decreased appetite in 8% with mean weight loss of –0.45 kg, with dosages of 60 mg/day over 15 weeks.


Major depression: –0.4 kg weight loss in first 4 weeks; no significant weight differences from placebo over 50 weeks of continuation/maintenance therapy for depression (Michelson et al. 1999); meta-analysis of studies using fluoxetine to treat obesity shows weight changes from –14.5 to +0.4 kg after 12 or more months (Li et al. 2005). (Note: Studies of fluoxetine targeting weight loss have typically involved higher dosages [~60 mg/day] than generally used for major depression [Li et al. 2005].)


Fluvoxamine


OCD: Decreased appetite in >5%; specific weight changes not reported in manufacturer’s package insert, other than no differences from placebo were observed.


None.


Levomilnacipran


Major depression: –0.5 to –0.8 kg across doses in 8-week acute depression trials (Asnis et al. 2013).


Mean weight change in 48-week open-label extension study for MDD: –0.6 kg; 10% gained >7% of initial body weight while 17% lost >7% of initial body weight (Citrome 2013a).


MAOIs other than transdermal selegiline: isocarboxazid, phenelzine, tranylcypromine


Incidence rates for weight change are not reported in manufacturers’ product information materials.


Weight gain during treatment for depression reportedly more common with phenelzine than tranylcypromine (Cantú and Korek 1988).


Mirtazapine


Major depression: Increased appetite in 17% of subjects in acute trials (cf. 2% with placebo); 7.5% of mirtazapine recipients gained ≥7% of their baseline weight (cf. 0% with placebo), as did 49% of subjects in pediatric trials (cf. 5.7% with placebo).


None.


Nefazodone


Major depression: Weight gain in >1% of subjects. No significant differences from placebo in incidence of substantial weight gain (i.e., ≥7% of initial body weight). Weight loss occurred in <1% of subjects.


None.


Paroxetine


Across indications: Increased appetite in 2%–4%; decreased appetite in 6%–9%. Average weight change in short-term trials was approximately –2.2 kg. Weight gain occurred in >1% across indications.


None.


Sertraline


Incidence rates for weight changes not reported in manufacturer’s product information materials (although weight increase reported as occurring in >1% of subjects across all FDA registration trials).


OCD: Mean +1.6-kg weight gain (+2.5% of baseline weight) over 2.5 years (Maina et al. 2004).


TCAs


Acute trials of tertiary-amine TCAs (e.g., imipramine or amitriptyline) have been associated with mean weight gains of 2.0–7.0 kg; secondary-amine TCAs (e.g., desipramine, nortriptyline) have shown minimal weight gain in trials, presumably because of lower H1 histamine or anticholinergic effects (Vanina et al. 2002).


None.


Transdermal selegiline


Major depression: Over 6–8 weeks, 2.1% of subjects gained ≥5% of their initial body weight, and 5.0% lost ≥5% of their baseline weight. Mean weight change was –0.5 kg (cf. +0.1 kg with placebo).


None.


Venlafaxine


Major depression: 7% of patients lost ≥5% of their initial body weight.


GAD, social anxiety disorder, or panic disorder: 3%–4% of subjects lost ≥7% of their initial body weight.


Across indications: Weight gain occurred in ≥1% of subjects.


None.


Vilazodone


Major depression: In 8-week placebo-controlled trials, no observed differences from placebo (+0.2 kg with either drug or placebo; gains of ≥7% from baseline weight occurred in 0.9% of vilazodone recipients and 1.2% of placebo recipients).


None.


Vortioxetine


Major depression: In published 8-week placebo-controlled trials, mean weight changes were –0.10 to +0.19 kg across dosages (no different from placebo; +0.46 kg).


In a 52-week open-label extension trial for completers of a randomized acute trial in major depression, mean weight change at study end was +0.67 kg (Alam et al. 2014).


Note. CI=confidence interval; FDA=U.S. Food and Drug Administration; GAD=generalized anxiety disorder; IR=immediate release; MAOI=monoamine oxidase inhibitor; OCD=obsessive-compulsive disorder; SR=sustained release; TCA=tricyclic antidepressant; XL=extended release.



The prevalence and magnitude of weight gain associated with antidepressants is less extensive than with SGAs, even though almost all classes of antidepressants—with the notable exception of bupropion—have been associated with some weight gain. FDA registration trials for most antidepressants involve relatively short durations of treatment (typically 4–8 weeks) for acute major depressive episodes, but changes in weight may be more likely to occur during long-term rather than short-term therapy. Among SSRIs, fluoxetine may have a lower incidence of weight gain than other agents, based mainly on early studies involving its use for the treatment of obesity. A few randomized trials comparing SSRIs over approximately 6–9 months found more weight gain with paroxetine than with sertraline, and often the least amount with fluoxetine. Significant weight gain also was more extensive during short- and long-term treatment with SSRIs or TCAs than with nefazodone (Sussman et al. 2001).


Lifestyle Modification


Lifestyle modification remains the first-line, and arguably safest and best studied, level of intervention to counteract psychotropic-induced weight gain, although in real life it is often very hard to achieve. The evidence base in support of this statement includes the following:




  • STRIDE, a 12-month group- and individually based dietary and lifestyle modification program for overweight or obese adults taking antipsychotic medications, reported a mean weight loss of 4.4 kg at 6 months and 2.6 kg at 12 months alongside an approximate 6-point reduction in fasting glucose levels as compared with control subjects receiving usual care (Green et al. 2015).



  • A 12-week randomized study of overweight or obese outpatients with psychotic disorders receiving a variety of SGAs, comparing usual care with individual twice-weekly exercise training plus nutritional counseling, found significant weight loss and decreased cholesterol: HDL ratio (Blouin et al. 2009).



  • A 24-week intensive program of diet, exercise, and nutritional counseling in 22 obese or overweight patients with chronic psychotic disorders yielded an average 6-kg weight loss (5.7% of baseline weight) and 11% reduction in blood pressure; 77% of subjects completed the program (Centorrino et al. 2006).



  • A 12-week program of exercise (20 minutes three times per week) plus nutritional and behavioral counseling (e.g., learning to read food labels, meal planning, portion control, healthy snacking) in 31 overweight or obese schizophrenia or schizoaffective disorder patients taking SGAs led to a 2.7-kg weight loss; 87% of participants completed the program (Vreeland et al. 2003). Notably, a 40-week extension of this program (completed by 65% of subjects) further demonstrated significant reductions from baseline in hemoglobin A1C, blood pressure, and hip and waist circumference, but not lipid parameters, and most of the observed weight loss occurred in the first 3 months with a subsequent plateau despite continued SGA therapy (Menza et al. 2004).



  • A 12-week study in 48 obese or overweight schizophrenia or schizoaffective subjects who had been taking olanzapine for at least 12 weeks and gained >7% of their pretreatment weight compared usual care versus a program of diet management (i.e., keeping a food diary, diet planning with a nutritionist, learning about food exchange tables, reading food labels, healthy snacking, and low-calorie food preparation) combined with exercise management (i.e., keeping an exercise diary and pursuing a tailored exercise plan with an exercise manager). Subjects randomly assigned to the weight management program lost a mean of 4 kg, with significant differences visible at week 8. No significant reductions in lipid parameters were observed. The protocol was completed by 75% of enrollees (Kwon et al. 2006).



  • An 18-month open, prospective comparison of usual treatment versus a supervised, facility-based exercise program with dietary counseling in 110 schizophrenia, schizoaffective disorder, or bipolar disorder patients with antipsychotic-induced weight gain revealed a 3.5% reduction in body weight; subjects in the weight management arm had significantly greater reductions in total cholesterol, LDL, triglycerides, and fasting glucose, as well as significantly greater increases in HDL when compared with subjects receiving usual care (Poulin et al. 2007).



  • In a 10-week open weight-control program involving 33 Taiwanese schizophrenia patients with obesity resulting from SGAs, observed weight loss was 2.1 kg after 10 weeks, 3.7 kg at 6 months, and 2.7 kg at 12-month follow-up, with significant declines in triglycerides but not other lipid or glycemic parameters (Chen et al. 2009).



Among the comprehensive issues relevant to weight management and metabolic risk, nutritional factors should be considered alongside pharmacological and lifestyle factors. Foods with a higher content of protein, fiber, and water have been associated with greater satiety. Efforts toward improving nutritional intake can often be aided by consultation with a registered dietitian, who can make specific recommendations tailored to an individual patient. Monitoring caloric intake and increasing physical activity can help to maintain a stable weight. Diet recommendations often include eating small, frequent meals throughout the day to minimize rebound hunger from prolonged daytime periods of not eating, as well as incorporating lean sources of protein with every meal and snack for satiety and more stable blood glucose levels following intake (spikes in blood sugar after high-carbohydrate meals lead to quick drops, and the patient will feel hungry soon after).


In addition to monitoring food intake, increasing physical activity should be strongly emphasized. Strategies include finding activities that patients enjoy (e.g., walking, dancing, tennis, gardening) so as to minimize the likelihood that exercise could feel like a chore. Before patients begin a new exercise regimen, the clinician must ensure the absence of any physical health constraints, such as unstable cardiopulmonary diseases. For weight loss, at least 60 minutes/day is recommended, whereas 45–60 minutes most days of the week is usually recommended to maintain a stable weight.


Pharmacological Management of Psychotropic-Induced Weight Gain


The management of weight gain caused by serotonergic antidepressants has received comparatively less attention than the weight gain caused by SGAs, for which more pervasive metabolic disturbances appear to be more extensive. Adjunctive topiramate represents one of the best studied remedies for weight gain associated with SSRI treatment, as well as with a range of other psychotropic agents. These studies, summarized in Table 15–12, are all limited by their small sample sizes, use of concomitant therapies, lack of treatment randomization, and heterogeneity of diagnostic groups and clinical states. Potential benefits also may be countered by other adverse effects caused by topiramate, such as cognitive impairment (see Table 17–1 in Chapter 17, “Neurological System”) or paresthesias (see the section “Paresthesias and Neuropathies” in Chapter 17). Nevertheless, the studies provide convergent data supporting weight loss with adjunctive topiramate for psychotropically induced weight gain.
































































TABLE 15–12.Open-label studies of adjunctive topiramate and weight loss in patients with mood and anxiety disorders


Study population


N


Duration


Dosing


Mean weight loss


Weight gain induced by SSRIs for anxiety disorders (Van Ameringen et al. 2002)


15


10 weeks, open label


Mean dose=135±44 mg/day


4.2±6.0 kg.


Bipolar or unipolar depressed patients (Kirov and Tredget 2005)


12


6–12 months


Begun at 25 mg/day and increased by 25–50 mg every 1–2 weeks to a maximum of 600 mg/day; mean dose=296 mg/day


At 3 months, 5.0±3.3 kg; at 6 months, 7.8±6.9 kg; patients completing 12 months lost a mean of 9.6±6.7 kg.


Bipolar I or schizoaffective manic patients (Chengappa et al. 1999)


20


5 weeks


Begun at 25 mg/day, increased by 25–50 mg every 3–5 days; mean dose at week 5=211 mg/day


–4.3 kg (range: –1.4 to –10.5 kg by 5 weeks).


Bipolar I, II, not otherwise specified, or schizoaffective bipolar disorder patients (Vieta et al. 2002)


31


≤6 months


Mean dose=202±65 mg/day


–2.3±1.3 kg.


Bipolar I, II, or schizoaffective bipolar disorder patients (Vieta et al. 2004)


26


12 months


Topiramate (25- to 50-mg/day weekly increases) plus olanzapine concurrently begun; mean modal topiramate dose = 271.1±117.6 mg/day


–0.5±1.1 kg.


Refractory bipolar disorder patients (Guille and Sachs 2002)


14


1–64 weeks (mean = 22.4 weeks)


Mean dose=100±72 mg/day


4 subjects with a baseline BMI>28 had a mean weight loss of 13.5±7.4 kg.


Diversity of mood, anxiety, psychotic, and personality disorders (Cates et al. 2008)


41


1–39 months (mean= 16.2 months)


Begun at 50 mg/day; median maximum dosage of 100 mg/day


Any weight loss occurred in 59% (mean weight loss=2.2 kg); modest reductions from baseline weight or BMI (<2%); more substantial weight loss occurred among those who had any weight loss (7.2 kg); any weight loss was more likely among heavier subjects (i.e., baseline weight >91 kg at topiramate initiation); 76% completed at least 6 months, 59% completed at least 1 year; 27% completed 2 years.


Adverse effects, reported in 17% of subjects, included cognitive dulling, appetite increase, behavioral activation, and gastrointestinal disturbances.


Note. BMI=body mass index; SSRI=selective serotonin reuptake inhibitor.



Psychostimulants, which are sometimes used to promote weight loss, have not been extensively studied specifically for counteracting psychotropic-induced weight gain. In patients with primary psychotic disorders, stimulants pose obvious concerns for the potential psychotomimetic effects. In children and adolescents receiving SGAs for aggression and disruptive behavioral disorders, no differences were found over 12 weeks in body weight or metabolic parameters among those who did (N=71) or did not (N=82) also receive stimulants under naturalistic conditions (Penzer et al. 2009). Notably, unlike amphetamine or methylphenidate, the novel stimulants modafinil or armodafinil do not appear to be associated with clinically meaningful weight loss.


A number of pharmacotherapies have been described to help counter obesity in otherwise healthy adults for whom weight gain was not the result of psychotropic medications. Such medications, which by extrapolation may warrant consideration as possible strategies for psychotropic weight gain, include the following:




  • Bupropion SR: A 24-week randomized comparison of placebo versus bupropion SR (300–400 mg/day) in obese, otherwise healthy adults found significantly greater reductions from baseline weight among those receiving bupropion SR 300 mg/day (7.2% loss from baseline) or 400 mg/day (10.1% loss from baseline) than among those receiving placebo (Anderson et al. 2002). In addition, a 26-week randomized placebo-controlled trial in 193 subsyndromally depressed subjects yielded a significantly greater mean weight loss in those taking bupropion SR (4.4 kg, or 4.6% of baseline weight) than placebo (1.7 kg, or 1.8% of baseline weight), with a significant correlation observed between improvement in depressive symptoms and weight loss (Jain et al. 2002). Among a small group (N=8) of diagnostically diverse outpatients with olanzapine-associated weight gain, an open trial of bupropion 150–300 mg/day resulted in a mean weight loss of 3.4 kg over 24 weeks (Gadde et al. 2006).



  • Bupropion SR plus naltrexone: This combination was examined on the basis of the ability of bupropion to activate hypothalamic pro-opiomelanocortin neurons and the theoretical ability of naltrexone to block opioid-mediated pro-opiomelanocortin autoinhibition. The combination of bupropion SR (360 mg/day) plus naltrexone (16 or 32 mg/day) was associated with substantial reductions from baseline weight over 56 weeks (half of subjects lost 5% of their baseline weight with the 16 mg/day naltrexone dose; a mean 6% loss from baseline weight occurred with the 32 mg/day naltrexone dose) in a 34-site study of 1,742 overweight or obese adults in the United States (Greenway et al. 2010).



  • Zonisamide plus bupropion: A 12-week open-label randomized study was conducted in 18 psychiatrically healthy obese women comparing the anticonvulsant zonisamide (begun at 100 mg/day and increased to 400 mg/day over 4 weeks) alone or with bupropion (the latter begun at 100 mg/day and then increased to 200 mg/day after 2 weeks). Combination therapy yielded significantly more weight loss (mean=7.2 kg) than zonisamide alone (mean=2.9 kg) (Gadde et al. 2007).



  • Phentermine: This amphetamine-like stimulant is an appetite suppressant used for the short-term management of obesity. In a pooled analysis of nine randomized trials occurring from 2 to 24 weeks, with dosages of 15–30 mg/day, subjects lost a mean of 3.6 kg (95% CI, 0.6–6.0 kg) (Li et al. 2005). Side effects of phentermine appear modest and bear mainly on its sympathomimetic effects (e.g., tachycardia, hypertension).



  • Phentermine plus topiramate: In a 56-week trial with 2,487 obese or overweight adults, the combination of phentermine (7.5 or 15 mg/day) plus topiramate (46 or 92 mg/day) produced significantly greater mean weight loss (–8.1 kg [95% CI, –8.5 to –7.1 kg] and –10.2 kg [95% CI, –10.4 to –9.3 kg] at each respective dose pairing) as compared with placebo (mean weight loss=–1.4 kg [95% CI, –1.8 to –0.7 kg]), with 62% and 70% losing at least 5% of their initial weight with each respective dose pairing of active drug arms; adverse effects that were more common with active drug than placebo included dry mouth, paresthesias, constipation, insomnia, dizziness, and dysgeusia (Gadde et al. 2011).


Clozapine-induced weight gain may at least partly derive from the more potent 5-HT2C antagonism caused by its metabolite norclozapine. Lu et al. (2004) capitalized on the pharmacokinetic effect of coadministering fluvoxamine (50 mg/day) with clozapine (250 mg/day), which raises clozapine levels by ~2.3-fold while decreasing norclozapine levels, to demonstrate significantly less weight gain over 12 weeks than with clozapine alone. Careful monitoring of serum clozapine levels during deliberate coadministration of fluvoxamine is important to minimize the risk of toxicity and seizures.


Finally, it is important to keep in mind that some psychiatric disorders, such as bipolar disorder, may involve an intrinsic risk for developing obesity or substantial weight gain, posing a confounding factor when attempting to apportion the etiology of weight gain to a treatment versus a disease state itself.



Among studies of pharmacotherapies used to counteract psychotropic-induced weight gain, a meta-analysis of 32 studies involving 1,482 subjects and 15 medications or medication combinations to remedy antipsychotic-associated weight gain, used over diverse time periods, found the most extensive mean weight loss as compared with placebo with metformin (2.9 kg), followed by D-fenfluramine (2.6 kg), sibutramine (2.6 kg), topiramate (2.5 kg), and the noradrenergic reuptake inhibitor reboxetine (1.9 kg) (Maayan et al. 2010). (d-Fenfluramine was withdrawn from the U.S. market by the FDA in 1997 due to reports of cardiac valve disease and pulmonary hypertension, and sibutramine was withdrawn from the U.S. market in 2010 because of excessive cardiovascular events [e.g., nonfatal heart attacks and strokes]; however, these agents are included here because of their historical role and known efficacy for weight loss.)


Table 15–13 summarizes major findings with randomized pharmacological intervention studies to counteract psychotropic-induced weight gain in patients with primary mood or psychotic disorders. Alternatively, psychiatrically stable patients who have gained weight from an SGA with high risk for weight gain (e.g., olanzapine) have been shown to lose significantly more weight and lower their total cholesterol levels by switching within class to another agent that may be less prone to cause weight gain (e.g., aripiprazole or ziprasidone); however, stable psychiatric symptoms have been shown to worsen after switching from olanzapine to aripiprazole (Newcomer et al. 2008), and clinicians cannot assume comparable efficacy among SGAs for patients with primary psychotic disorders. Significant weight loss also has been demonstrated after switching stable schizophrenic outpatients from olanzapine to ziprasidone (median ziprasidone dose=90 mg/day; mean weight loss=1.8 kg) or from risperidone to ziprasidone (median ziprasidone dose=92 mg/day; mean weight loss=0.9 kg) (Weiden et al. 2003a). Stable but symptomatic schizophrenia patients who were switched from either olanzapine or risperidone to ziprasidone demonstrated weight loss but neither improvement nor decline in global symptoms (Weiden et al. 2003b).


Finally, it is worth noting that the selective 5-HT2A inverse agonist pimavanserin, FDA-approved to treat psychosis in Parkinson’s disease, has been associated with weight loss; FDA registration trials reported significant reductions in BMI (42%) more often than increases (2%), although clinically significant weight gain was more likely in subjects with a low baseline BMI. Data with pimavanserin outside of its use for psychosis in Parkinson’s disease are not extensive; however, in one 6-week trial of risperidone for non-first-episode schizophrenia patients, coadministration with pimavanserin was associated with significantly less weight gain and lower rises in fasting glucose than was seen in patients taking risperidone plus placebo (Meltzer et al. 2012).





























































TABLE 15–13.Pharmacological strategies with at least one randomized trial to manage psychotropic-induced weight gain


Agent


Rationale


Study designs and findings


Amantadine


Possible dopaminergic and noradrenergic anorexic effect; or via effects of adrenal and gonadal steroids through reduction of prolactin.


Randomized comparison of adjunctive amantadine (up to 300 mg/day) (N=60) or placebo (N=65) over 16 weeks in schizophrenia, schizoaffective, schizophreniform, or bipolar disorder patients who gained ≥5% of their initial body weight with olanzapine. Significantly greater weight loss with amantadine (mean=–0.2±4.6 kg) than placebo (+1.3±4.3 kg) (Deberdt et al. 2005).


Randomized comparison of adjunctive amantadine (N=12) or placebo (N=9) for 12 weeks in schizophrenia, schizoaffective, or bipolar disorder patients who had gained ≥2.3 kg from olanzapine; amantadine recipients lost a mean of 0.4±3.5 kg, whereas placebo recipients gained a mean of 4.0±5.9 kg (Graham et al. 2005).


Aripiprazole


Considered among the more weight-neutral SGAs, potentially via its modest H1 antihistamine blockade and serotonin type 2C (5-HT2C) agonism; may promote weight loss despite concomitant treatment with other weight-promoting agents.


10-week placebo-controlled double-blind crossover study of adjunctive aripiprazole (15 mg/day) in overweight schizophrenia patients (N=15) stable on olanzapine for at least 1 month; aripiprazole was associated with significantly more weight loss (mean=–1.3±2.1 kg) than placebo (mean gain=+1.0±1.5 kg), as well as greater reduction in triglycerides (–52 mg/dL vs. –48 mg/dL, respectively) and very-low-density lipoprotein reductions (Henderson et al. 2009a).


Lamotrigine


Apparent weight neutrality or weight loss observed in clinical trials for bipolar disorder.


18-month maintenance comparison of lamotrigine (N=217), lithium (N=166), or placebo (N=190); mean weight changes were –1.2 kg (lamotrigine), +2.2 kg (lithium), and +0.2 kg (placebo) (Sachs et al. 2006a). Among obese subjects in this group (N=155), mean weight changes at 52 weeks were –4.2 kg (lamotrigine), +6.1 kg (lithium), and –0.6 kg (placebo) (Bowden et al. 2006a).


Weight loss observed in obese nonpsychiatric patients.


26-week study involving 40 obese psychiatrically healthy adults; significantly greater weight loss with lamotrigine (200 mg/day) than placebo (–2.9±4.7 kg vs. –0.5±3.2 kg, respectively) and mean changes in BMI from baseline to endpoint (–1.5±2.8 and –0.1±1.1 for lamotrigine and placebo, respectively) (Merideth 2006).


α-Lipoic acid (ALA)


Antioxidant associated with weight loss in rodent studies.


12-week placebo-controlled randomized trial involving 22 stable schizophrenia patients; ALA dosing 600–1,800 mg/day. Significantly greater weight loss with ALA (–1.3±1.6 kg) than placebo (+0.7±1.9 kg) (Kim et al. 2016).


Metformina


Oral hypoglycemic agent; decreases insulin sensitivity and prolongs the duration of postprandial falls in plasma levels of ghrelin, the gastrointestinal hormone that promotes satiety (English et al. 2007); inhibits expression of neuropeptide Y and may increase expression of hypothalamic leptin receptors (Aubert et al. 2011).


12-week comparison of placebo, metformin (250 mg tid with meals), metformin plus lifestyle intervention, or lifestyle intervention alone in 128 adults with schizophrenia in China whose weight increased >10% from antipsychotics. Mean reductions in BMI were greatest among subjects randomly assigned to metformin plus lifestyle intervention (1.8), followed by metformin alone (1.2), and lifestyle alone (0.5) (Wu et al. 2008).


16-week comparison of placebo or metformin (initially 500 mg with dinner for 1 week, then 500 mg with breakfast and dinner for 1 week, then 850 mg with breakfast and dinner) in 39 children and adolescents who had >10% weight increase from olanzapine, risperidone, or quetiapine. Placebo recipients gained an additional mean of +4.0±6.2 kg, whereas metformin recipients lost a mean of –0.1±2.9 kg (Klein et al. 2006).


14-week double-blind placebo-controlled trial in 40 schizophrenia patients taking olanzapine; glucose levels declined significantly with metformin but no significant changes observed in weight gain or insulin resistance (Baptista et al. 2006).


Naltrexone


Antipsychotics may disrupt endorphin-mediated food reward.


8-week randomized comparison of naltrexone 25 mg/day (N=11) or placebo (N=12) in overweight women with schizophrenia or schizoaffective disorder. Significantly greater weight loss with naltrexone (mean=–3.4 kg) than placebo (mean=+1.4 kg) (Tek et al. 2014).


Nizatidine


H2 receptor antagonism may exert a direct appetite-suppressant effect or an indirect weight loss effect by reducing gastric acid secretion.


16-week comparison of nizatidine 150 mg or 300 mg bid versus placebo in 175 schizophrenia patients beginning treatment with olanzapine; significantly less weight gain with high-dose nizatidine than placebo at weeks 3 and 4, but not at week 16 (Cavazzoni et al. 2003).


8-week randomized comparison of adjunctive nizatidine or placebo in 35 schizophrenia patients who gained >2.3 kg from SGAs; significant weight loss and reduction in serum leptin levels (Atmaca et al. 2004).


2.5-month open-label adjunctive nizatidine (N=47) 150 mg bid followed by 8-week randomized adjunctive nizatidine or placebo (N=28) for quetiapine-associated weight gain in schizophrenia patients; no significant reductions in weight or serum leptin levels (Atmaca et al. 2004).


Orlistat


Interferes with absorption of intestinal fat.


16-week randomized, placebo-controlled study of orlistat dosed at 360 mg/day in 63 obese or overweight schizophrenia patients taking clozapine or olanzapine. Men (but not women) had significantly greater weight change with orlistat (loss of –2.36 kg) than with placebo (gain of +0.62 kg) (Joffe et al. 2008).


A 16-week open-label extension phase trial in 44 of these subjects yielded significant further weight loss (–1.29±3.04 kg), with men but not women showing the most robust declines (Tchoukhine et al. 2011).


Topiramate


Direct appetite suppressant effect by unknown mechanism; may reduce fat deposition by stimulating energy expenditure.


24-week randomized comparison of flexibly dosed topiramate (mean dose=209±145 mg/day) or sibutramine (mean dose=12±7 mg/day) in 46 overweight bipolar disorder outpatients; statistically similar magnitude of weight loss with topiramate (–2.8±3.5 kg) or sibutramine (–4.1±5.7 kg) but high dropout rates in both groups (McElroy et al. 2007).


12-week double-blind comparison of olanzapine plus topiramate (100 mg/day) or placebo in first-episode schizophrenia: mean weight loss of –1.3±2.3 kg with topiramate (significantly greater than placebo) alongside significantly greater reductions in serum leptin and other metabolic parameters (Narula et al. 2010).


Zonisamide


Possible dopaminergic and serotonergic effects may affect satiety.


In randomized study, 60 obese, psychiatrically healthy adults had significantly more weight loss (mean=–5.9 kg at 16 weeks and –9.2 kg at 32 weeks) with zonisamide (initially 100 mg/day increased to a maximum of 600 mg/day) than with placebo (Gadde et al. 2003).


In a 16-week randomized comparison of zonisamide (mean dose=380 mg/day) versus placebo in obese bipolar patients taking olanzapine, significantly less weight gain occurred with zonisamide (mean=0.9 kg) than with placebo (5.0 kg) (McElroy et al. 2012).


In a 10-week double-blind randomized comparison of zonisamide 150 mg/day (n=21) or placebo (n=20), there was significantly greater weight loss with zonisamide (mean=–1.1±1.4 kg) than with placebo (mean=+1.9±2.2 kg) (Ghanizadeh et al. 2013).


Open trial of adjunctive zonisamide (final mean dose of 375±206 mg/day; range: 75–800 mg/day) in 25 obese recovered bipolar I or II patients over a mean of 14 weeks; mean weight loss of 1.2±1.9 BMI points; notably, 44% of subjects prematurely discontinued participation due to worsening mood symptoms (Wang et al. 2008).


Note. bid=twice daily; BMI=body mass index; SGA=second-generation antipsychotic; tid=three times daily.


aIn the United States, only 500-mg nonscored tablets of metformin are manufactured, and these cannot easily be split.



Weight Loss Supplements


There are a number of over-the-counter supplements that people sometimes use in attempts to hasten weight loss. Although evidence to support the efficacy of such approaches is often inconsistent, clinicians should be aware of safety considerations relevant to commonly used supplements, as summarized in Table 15–14.


Weight Loss


General Recommendations


Stimulants and some antidepressants (certain SSRIs or SNRIs, bupropion, nefazodone) may be associated with weight loss. If significant or undesirable weight loss occurs, drug discontinuation and substitution may be advisable (e.g., switching methylphenidate or amphetamine to atomoxetine, guanfacine, or modafinil/armodafinil).



Psychotropic-induced weight loss is a generally less common phenomenon than weight gain but nevertheless may pose an obstacle to treatment with a number of causal agents. The most well known among medications that can exert a proanorectic effect are psychostimulants (i.e., methylphenidate and amphetamine). No clear differences exist among specific preparations of these compounds (e.g., methylphenidate preparations Ritalin LA vs. Concerta vs. Focalin) or between methylphenidate versus amphetamine. In the treatment of attention-deficit disorder, nonstimulant treatment options such as atomoxetine or guanfacine may be viable alternatives with relatively lesser risk of weight loss. Among antidepressants, some SSRIs (notably, fluoxetine or bupropion) are thought to promote weight loss in some patients, and controlled trials with SNRIs such as duloxetine, venlafaxine, or desvenlafaxine also tend to show somewhat less weight gain than occurs with other antidepressant classes.


The evaluation of weight loss or appetite reduction should include careful assessment of possible noniatrogenic causes, both medical and psychiatric, including the presence of 1) depression, 2) anorexia nervosa or other eating disorders, 3) hypothyroidism, or 4) malignancy.











































































TABLE 15–14.Nutritional supplements commonly used to promote weight loss


Supplement


Rationale


Evidence


Possible adverse effects


Caffeine


Modest appetite suppression and stimulation of thermogenesis.


Most trials involve combinations of caffeine with thermogenic drugs such as ephedra or ephedrine.


Hypertension; reduces glucose tolerance.


L-Carnitine


Carnitine deficiency impairs fatty acid β-oxidation.


No differences from placebo in controlled trials.


None known.


Chromium picolinate


Trace element that can decrease insulin sensitivity and reduce carbohydrate craving in patients with atypical depression.


12-week randomized trial in overweight healthy adults found no differences in BMI or central adiposity (measured by computed tomography) between chromium picolinate (1,000 μg/day) and placebo (Yazaki et al. 2010).


Reports of acute renal failure, concerns about potential for causing chromosomal damage (clastogenicity).


Cissus quadrangularis (CQ) or CQ plus Irvingia gabonensis (CQ-IG)


Unknown.


10 weeks of CQ (150 mg bid) or CQ-IG (250 mg bid) in 72 obese or overweight adults led to an 8.8% reduction from baseline weight with CQ and an 11.9% reduction with CQ-IG (both superior to placebo) (Oben et al. 2008).


Headache, insomnia, GI upset.


Citrus aurantium and synephrine alkaloids


Direct appetite suppression.


Case reports but only one (negative) placebo-controlled trial (Bent et al. 2004).


Headache, tachycardia, and hypertension (although touted as a safer alternative to ephedra); cerebrovascular and cardiovascular events reported; tyramine content poses hazard when taken with MAOIs.


Ephedra (ma huang)


Increased metabolic rate.


Modest short-term weight loss (about 0.9 kg/month) for up to 6 months, based on meta-analysis of 284 reports (Shekelle et al. 2003).


Hypertension, excessive cardiovascular stress leading to strokes or arrhythmias; consumer alert issued by the FDA in 2008.


Garcinia atroviridis


Thought to block lipogenesis and promote lipid oxidation.


Favorable animal studies (for review, see Hasani-Ranjbar et al. 2009).


None known.


Garcinia cambogia–derived (–)hydroxycitric acid (HCA)


Competitive inhibitor of ATP citrate lyase, which in turn facilitates fatty acid synthesis.


Meta-analysis of 12 placebo-controlled trials revealed a small, significantly greater short-term weight loss with HCA than placebo (mean difference= 0.88 kg) (Onakpoya et al. 2011).


GI upset.


Green tea catechins with caffeine


270–1,200 mg/day empirically observed to reduce appetite; may promote thermogenesis and fat oxidation.


Meta-analysis of 15 studies indicates statistically but not clinically significant reductions in BMI (~0.55) or weight (~1.4 kg) (Phung et al. 2010).


Tachycardia, insomnia, dizziness, nausea.


Hydroxycut


Nutraceutical mixture containing Garcinia cambogia, Gymnema sylvestre, chromium polynicotinate, caffeine, and green tea.


No peer-reviewed published efficacy data.


Liver failure, rhabdomyolysis, death; recalled by the manufacturer after the FDA issued a warning in May 2009; reformulated and placed back on market.


Sambucus nigra (elderberry)


Antioxidant; possible weight loss mechanism unknown.


Favorable animal studies (for review, see Hasani-Ranjbar et al. 2009).


None known.


Note. ATP=adenosine triphosphate; bid=twice daily; BMI=body mass index; FDA=U.S. Food and Drug Administration; GI=gastrointestinal; MAOI=monoamine oxidase inhibitor.


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The symbol ■ is used in this chapter to indicate that the FDA has issued a boxed warning for a prescription medication that may cause serious adverse effects.

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Sep 1, 2019 | Posted by in PSYCHOLOGY | Comments Off on Metabolic Dysregulation and Weight Gain
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