Valproate may cause significant weight gain, which may be due to increased appetite and food intake, reduced energy expenditure or slower metabolism. One particular study of interest found that a group of subjects with epilepsy treated with valproate who gained weight also manifested a reduced metabolic rate, rather than an increased intake of calories [6]. A review of weight gain in patients with epilepsy showed that up to 71 % of patients treated with valproate gained weight (M = 22 kg, ranging from 8 to 49 kg) [7]. Furthermore, a recent study of patients who gained weight during valproate therapy also presented with significantly higher serum leptin concentrations. This may be indicative of leptin resistance and thus a reduced sensitivity of hypothalamic receptors to leptin action. This may produce a dysfunction in the sense of satiety and food intake control—more in women than in men [8]. The frequency of carbohydrate craving was 25.8 % higher in women and 14.3 % in men. In a study by Pylvänen and colleagues [9, 10], 51 patients receiving monotherapy with valproate and 45 healthy controls were evaluated, after an overnight fast, for differences in fasting plasma glucose and serum insulin, as well as in proinsulin and C-peptide, which are precursor molecules to insulin, synthesized in the beta cells of the pancreas. Patients receiving valproate showed fasting hyperinsulinemia although the fasting serum proinsulin and C-peptide levels were not higher in patients compared to control subjects, indicating that valproate did not increase insulin secretion, but may have altered insulin metabolism in the liver. In addition, proinsulin/insulin and C-peptide/insulin ratios results were lower in patients compared to controls. Moreover, valproate also is associated with increased androgen levels, which along with weight gain and hyperinsulinemia, is a feature of polycystic ovary syndrome (PCOS) [11].

Finally, valproate-treated patients had lower fasting plasma glucose concentrations than the control subjects. These changes were seen regardless of concomitant weight gain, suggesting that weight gain may be induced by increased insulin concentrations and not vice versa. In another study [9, 10], the same authors observed an association of valproate therapy with increased circulating insulin concentrations relative to body mass index. The participant sample in this trial was composed of lean and obese outpatients treated with valproate and a control group, which also included lean and obese subjects. The results suggest that the high insulin levels are not a consequence of obesity, as the rate of hyperinsulinemia was higher in patients treated with valproate than control subjects, and also higher in lean and obese patients treated with valproate than in lean and obese control subjects.

Although valproate is likely contributing to David’s obesity, due to David’s current unstable clinical situation, this may not be the best time to switch mood stabilizers. A change to a new mood stabilizer, with a reduced propensity for weight gain would be best considered as an adjunct treatment first, followed by a completed switching during the maintenance treatment phase .

Considering David’s diagnosis of bipolar I disorder, carbamazepine (CBZ) could be another pharmacological choice. Indeed, the majority of the published studies report a relatively low rate and magnitude of weight gain in patients treated with CBZ. Specifically, in a review, weight gain has been reported in 2.5–14 % of patients with epilepsy who were treated with CBZ [7] and a 6-month study by Ketter and colleagues [12] suggested that weight gain in patients with bipolar disorder is minimal during long-term treatment with CBZ. In fact, this study reported a mean weight gain of 0.7 %. However, treatment with CBZ may affect blood-cholesterol concentrations. CBZ’s effects on lipid metabolism were observed in a prospective study of adults with normal lipid indexes [13]. Significant increases in total cholesterol (by 13 +/− 15 %; p = 0.02), apolipoprotein B (apoB) -containing lipoproteins (very-low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], and low-density lipoprotein [LDL]) and increased levels of triglycerides were noted, with no increase in high-density lipoprotein (HDL). According to the authors, this could be due to changes in the conversion cascade of IDL particles, possibly as an indirect effect related to a thyroid hormone decrease.

Carbamazepine would have a lower risk of obesity. However, co-administration of valproate and CBZ is not recommended due to their pharmacodynamic interactions, as CBZ usually decreases valproate levels, and valproate may alter CBZ levels in unpredictable ways. Furthermore, valproate may prolong the elimination half-life of CBZ [ 14 ]. However, a possible change to carbamazepine may be considered in the future and we may opt to increase his dosage of valproate in the meantime as David’s latest blood concentration of valproate was 59 ug/mL at 2000 mg/ day .

Weight gain has been reported in virtually all published studies of this medication [21]. In particular, in a 4-week, randomized, double-blind, parallel study with a sample of 115 bipolar patients, Tohen and colleagues [28] described a weight gain of 2.11 kg (SD = 2.83 kg), and in a 6-month, double-blind study with 113 bipolor I patients, Sanger and colleagues [29] described a weight gain of 6.64 kg (SD = 8.51 kg).

Dyslipidemia has been well documented as one of the most common side effects. For instance, the association between olanzapine and hyperlipidemia was evaluated in a sample of 18,309 individuals with schizophrenia, with a finding that olanzapine use was associated with a nearly fivefold increase in the odds for developing hyperlipidemia, compared with no antipsychotic exposure (odds ratio [OR] = 4.65; 95 % CI: 2.44–8.85; p < 0.01) as well as a greater than threefold increase compared with those receiving conventional agents (OR = 3.36; 95 % CI: 1.77–6.39; p < 0.01) [30]. Moreover, several studies, including prospective trials, retrospective studies and single case reports, have increasingly implicated olanzapine as causing or exacerbating type 2 diabetes [21]. Indeed, Koller and Doraiswamy [31] documented 237 cases of olanzapine-associated hyperglycemia, where most cases (73 %) occurred within 6 months of therapy initiation, and 188 patients developed a new-onset of diabetes. Glucose levels were greater than 1000 mg/dL in 41 patients and 78 % of patients improved following medication discontinuation or dose reduction. Hyperglycemia recurred in 80 % of cases that were recruited for new course of olanzapine.

Although David’s manic symptoms have been historically managed well with olanzapine, it would be worth trying a medication with a lower metabolic risk .

Clozapine has an even greater propensity than olanzapine toward weight gain, diabetes, and hypertriglyceridemia [27, 32]. A 3-year, large, non-randomized, observational study evaluating 10,972 schizophrenic patients showed that clozapine (n = 188) induced body weight gain, ranging from 3.3 to 6.6 kg [33]. This evidence is supported by a review covering 16 clinical trials (n = 798) with early onset of schizophrenia that also highlights relevant weight gain due to the treatment with clozapine with an incidence of 20–64 %. Clozapine may contribute to the development of metabolic abnormalities, in particular hypertriglyceridemia (8–22 %) and diabetes (6 %) [34].

Although the risk of weight gain, diabetes, and dyslipidemia is lower with risperidone than with olanzapine, this compound is associated with a significant risk of hyperprolactinemia . For instance, in a randomized controlled trial [35], 90.5 % of subjects who received risperidone showed an increase in serum prolactin levels above the upper limit of the reference range (2–29 ng/mL). Only a few case reports and studies have suggested risperidone as an agent that increases the risk for diabetes and many schizophrenia trials suggest that risperidone does not have a high risk for hyperlipidemia or increase the incidence of diabetes [21].

Risperidone would represent an acceptable option for David’s manic symptomathology, but the risk for hyperprolactinemia is high and thus avoiding a further endocrinological worsening is warranted.

Quetiapine, compared to olanzapine and clozapine, has a lower propensity toward weight gain, but a higher one compared to risperidone. In a study by Brecher and colleagues [36], 352 patients were treated with quetiapine for 52 weeks. Overall, 37 % of patients gained 7 % or more of their baseline body weight. Interestingly, the rate of weight gain was inversely related to baseline body mass index. The mean weight gain at study end was 3.19 kg. In patients treated with <200 mg/day of quetiapine, mean weight gain was 1.54 kg, compared with 4.08 kg for 200–399 mg/day, 1.89 kg for 400–599 mg/day, and 3.57 kg for > or = 600 mg/day; median weight gain was 0.95 kg, 3.40 kg, 2.00 kg, and 3.34 kg, respectively. Of note, most weight gain (>60 %) occurred within the first 12 weeks of quetiapine treatment, with modest changes after 6 months. In a large study for patients with psychosis, quetiapine and risperidone patients had estimated odds of receiving treatment for type 2 diabetes that were no different than those of subjects who were never treated with antipsychotics or who were treated with conventional antipsychotics. However, other studies have suggested that quetiapine may share with other dibenzodiazepine-derived atypical antipsychotics, primarily olanzapine and clozapine, with a propensity to increase serum triglycerides levels [21].

Given that David is in a phase of his disease also characterized by delusional thoughts, we would like to choose a drug with timely action on these psychotic symptoms, but the pharmacological profile of quetiapine gives a high affinity to dopamine receptors only at high doses (600–800 mg/day), and this would require a longer time of titration than other atypical antipsychotics. For these reasons above, we decided not to introduce quetiapine .

Ziprasidone treatment is associated with low metabolic risks and analysis of laboratory data from the short-term studies showed that the incidence of abnormal elevations in random glucose measurements was the same as placebo (8 %). In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study [37], patients with schizophrenia treated with ziprasidone (n = 185) lost a median of 0.91 kg, with no significant change in serum glucose or glycosylated hemoglobin levels. Also, a reduction in total cholesterol and triglycerides (possibly due to the discontinuation of previous medications) was observed. Other switch studies with ziprasidone showed a reduction in body weight and other metabolic effects [38].

Ziprasidone could be a viable option for David. However, we decided to not prescribe ziprasidone medication at this point because of its risk of QTc interval prolongation, an electrocardiographic abnormality which increases the risk of irregular heart rhythm and “torsades de pointes.” Although the clinical relevance of this risk for ziprasidone has been recently questioned [ 39 ], we preferred to avoid this medication as a first choice drug because of David’s preexisting coronary artery disease and the risk of ischemia-induced arrhythmia.