The use of atypical antipsychotics in the therapy of depressive episodes in patients with bipolar disorder

Introduction

Bipolar disorder is an endogenous affective disorder that manifests itself with episodes of mania (hypomania) and depression [1].

Currently, there are two types of bipolar disorder: type I and type II [2]. Type I bipolar disorder is manifested by mania and mixed states [3]. Type II bipolar disorder is characterized by depressive and hypomanic episodes. Manic episodes do not occur in patients suffering from this disorder type.

Depressive episodes are more usual in type II than in type I [4]. Depressive episodes are the leading disease manifestation in patients with bipolar disorder [5]. During a systematic review of the literature describing the patients with type I bipolar disorder (who underwent long-term treatment), the academic specialists concluded that depression occupied approximately 70% of the time of affective episodes [6].

The prevalence of bipolar disorder ranges from 1% to 2.4% [7]. The percentage of suicides in patients with bipolar disorder is therefore 4–19% [8].

Problems of treatment of depressive episodes in the cases of bipolar disorder

The adequate treatment of recurrent depressive episodes in bipolar disorder was considered as a clinical problem, since antidepressants have not been able to demonstrate sufficient effectiveness in bipolar depression in short- and long-term studies [9].

Long-term treatment for type 2 bipolar disorder is mainly “preventive”, since it is aimed at preventing and/or reducing the frequency and severity of relapses of affective symptoms by means of using a combination of pharmacological and additional psychological interventions [10]. Compared with type I bipolar disorder, there is a limited number of studies confirming the sufficient effectiveness of one treatment option over others in type II bipolar disorder [11].

The use of atypical antipsychotics in bipolar depression

Lurasidone

Lurasidone is an atypical antipsychotic medicine with a high affinity for dopamine D2 receptors, serotonin 5-HT7 and 5-HT_2A receptors, moderate affinity for the serotonin 5-HT_1A receptor, and no noticeable affinity for H1-histamine and M1-muscarinic receptors [12].

Ishigooka et al. conducted a 28-week study of the safety and efficacy of lurasidone. For this purpose, patients were selected from a 6-week double-blind randomized trial, in which patients were divided into three groups: those taking the medicine in dosages from 20 to 60 mg, those taking 80 to 120 mg, and patients taking a placebo. The effectiveness was evaluated according to the Montgomery-Asberg Depression Assessment Scale (MADRS). By the end of the 28^th week, the overall average score on the MADRS scale decreased both in the group that had previously taken lurasidone for 6 weeks (by 8.9 points) and in the group that had previously taken a placebo (by 11.3 points). Among the side effects, akathisia, headache, and drowsiness were noted [13].

Raison et al. conducted a double-blind, 6-week placebo-controlled study in order to investigate the relationship between the levels of highly sensitive C-reactive protein (CRP) before treatment and changes in depressive symptoms and cognitive functions in patients aged 10–17 years with bipolar disorder. Therefore, patients were divided into groups – those taking flexible doses of lurasidone (20–80 mg) and groups taking a placebo. During the research course, it was found that in patients with an initial high CRP level, the response to treatment with lurasidone was better than in groups where the initial CRP level was low, but it was applicable only in patients with normal or low levels of body mass index (BMI). Lurasidone was more effective than placebo, regardless of the initial CRP [14].

Cariprazine

Cariprazine is a partial agonist of the dopamine receptors D2 and D3, and the serotonin receptor 5-HT_1A [15]. The unique affinity to the D3 receptor can mediate the antianhedonic, procognitive, and antidepressant effects of cariprazine [16–17].

Durgam et al. conducted an 8-week randomized, double-blind, placebo-controlled trial in order to study the efficacy and safety of cariprazine in patients with a major depressive episode with bipolar disorder. Patients were randomly assigned to groups of those taking aplacebo and those medicated with cariprazine at doses of 0.75, 1.5, and 3.0 mg/day. The effectiveness was evaluated according to MADRS and the “severity” subscale of the general clinical impression scale (GCI-S). Thus, cariprazine at a dose of 1.5 mg/day showed a significant decrease in MADRS scores from the baseline level by the 6^th week of the study compared with placebo (the difference in the mean values of the least squares was -4.0). While taking cariprazine at a dosage of 3 mg/day, the patients demonstrated the difference in the average values of the least squares (-2.5). The dosage of 0.75 mg/day was similar to the placebo dose.

The most common undesirable side effects in patients treated with cariprazine were akathisia and insomnia. Weight gain was slightly higher in patients taking cariprazine than in those taking a placebo [18].

In another double-blind, placebo-controlled study of the cariprazine safety and efficacy, conducted by Earley et al., similar results were obtained as well. As for the study, patients aged 18–65 years who met the DSM-5 criteria for type I bipolar disorder with a current depressive episode were selected. Also, patients were divided into three groups: those taking 3 mg of cariprazine per day, those taking 1.5 mg of cariprazine per day, and patients taking a placebo. The effectiveness was evaluated according to MADRS and GCI-S. After 6 weeks, it was evident that both doses of cariprazine were significantly more effective than placebo. Both doses of cariprazine were associated with lower CGI-S scores compared to placebo, but the differences did not reach statistical significance. Side effects in the groups of patients taking cariprazine were recorded twice as often as in the placebo group. The most common side effects were nausea, akathisia, and dizziness [19].

Olanzapine

Olanzapine is a type of medicine that has an affinity for serotonin _5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₆, D₁, D₂, D₃, D₄ and D₅, muscarinic, adrenergic a1 and histamine H1 receptors [20].

Katagiri et al. conducted a 6-week double-blind randomized study of the efficacy and safety of olanzapine in bipolar depression. Compared with placebo, patients from the “olanzapine” group showed a decrease in MADRS scores. However, in this group, side effects were more common, such as weight gain, increased cholesterol, triglycerides, low-density lipoproteins, and a decrease in the level of high-density lipoproteins [21].

Pan et al. found out that olanzapine was more effective than lamotrigine in the prevention of depressive episodes in patients with bipolar disorder [22].

Quetiapine

Quetiapine is an atypical antipsychotic that blocks the dopamine D2 and serotonin 5-HT2 receptors [23].

Kishi et al. studied the efficacy and safety of prolonged-action quetiapine at a dosage of 300 mg/day and olanzapine at a dosage of 5–20 mg/day in patients with bipolar depression according to Bayesian analysis. As a result, it was found that there was no significant difference in effectiveness between these medicines. In patients taking quetiapine, drowsiness was a frequent side effect, and in the group taking olanzapine, frequent side effects were: increased body weight, increased prolactin levels in the blood, and a decrease in the level of high-density lipoproteins [24].

Simon et al. conducted a multicenter, double-blind, placebo-controlled study in order to compare the effectiveness of quetiapine monotherapy and the combination of quetiapine with lamotrigine. It was found out that the combination of quetiapine with lamotrigine was more effective compared to quetiapine monotherapy [25].

Risperidone

Lindström et al. conducted a meta-analysis of 15 randomized clinical trials (RCTs) in order to study the effectiveness of using atypical neuroleptics for the period from 6 months to 4 years in 6142 patients suffering from bipolar disorder. It was found out that as monotherapy, olanzapine, quetiapine, and risperidone were superior to placebo in reducing the overall risk of relapses [26].

A retrospective study of the risperidone effectiveness (when the medicine was taken in order to reduce the risk of developing affective episodes in patients with bipolar disorder) showed that additional medication reduced the risk of developing manic episodes, but did not reduce the risk of developing depressive episodes [27].

In the course of comparing the safety of quetiapine and risperidone in patients with bipolar affective disorder, it was found that risperidone therapy also caused such side effects as weight gain and increased prolactin level [28].

Aripiprazole and ziprasidone

Bahji et al. conducted a systematic review and meta-analysis of the RCT of the pharmacological therapy efficacy and safety for bipolar depression. Fifty (50) studies with 11,448 patients were analyzed therefore. Thus, aripiprazole and ziprasidone were ineffective compared to placebo in the bipolar depression treatment. Aripiprazole caused side effects more often than placebo.

 Olanzapine, quetiapine, and cariprazine were more effective than placebo in the bipolar depression treatment [29].

As for another systematic review and meta-analysis conducted in order to study the aripiprazole efficacy and safety in bipolar disorder, it was found out that the medicine was effective in the treatment of mania, psychosis, but did not show effectiveness in the bipolar depression treatment [30]

Conclusion

Lurasidone, cariprazine, olanzapine, and quetiapine were significantly more effective than placebo.

Risperidone, aripiprazole, and ziprasidone were ineffective in the treatment of bipolar depression.

Olanzapine causes more serious side effects (weight gain, increased cholesterol, triglycerides, low-density lipoproteins, and a decrease in high-density lipoproteins) than lurasidone, cariprazine, and quetiapine.

Combined administration of quetiapine with lamotrigine is more effective than monotherapy with an antipsychotic.

In the cases of children and adolescents with normal weight and higher levels of CRP, the lurasidone medication before treatment was accompanied by a better response to antidepressant therapy compared to those patients taking a placebo. CRP and BMI may be useful diagnostic and prognostic biomarkers in the lurasidone treatment of children and adolescents suffering from bipolar depression.