Comparison of the efficacy of venlafaxine and bupropion in the treatment of depressive episode in patients with bipolar II disorder : Journal of Family Medicine and Primary Care

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Original Article

Comparison of the efficacy of venlafaxine and bupropion in the treatment of depressive episode in patients with bipolar II disorder

Fakhri, Ahmad1; Asadi, Khatereh2; Pakseresht, Sirous2; Norouzi, Shahin2; Rostami, Hamzeh2,

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Journal of Family Medicine and Primary Care 12(3):p 440-445, March 2023. | DOI: 10.4103/jfmpc.jfmpc_1258_22
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Bipolar disorder (BP) is determined by recurrent periods of highs and lows of mood, thinking, activity, of varying severity, duration, and frequency, including combinations of manic or hypomanic and depressive symptoms in the same episode.[1]

Bipolar I and II represent the most prevalent and severe subtypes of BD.[2] The diagnosis of bipolar I requires the presence of at least one manic episode, with or without a history of major depressive episodes, whereas bipolar II disorder (BD II) requires at least one hypomanic and one major depressive episode.[3]

Even though polarity – the presence or absence of manic/hypomanic episodes – is the defining feature in our classification of primary mood disorders, distinguishing unipolar from BD depression is the dominant pole. Overall, including both bipolar I and II patients, bipolar individuals spend three times as many weeks depressed as they do manic/hypomanic.[4,5] Depression is related to an increased risk of suicide and disruptive psychosocial function.[6]

The use of antidepressants (ADs) in the treatment of BD is a subject of remarkable controversy. Information on the efficacy and safety of ADs in both acute and long-term treatment of BD is generally changeable.[7–9] The data on effectiveness of ADs in BD II are limited and conflicting.[8,10] Few studies have compared BD I versus BD II patients with respect to clinical correlates of antidepressant use.[11,12] Comprehension of demographic and illness characteristics in BD II patients, could improve our understanding of how and when ADs are used for treatment of BD in clinical practice.

A prior meta-analysis exploring the advantages and risk of long-term ADs treatment for BD patients indicated that long-term adjunctive ADs treatment had little protection for depression relapse while obviously increased risk of affective switch.[13]

To our knowledge, no study has been conducted on the treatment of depressive BD II in Iran; the aim of this study was to compare the efficacy of venlafaxine and bupropion in the treatment of patients with depressive episode of BD II.

Methods and Materials

Study design and participants

The present study is a triple-blind randomized controlled clinical trial comparison of bupropion monotherapy versus venlafaxine monotherapy for BD II depression. Forty patients with BD II who were referring to Golestan Hospital affiliated with Ahvaz Jundishapur University of Medical Sciences in 2020 were included in this study. Patients aged more than 18 years old with BD II based on the DSM-V diagnosed by a psychiatrist were enrolled in the study if they fulfill the following inclusion criteria: 1) Diagnosis of depressive episode of BD II based on DSM-V criteria and confirmation of the patient’s hypomania course or courses based on Mood Disorder Questionnaire (MDQ) and 2) the patient has not used any other antidepressant 4 weeks before the start of the study.

Depression caused by a physical illness, substance abuse or medication, existence of any severe and chronic physical diseases, history of gastric ulcer, mental retardation, psychosis, periodic history of mania, consumption of alcohol and drugs during the last 6 months, incidence of intolerable side effects of the drug, psychotic depression, and active suicidal thoughts were the exclusion criteria.

The eligible subjects were randomly assigned to either bupropion (N = 20) or venlafaxine (N = 20) for 4 weeks using a four-block randomization method. One group was treated with bupropion 100 mg/day and the other group was treated with venlafaxine 75 mg/day. Treatment was started with one pill a day and could be increased up to three times this dose, based on the patient’s response and tolerance. In both groups, drugs were similar in terms of shape, color, and size. All patients were followed up by the same psychiatrist at predetermined times: before the treatment initiation, subsequently 4 weeks after treatment initiation.

Measurements and outcomes

In current study, diagnosis of hypomania was assessed based on the MDQ. To assess the severity of depressive disorder, the Hamilton Depression Rating Scale (HDRS) was used. Patients in both groups completed HDRS questionnaire before and after the intervention (at the beginning of the intervention and 4 weeks after starting treatment). Then, the two groups were compared in terms of the severity of depressive disorder. The primary outcomes were change over time in HDRS scores and suicidal thoughts. In current study, all members of the research team, patients, and statistical analyzers were blind of the designed treatment groups.

Ethical considerations

The study was approved by the Medical Ethical Committee of Ahvaz Jundishapur University of Medical Sciences (Ethics code: IR.AJUMS.REC.1398.831), and this trial was registered in the Iranian clinical trial system with the patented number of IRCT20200913048698N1. In this study, the written informed consent was obtained from each patient.

Statistical analysis

Data were analyzed using SPSS software version 22 (SPSS Inc., Chicago, IL, USA). Descriptive statistics were presented as mean ± standard deviation for quantity values and frequency (percentage) for qualitative values. Kolmogorov–Smirnov test was applied to test for the data normality. Differences were compared by using the paired sample t-test. Homogeneity of variance was assessed by the Leven test. Pearson’s and Chi-square tests were used to investigate the correlation between quantitative and qualitative variables. P value less than 0.05 was considered significant.


The current clinical trial study included 20 patients in each group. According to demographic information, the mean age estimate was 34.45 ± 6.95 and 31.05 ± 7.69 in venlafaxine and bupropion groups, respectively. This difference was not statistically significant (P value = 0.15). Also, the sex distribution between the two groups was homogenous (P value = 1.00).

MDQ was evaluated between two groups and it was found the symptoms of mania/hypomania are not statistically significant (P value = 0.326). The mean of section 1 in the MDQ was estimated at 7.35 ± 1.56 and 6.95 ± 0.88 in venlafaxine and bupropion groups, respectively. Besides no difference was seen in Section 2 and 3 of MDQ.

To assess the effectiveness of the intervention, HDRS was compared and it was not found any differences before (P value = 0.43) and after the treatment (P value = 0.15). In addition, the rate of change in HDRS score was not significantly different between the two treatment groups. HDRS score in both groups significantly decreased after 4 weeks (P < 0.0001). Although the rate of decrease in depression score was more in venlafaxine than in bupropion, these differences were not significant (36.7 ± 21.8% vs. 45.3 ± 17.9%, P value = 0.17). To evaluate the intervention, the creation of suicidal thoughts was estimated between and within groups. The two groups were homogenous before the intervention (2.00 ± 0.79 vs. 2.10 ± 0.78, P value = 0.69), also after the treatment, it was decreased, although the differences were not meaningful between them (1.65 ± 1.33 vs. 1.00 ± 0.97, P value = 0.06) [Table 1].

Table 1:
Baseline and clinical characteristics of patients in two groups

Within comparison has shown significance only in the bupropion group (P value < 0.001), whereas the P value was estimated 0.26 within the venlafaxine group [Table 2].

Table 2:
Baseline and clinical characteristics of patients before and after intervention

Gender and age as the baseline covariates were investigated for treatment response. The results of HDRS changes showed venlafaxine had similar efficacy in men and women (P = 0.823). Bupropion was more effective in women than men; therefore, HDRS score showed a greater decrease in women than men after 4 weeks (P value = 0.007). No relationship was found between treatment response and age of patients (Pearson’s correlation = 0.43, P value = 0.056).


The aim of this study was to evaluate the efficacy of venlafaxine compared with bupropion in the treatment of patients with depressive episode II. In the current study, the two groups were matched in terms of age and sex, and also in terms of the severity of mood disorders before treatment were not significantly different from each other, which indicates that these factors do not affect the results, the samples are completely random.

The results of the present study showed that HDRS decreased significantly after 4 weeks of treatment in each group. On average, after 4 weeks of treatment, the depression score in the venlafaxine and bupropion groups decreased by 36.7% and 45.3%, respectively. But the change in HDRS between the two treatment groups did not show a significant difference. Furthermore, the score of suicidal thoughts before and after treatment was not considerably different between the two groups. These findings indicate similar efficacy of ADs both venlafaxine and bupropion in the treatment of depressive episode of BD II.

Well-designed controlled trials with AD monotherapy for episodes of BD are very limited and have shown conflicting results.[14–16] Several meta-analysis studies have reported the potential efficacy of various ADs in bipolar depression,[17,18] While another study showed the ineffectiveness of ADs in bipolar patients.[19] Despite limited and contradictory studies, there is clear evidence that these drugs are appropriate for some BD patients, and in particular their safety for BD-II depression.[16,20]

Venlafaxine is a class of serotonin-norepinephrine reuptake inhibitors and works by inhibiting the reuptake of serotonin, norepinephrine, and dopamine in the brain. Inhibition of reabsorption of these neurotransmitters increases their access and overall effect.[21]

Amsterdam et al.[22] reported that treatment with venlafaxine for 12 weeks significantly reduced HDRS depression score in patients with major depressive episode in BD II and had no serious side effects. In another randomized clinical trial by Amsterdam et al.,[23] it was observed that taking venlafaxine monotherapy for 12 weeks significantly improved patients with BD II depressive episode. These results are consistent with the findings of the present study. Venlafaxine monotherapy is a safe and effective option for treating bipolar depression.

Bupropion with unique pharmacocytics as an aminoketone and a reabsorning norepinephine-dopamine has been approved by the FDA since 1989.[24] In addition, bupropion is widely used to treat BD II, especially people with depression episodes.

Furthermore, because of its ability to improve the symptoms of depression at a lower risk of shifting than other antidepressant, some guide-based bipolar treatment, monotherapy, or in combination with other medications is recommended.[25]

The results of a meta -analysis by Li et al.[26] aimed at evaluating the effectiveness of bupropion in the treatment of BD showed that the bupropion significantly improves the severity of the disease in BD, and there is no significant difference in the effectiveness of bopropion therapy compared to other ADs. These results match the findings of the present study. Other studies have reported that the effectiveness of the bopropion in reducing the severity of the symptoms of depression in BD is similar to other ADs.[27]

Post et al.[28] Reported that the three ADs bupropion, venlafaxine, and sertraline had similar efficacy in response to treatment and remission in patients with BD for 10 weeks.

Also in a meta-analysis study with 11 randomized controlled trials consisting of 692 patients on the effectiveness of various depressants (including popropion and venlafaxine) for BD, the results showed that ADs reduced new episodes of depression, without increase the risk of manic and hypomanic episodes, both monotherapy and in combination with mood stabilizers were superior to placebo and mood stabilizers.[29]

The results of Leverich et al.[24] study showed that the treatment with different ADs (venlafaxine, sertraline, and bupropion) for patients with depressive episode of BD II in a short time (10 weeks) causes a response to treatment and significant improvement in patients. The total rate of switching to hypomania was 19.3% that the highest and lowest rates were reported for venlafaxine and bupropion, respectively. In another meta-analysis, a review of 1,117 patients from three random trials showed that bupropion was as effective as venlafaxine in treating patients with major depressive disorder and reducing the HDRS depression score,[21] which is similar to the results of our study.

According to our findings, venlafaxine had similar efficacy in male and female but bupropion had better efficacy in female than male, so that HDRS score after 4 weeks of treatment was significantly lower in female.

Briefly, the results of the current study showed that treatment with two ADs, bupropion and venlafaxine, is effective, has no dangerous and serious side effects, and can be used as an affordable and safe drug in the treatment of depressive episodes in patients with BD II.

Because both venlafaxine and bupropion act by boosting certain neurotransmitters in brain, including norepinephrine and dopamine, their similar efficacy in reducing depressive symptoms is not unexpected. Mechanisms of noradrenergic/dopaminergic action play an important role in BD, and the balance of these neurotransmitters can help improve mood, better sleep, improve appetite, and focus. Although the use of ADs to treat depressive episodes in patients with BD raises concerns about the shift from depression to mania and rapid cycling, these are commonly prescribed for bipolar depression.[30] Therefore, because of the lack of sufficient evidence in this field, randomized controlled clinical trials are necessary to determine the role of different ADs in the treatment of bipolar depression.

This study had several limitations. First, only short-term effects of drugs were studied and the effects of using these drugs for a longer period and their effect on disease recurrence were not evaluated. Second, the placebo group was not considered, which did not determine the true efficacy of the drugs in BD II depression. Third, the effect of the number of previous episodes and the history of previous psychiatric hospitalization on the effectiveness of drugs was not investigated. Finally, we can point to the small number of samples.


The results of the present study showed that the two ADs venlafaxine and bupropion are equally effective in treating the depressive episode of BD II and no significant difference was observed in reducing depressive symptoms based on the HDRS between the two groups. Therefore, because of their safety and effectiveness, these two ADs can be used clinically to treat patients with BD II, in addition to reducing patients’ symptoms, to alleviate the high cost of treatment and possible complications because of depression in these patients. It is suggested that further studies be performed to compare the efficacy of venlafaxine and bupropion as adjuvant therapy, with larger sample size, over longer periods of time and the effect on disease recurrence.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest..


The authors acknowledge financial support from the Ahvaz Jundishapur University of Medical Sciences (Grant Number: U-98247).


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Bipolar II disorder; Bupropion; depressive episode; venlafaxine

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