The Efficacy of Bupropion in Alleviating Negative Symptoms of Schizophrenia: A Systematic Review and Meta-Analysis article

The Efficacy of Bupropion in Alleviating Negative Symptoms of Schizophrenia: A Systematic Review and Meta-Analysis article Saleh A. Alghamdi Imam Mohammad ibn Saud Islamic University [email protected] 00966503778164 https://orcid.org/0000-0003-3264-7397 The Efficacy of Bupropion in Alleviating Negative Symptoms of Schizophrenia: A Systematic Review and Meta-Analysis article Abstract: Background:Negative symptoms in schizophrenia frequently show resistance to standard antipsychotic therapies and play a substantial role in adverse functional outcomes. Bupropion, classified as an atypical antidepressant, has been explored as a possible adjunctive treatment for symptom relief; however, the evidence is still inconclusive. Objectives: To systematically evaluate the effectiveness of bupropion in alleviating negative symptoms of schizophrenia by synthesizing data from existing randomized controlled trials and observational studies. Methods: A thorough search was performed in PubMed, Embase, PsycINFO, and Cochrane Central from inception until March 2025. Eligible studies comprised adult patients diagnosed with schizophrenia and a specified evaluation of negative symptoms, comparing bupropion (either as monotherapy or adjunctive therapy) to placebo or standard treatment. The assessment of risk of bias was conducted utilizing the Cochrane RoB 2.0 and ROBINS-I tools. A random-effects meta-analysis was conducted to compute standardized mean differences (SMDs) and evaluate heterogeneity. Results:A total of twelve studies were included, with sample sizes varying between 12 and 196 participants. Pooled data indicated a modest yet statistically significant effect of bupropion in alleviating negative symptoms, especially when utilized as an adjunct to antipsychotics. Moderate heterogeneity and methodological variations were observed across the studies.Limitations:The overall certainty of evidence was low, primarily due to small sample sizes, inconsistent outcome measures, absence of blinding, and moderate heterogeneity. The differentiation between primary and secondary negative symptoms has been insufficiently examined. The limited number of studies constrained sensitivity analysis and publication bias assessments.Conclusion:Bupropion may offer potential benefits in ameliorating negative symptoms associated with schizophrenia; however, however, findings necessitate cautious interpretation. Additional high-quality randomized controlled trials employing standardized measures and extended follow-up are required to validate its efficacy and safety. Registration: This review has not been registered in a public database. Introduction Schizophrenia is one of the most serious mental disorders that is classified as a chronic disease. There are about 20 million individuals all over the world who struggle with this kind of condition (Charlson et al., 2018). Notably, it has been referred to as a mix of positive symptoms (hallucinations, delusions, and disorganized speech), negative symptoms, and cognitive deficits. Although positive symptoms tend to respond to antipsychotic medication, negative ones are less susceptible to medication and closely associated with chronic disability (Ricci et al., 2025). The symptoms impair the quality of life, social integration, and vocational outcomes not only in individuals with schizophrenia alone but also make it difficult to recover in terms of functionality. Thus, managing negative symptoms is one of the priorities in clinical and research settings. The current pharmacological interventions, such as the first and the second generation of antipsychotics, have little effect on the significant decrease of primary negative symptoms (Cerveri et al., 2019). Despite the limited benefits of the few antipsychotics (e.g., cariprazine), many patients still present residual deficits despite positive symptoms being successfully controlled. This is associated with a treatment gap in which clinicians have focused on research on adjunctive pharmacotherapies to enhance motivation, social activities, and responsiveness. In that regard, antidepressants have been of specific interest, owing to both their possible uses to treat the comorbid depressive symptoms associated with neurochemical ways that contribute to adverse symptomatology. Drugs that are used to treat depression include bupropion, marketed as wellbutrin and Zyban, which is a norepinephrine-dopamine reuptake inhibitor (NDRI) with added nicotinic acetylcholine receptor blocking actions (Chang et al., 2022). Bupropion was initially formulated and licensed to be used as an antidepressant, but now it is known to be a popular smoking cessation agent. It has a pharmacological profile that, compared to more frequently prescribed antidepressants, is unique in that it has pronounced dopaminergic action, perhaps of particular pertinence to the pathophysiology of the negative symptoms of schizophrenia. Mesocortical Hypodopaminergia has traditionally been considered in relation to motivational disorders and anhedonia, with the implication that drugs that increase the transmission of dopamine in the prefrontal cortex could treat these conditions. Besides, the noradrenergic effects of bupropion may amplify attention and energy, leading to improved functioning (Clark et al., 2023). Even with such theoretical benefits, bupropion use in the treatment of negative symptoms of schizophrenia is yet to be formalized and is an off-label use. There is high heterogeneity with a low-quality body of evidence. Some clinical trials and case reports suggest modest negative symptom improvements at least in patients with comorbid depression or smokers, and some studies have found no meaningful differences between active drug and placebo (Kozak & George, 2020). Also, the extent to which improvements observed are due to observed changes in primary negative symptoms or secondary to symptoms of depression, side effects of medications, or the environment is often not apparent. It is essential to differentiate these to determine the effectiveness of bupropion in such a situation. The currently available literature is disjointed and comprises small randomized controlled trials, open-label work, and case series. The sample sizes are also generally insufficient to detect any clinically significant treatment effect and methodological variability, such as using varied scales to measure negative symptoms, varying lengths of the treatment parameters, and antipsychotic combinations. Thus, the comparison between studies would be hard. Other research papers also fail to include confounding variables such as cigarette smoking, which is highly prevalent among patients with schizophrenia, and may hence skew the parameters of the dopaminergic tone and the efficacy of bupropion. Consequently, clinicians are still uncertain about the appropriateness of bupropion for the management of negative symptoms, particularly due to the reliance on anecdotal reports and limited empirical evidence. Nevertheless, this has contributed to the increasing use of bupropion in clinical practice. This systematic review and meta-analysis seek to answer the question: What is the efficacy of bupropion in alleviating the negative symptoms of schizophrenia, and how do study characteristics, patient factors, and methodological differences influence observed treatment effects? By explicitly addressing this question, the study aims to synthesize the available evidence, clarify the potential role of bupropion in clinical practice, and identify key areas for future research. Objectives: A systematic review and meta-analysis of the effectiveness of bupropion in the treatment of negative symptoms of schizophrenia has been developed to fill in this gap. In particular, it will: (1) summarize the results of studies conducting randomized controlled trials and other pertinent studies that measured the effects of bupropion on negative symptoms scales; (2) investigate whether treatment effects vary according to the study design, characteristics of the intervention, smoking or baseline severity of symptoms; (3) summarize the findings of secondary outcomes, such as depressive symptoms, global functioning, and side-effects; and (4) determine the overall quality of the evidence with the help of the risk-of-bias and evidence grading measures. This work aims to offer evidence for clinicians who want to adopt bupropion as an auxiliary medication against negative symptoms and point out research priorities by combining the findings of different studies. Background and its Rationale (Rationale Literature Review): Negative Symptoms of Schizophrenia: The Significance of the Clinical Spectrum Negative symptoms are one of the most troublesome symptoms of schizophrenia to cure and control. In contrast to positive symptoms, which are revealed in recognizing gross distortion of perception and thoughts, negative symptoms are implicated in the impairment or loss of standard functions (Correll & Schooler, 2020). Blunted affect, alogia (the poverty of speech), avolition (the inability to become motivated), anhedonia (decreased ability to experience pleasantness), and asociality are the main areas. This severely affects social functioning, self-support, and career activities. Epidemiological studies show that nearly 60 percent of people with schizophrenia develop negative symptoms during the illness development, with minimal or no effect towards controlling the positive symptoms affecting them efficiently (Galderisi et al., 2021). Perpetual deficiencies are a key cause of irreversible disability, loss of functionality, and social/healthcare welfare systems. Furthermore, negative symptoms are an effective predictor of functional outcome, especially compared to positive symptoms or cognitive impairment. The distinction between primary and secondary negative symptoms is a key issue in research and practice settings. Initial symptoms are inherent to the disease and probably connected with fundamental neurobiological changes. Secondary symptoms, on the other hand, can be caused by the presence of depression, extrapyramidal side effects of medications, or due to the issue of social deprivation (Correll & Schooler, 2020). That is essential as medications to alleviate secondary symptoms might not necessarily aim at the underlying primary deficits. Regrettably, too many clinical trials fail to distinguish between these types well enough, bringing about heterogeneity of reported results. Neurobiological Basis of Negative Symptoms: Studies of the pathophysiology of negative symptoms have always involved dysregulation of the dopaminergic and glutamatergic neurotransmission. Dysfunctional hypodopaminergia in the mesocortical pathway (especially in the frontal cortex) correlates with motivation, reward processing, and goal-directed actions. Cortico-striatal circuitry may also be distorted by glutamatergic abnormalities, partly by N-methyl-D-aspartate (NMDA) receptor hypofunction, heightening motivational and affective responsiveness problems. There is decreased use in the ventral striatum when rewards are forthcoming, and hypoactivation of the prefrontal cortex is observed during executive control-oriented tasks in functional neuroimaging studies. The above patterns indicate an impairment in the neural circuit, which integrates motivation, cognitive control, and emotional expression. Based on these results, it has been postulated that adverse symptom therapeutic action occurs with agents that promote neurotransmission of the dopaminergic and/or noradrenergic system in these brain areas. Bupropion and Pharmacology of Bupropion and its Theoretical Relevance: Bupropion is the only antidepressant that is characterized by a special mechanism of action as a norepinephrine-dopamine reuptake inhibitor (NDRI). It enhances the concentration of these neurotransmitters, namely dopamine and norepinephrine, at the synaptic levels, especially in the prefrontal cortex, by blocking dopamine transporter (DAT) and norepinephrine transporter (NET) proteins (Deang et al., 2019). Bupropion stands apart among most other antidepressants in possessing low serotonergic activity, which might decrease the potential risk of some side effects, such as sexual dysfunction, that might further exacerbate motivational failures. Besides inhibiting the monoamine reabsorption, bupropion is a non-competitive inhibitor of the nicotinic acetylcholine receptors (Simões, 2024). Its activity in smoking cessation is because of this property, and it can also be responsible indirectly for dopaminergic release. Given that nicotine dependence is so common in schizophrenia, the nicotinic antagonism of bupropion may have two clinical advantages: treating nicotine addiction, in addition to possibly rewiring neuronal pathways that involve reward and motivation (Patidar et al., 2025). Clinical Research Landscaping: Despite the pharmacology of bupropion implying that it might be helpful in negative symptoms, the empirical support is beginning to mix. Its use has been retained in small randomized controlled trials (RCTs) as an adjunct antipsychotic therapy and less frequently as monotherapy in the schizophrenia spectrum disorders (Tsapakis et al., 2024). Other studies found a statistically significant improvement in the Scale of negative symptoms, in terms of Positive and Negative Syndrome Scale (PANSS) negative subscale or Scale for the Assessment of Negative Symptoms (SANS). Such benefits were also concomitant with decreased depressive symptoms in some trials, raising the possibility of a dual effect. Nevertheless, other findings have not been replicated. On the one hand, negative symptoms did not constantly improve significantly more than placebo, or the changes were possible to explain by improvement of secondary depressive symptoms other than primary negative symptoms. Trial periods are not very long and are usually between four and twelve weeks, thus making it hard to determine the sustainability of benefits. Confounding Factors and Moderators: Cigarette smoking status is one of the essential factors to be considered in the assessment of the effect of bupropion in schizophrenia. The use of cigarettes among patients with schizophrenia is very high, and it is common to find someone who smokes exceeding 60-70 percent (Caponnetto & Polosa, 2020). Nicotine affects routes of dopaminergic activity and has the potential to change the pharmacodynamic effects of bupropion. Also, smoking may cause induction of hepatic cytochrome P450 enzymes, which may influence drug metabolism. It has been postulated in some studies that the use of bupropion in smokers might be associated with larger improvements in mood and motivation, but this may represent only an extended benefit of smoking cessation with bupropion. Another moderator possibility is depression. Since bupropion has antidepressant effects, the resulting positive impact on negative symptoms may be due to the alleviation of depressive symptoms as opposed to the core adverse symptomatology (Pannu & Goyal, 2025). This presents methodological challenges: numerous clinical trials do not stratify patients according to the presence or absence of clinically significant depressive symptoms in their analyses, complicating the disentanglement of these effects. Methods: Systematic Review Meta-Analysis Protocol: The purpose of the review was to summarize all pieces of evidence assessing the effectiveness of bupropion in alleviating the negative symptoms of schizophrenia. The PICOS framework clearly defined the inclusion and exclusion criteria in this respect. The study population of interest includes adults with schizophrenia or alternative disorders in the schizophrenia spectrum, including schizoaffective and schizophreniform disorder, based on accepted diagnostic criteria, either DSM or ICD. Any formulation (immediate, sustained, or extended release) and dose (any therapeutic dose) of bupropion used as monotherapy or first-line treatment adjunctively with antipsychotics was the intervention considered. The comparators were placebo, no treatment, or active control interventions. The key effect was adjusted negative symptoms based on such scales as the Positive and Negative Syndrome Scale (PANSS) negative subscale, the Scale for the Assessment of Negative Symptoms (SANS), or the Brief Negative Symptom Scale (BNSS). Depressive symptoms, global functioning, quality of life, and incidences of adverse events, such as treatment discontinuation, were secondary outcomes. The inclusion criteria of suitable study designs were randomized controlled trials (RCTs), controlled clinical trials, and prospective observational studies. However, case reports, review articles, editorials, letters, and commentaries were excluded from the meta-analysis. Nevertheless, select case reports and case series were reviewed narratively to offer supplementary clinical context. A comprehensive literature review was conducted in PubMed, Embase, PsycINFO, and Cochrane Central from inception until March 2025. The search strategy included controlled vocabulary terms (e.g., MeSH) and free-text keywords concerning bupropion, Wellbutrin, schizophrenia, negative symptoms, and outcome measures. The publication date was mainly between 2010 and 2025, and research conducted in all languages was considered, including translations where the articles were available. Unpublished and ongoing trials were sought using Grey literature resources such as ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. Another effort to retrieve more eligible records included screening reference lists of included studies and pertinent reviews. The screening of titles and abstracts to ascertain the study's eligibility included two independent reviewers. Articles that could likely be used are evaluated using their full texts concerning the inclusion criteria. Arguments during any phase would be settled with discussion and arbitration by a third reviewer if necessary. Two reviewers performed data extraction in duplicate using a predesigned form. They entered data included in the following categories: study design, population characteristics, details of the intervention, type of comparator, outcomes of measurement, follow-up time, and numerical data. Primary study authors were contacted wherever possible to clarify unclear research data or make missing information available. The included RCTs ' risk of bias and methodological quality were measured with the Cochrane Risk of Bias 2 tool, whereas non-randomized studies were measured with the ROBINS-I tool. The grade of overall certainty of evidence of each outcome was assigned based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach, considering risk of bias, inconsistency, indirectness, imprecision, and publication bias (table 1). Considering that the measurement of negative symptoms of schizophrenia was heterogeneous in the included studies, forest plots were used to analyze effect sizes using the Standardized Mean Difference (SMD) technique. In studies that presented continuous results on various scales, the raw means and standard deviations were transformed to a common unit so that they could be compared. Means and standard deviations were calculated when medians and interquartile ranges were provided, ensuring no change in the value of the results (e.g., Wan et al., 2014). In case of a study that showed change-from-baseline scores, they were prioritized; otherwise, endpoint scores were taken. Standard deviations were back-estimated where standard errors or intervals were used. In quantitative synthesis, continuous outcome measures used the standardized mean differences (SMD) of the results with 95 % confidence intervals, which enable pooling the study findings with different negative symptom scales. Between-study variability was considered using a random-effects model, using the DerSimonian and Laird method. The I² statistics have been used to measure statistical heterogeneity, and values greater than 50 % (>50%) are considered substantial heterogeneity. Subgroup analyses were to be carried out where adequate studies were available to investigate moderators, such as the duration of the treatment (<8 weeks versus >=8 weeks), smoking status, the severity of the negative symptoms at baseline, and whether treatment with bupropion was monotherapy or adjunctive therapy. Pre-specified sensitivity analyses were also implemented, such as omitting the studies with a high risk of bias and using fixed-effect models. Visual assessment of publication bias and the Egger test were carried out when more than ten studies were present on the primary outcome. Meta-analysis was done using Review Manager (RevMan) and R software using the metafor package. Table (1): full GRADE Summary of Findings Table Results: The meta-analysis and systematic review aimed at establishing the usefulness of bupropion in reducing the negative symptoms of schizophrenia and intend to summarize the evidence across the available studies by integrating the studies that cover both clinical trials and observational studies, as well as case reports. The total number of unique records returned after the de-duplication of the search strategy was 632. After screening titles and abstracts, 78 articles were found to be under review in full text. Out of these, 14 fulfilled the inclusion criteria and were used in a final synthesis. These included eight randomized controlled trials (RCTs), and three prospective cohort studies. Three case series/case reports and a case series indicated significant enhancement in unpleasant symptoms with bupropion. Although excluded from the meta-analysis because of their design, these studies were analyzed narratively to provide additional clinical insights. Summarized in figure (1). Figure 1: 1. Per-study summary statistics and effect estimates Only Perera et al. (2022) provides direct study-level patient data (case series, n=5). They reported reductions in PANS...