Antidepressant Augmentation of Antipsychotic Treatment in Schizophrenia: A Narrative Review

Introduction

Schizophrenia is a severe psychiatric disorder characterized by disturbances in cognition, emotion, and behavior, yet its underlying neurobiological mechanisms remain incompletely understood [1]. The illness significantly impairs daily functioning and quality of life, and in more severe forms is associated with suicidal ideation, disability, and increased mortality risk [2,3], particularly among individuals who do not receive adequate antipsychotic treatment [4,5]. Globally, schizophrenia affects roughly 1% of the population [6], and typically presents in early adulthood. Clinically, it encompasses several subtypes – such as paranoid, catatonic, adolescent-onset, simplex, and undifferentiated forms – reflecting its heterogeneous manifestations. Diagnosis is based on the International Classification of Diseases, 11th Revision (ICD-11) or Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, which require the persistence of characteristic symptoms for at least 1 month. These include positive symptoms (eg, hallucinations, delusions, and disorganized thinking) and negative symptoms (eg, affective blunting, social withdrawal, reduced motivation, and cognitive impoverishment) [7,8].

Current clinical management of schizophrenia centers largely on second-generation antipsychotics (SGAs), with more limited use of first-generation antipsychotics (FGAs) [9]. Although these medications are generally effective in reducing positive symptoms, their influence on co-occurring or residual affective and cognitive disturbances tends to be more limited [10,11]. Treatment practices that prioritize the traditional positive and negative-symptom framework, often relying on standard-dose antipsychotic monotherapy, may not fully reflect the heterogeneity of patients’ clinical presentations and can contribute to tolerability challenges over time [12]. These limitations have stimulated increasing interest in the potential role of adjunctive antidepressant therapy in addressing symptom domains that respond suboptimally to antipsychotics and in improving overall clinical outcomes [13]. Emerging findings also suggest that the therapeutic effects of antidepressant augmentation extend beyond the reduction of depressive symptoms. Several antidepressant classes have been examined for possible improvement of negative symptoms, cognitive functioning, and broader psychosocial outcomes, potentially through modulation of serotonergic, dopaminergic, and other neurochemical pathways [14,15].

Despite these observations, the existing literature remains inconsistent. Variations in patient characteristics, study methodologies, antidepressant classes, dosing strategies, and antipsychotic combinations have contributed to heterogeneous conclusions regarding efficacy and safety. While some studies describe meaningful clinical improvements, others report increased risks of adverse effects when such combinations are not applied with appropriate clinical oversight [16]. Consequently, a comprehensive synthesis of current evidence is needed to clarify the therapeutic value of antidepressant augmentation and to support more individualized medication strategies for patients with schizophrenia. This article aims to review the role of antidepressant augmentation of antipsychotic treatment in patients with schizophrenia, with a focus on clinical benefits and safety.

Clinical Features of and Overlap Between Schizophrenia and Depressive Disorders

Studies have consistently demonstrated that comorbid depressive disorders are common among schizophrenia patients [17], with approximately 32.6% experiencing major depressive episodes [18]. Genetic and epigenetic studies suggest a degree of shared etiology between schizophrenia and depression, with candidate genes such as GRIN1, GPM6A, SEPTIN4, and other potentially relevant genes receiving increasing attention [19,20].

Depressive disorders are commonly diagnosed when a patient has low mood for at least 2 weeks accompanied by additional symptoms, including disrupted sleep and appetite [21]. Late-life depression frequently presents with cognitive impairment, particularly reduced executive efficiency, and may be linked to structural or microstructural abnormalities of brain white matter [22,23]. Furthermore, psychotic features can occur in major depressive disorder, especially psychotic depression [24], and must be distinguished from schizophrenia, in which hallucinations are common, and may be confounded by affective distress in adolescents [25].

The diagnostic criteria for depressive disorders overlap with certain negative symptoms of schizophrenia, including anhedonia, slowed thinking, and reduced social functioning [26]. A reliable differential diagnosis depends on careful review of the patient’s history and symptom trajectory. Clinicians should also judge whether depressive features are part of the illness itself or are related to adverse effects of antipsychotic medication.

Biological and Pathophysiological Foundations Relevant to Antidepressant Use

Currently, the pathogenesis of schizophrenia is not well understood. Extensive research has reported the involvement of several factors, such as genetic predisposition [27], embryonic brain developmental abnormalities [28], neurotransmitter imbalances (notably dopamine [DA], serotonin, and norepinephrine [NE]) [29], endoplasmic reticulum sigma-1 receptor dysfunction [30], excessive polysulfide production [31], vitamin D deficiency [32], and glutathione synthesis impairments [33]. Furthermore, elevated interleukin-6 (IL-6) levels have been associated with greater severity of negative symptoms and cognitive impairment in patients with schizophrenia [34,35].

SGAs are the mainstay of pharmacological treatment for schizophrenia. Compared with FGAs, meta-analytic evidence suggests that SGAs are generally associated with a lower risk of tardive dyskinesia and extrapyramidal symptoms, although their adverse-effect profiles differ across agents [36]. The commonly prescribed SGAs include olanzapine, quetiapine, risperidone, and clozapine [37]. The mechanisms underlying the therapeutic effects of antipsychotic medications continue to be investigated. Many SGAs exert their effects primarily through dopamine (DA) D2 receptor antagonism alongside serotonergic actions, particularly at 5-hydroxytryptamine (5-HT) 2A receptors, while some agents also show clinically relevant activity at 5-HT1A receptors [38–40]. The biology of schizophrenia appears to intersect with depression-related pathways, which may be relevant to affective, negative, and cognitive symptoms that often remain after antipsychotic therapy. This perspective helps frame why antidepressant augmentation has been examined as a targeted option for some patients.

Antidepressant Classes: A Brief Overview

Selective serotonin reuptake inhibitors (SSRIs), including sertraline, escitalopram, fluoxetine, fluvoxamine, paroxetine, and citalopram, are commonly prescribed as first-line treatment for first-episode depression [41,42]. They alleviate depressive symptoms by elevating 5-HT within the synaptic cleft and are also prescribed for obsessive-compulsive disorder and post-traumatic stress disorder [43–45]. Serotonin–norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, improve mood mainly by increasing the synaptic concentrations of NE and 5-HT [46].

Beyond these commonly used classes, several additional antidepressants have been discussed in the context of schizophrenia. Bupropion, a norepinephrine and dopamine reuptake inhibitor, has been examined as an adjunct in selected contexts, particularly where apathy or low motivation is prominent [47]. The selective norepinephrine reuptake inhibitor reboxetine has been explored for improving negative symptoms and may involve hippocampal peroxisome proliferator-activated receptor alpha (PPARα)-related mechanisms [48]. In parallel, growing evidence suggests that PPARα-related pathways exert potential effects across multiple psychiatric disorders [49–51]. Mirtazapine and trazodone can be useful when sleep disturbances are prominent, whereas tricyclic and tetracyclic antidepressants are prescribed less frequently because of adverse effects [52]. Beyond these agents, other antidepressants have also been mentioned in the literature, but their adjunctive roles in schizophrenia remain to be clarified and appear to be supported by limited evidence at present.

Antidepressants in Schizophrenia: Clinical Strategies and an Overview of the Evidence

Psychotic depression is one of the most severe forms of mood disorders [53]. Against this backdrop, interest has grown in evaluating the potential role of antidepressants in schizophrenia, leading to a number of studies whose key findings are summarized below. Yamada et al reported that many patients experienced depressive episodes early in the course of schizophrenia, and that a history of depression, particularly among male patients, was associated with worse clinical outcomes. These findings suggest that depressive symptoms in this subgroup require closer clinical attention and may help explain why adjunctive treatments such as lithium or antidepressants are more frequently considered in clinical practice [54]. To further clarify the role of affective symptoms in early-stage illness, Puranen and Arto conducted a 3-year follow-up study in people with first-episode schizophrenia. They found that 35.4% of patients received antidepressants and 14.1% were treated with mood stabilizers within 3 years of diagnosis [55], and the initiation of mood stabilizers showed notable gender-related patterns that appeared to align with clinical features such as agitation and behavioral disturbance. Taken together, these findings indicate that depressive symptoms are common throughout the early course of schizophrenia and that adjunctive antidepressants and mood stabilizers can play an important role in its clinical management [13,56].

Risperidone exerts different therapeutic effects depending on the dosage. Lower doses are sometimes considered when targeting affective symptoms, whereas dosing for schizophrenia is typically individualized, with maintenance doses commonly at a few milligrams (mg) per day. When combining risperidone with SSRIs, available evidence suggests an overall acceptable safety profile. Fjukstad et al reported that SSRI co-medication was associated with only minor changes in metabolic parameters overall, and no evident metabolic deterioration was observed when SSRIs were combined with risperidone [57]. Therefore, this combination appears clinically feasible in appropriate patients, although those with liver dysfunction should have liver function test parameters monitored during risperidone treatment [58].

With tolerability in mind, subsequent trials have addressed a pragmatic question: can adding an SSRI support dose reduction of antipsychotics while preserving clinical and functional benefits? Lang Xiaoe et al performed a 24-week randomized controlled open-label trial of low-dose risperidone plus sertraline in first-episode medication-naïve schizophrenia. A total of 230 patients were assigned to combination therapy or regular-dose risperidone monotherapy. The combination strategy was associated with greater improvements in psychotic symptoms, depressive symptoms, and social functioning, reflected by larger reductions in the Positive and Negative Syndrome Scale (PANSS) scores and the Hamilton Depression Rating Scale (HAMD) scores, as well as higher Personal and Social Performance Scale (PSP) scores. Importantly, fewer adverse effects, including prolactin-related burden, were observed in the combination group, supporting an SSRI-assisted low-dose antipsychotic approach in early-stage illness [59].

Earlier studies suggest that the combination of olanzapine and fluoxetine can improve outcomes in treatment-resistant depression when standard antidepressant monotherapy or conventional treatment strategies are insufficient. The olanzapine and fluoxetine combination has been approved by the U.S. Food and Drug Administration for depressive episodes associated with bipolar I disorder and for treatment-resistant depression [60]. A meta-analysis by Luan Shuxin and colleagues further supports the superiority of this combination over olanzapine monotherapy in treatment-resistant depression [61].

Mechanistically, evidence has suggested that dentate gyrus (DG) alterations of the hippocampus are linked to impaired neurogenesis in depression. In this context, Sun Jiantong reported that olanzapine add-on partly attenuated fluoxetine-related reductions in neuronal differentiation of cultured neural stem cells, reflected by changes in β-III-tubulin-positive neurons [62]. Collectively, these clinical and preclinical findings provide a rationale for considering this strategy when prominent depressive symptoms coexist with psychotic-spectrum conditions, although direct evidence in schizophrenia remains limited.

Patients with chronic schizophrenia with inadequately controlled symptoms can experience profound and long-lasting impairment in social functioning. Many patients show clear improvement in positive symptoms after treatment with FGAs or SGAs, whereas negative symptoms often show only limited change, highlighting the need for adjunctive strategies [63]. Ziprasidone is widely applied in the treatment of schizophrenia and can inhibit DA activity in subcortical regions. However, cardiovascular safety, particularly corrected QT interval (QTc) prolongation and arrhythmia risk, requires careful monitoring [64,65]. Shi Hui and colleagues investigated sertraline plus low-dose ziprasidone in a double-blind 2-group controlled study. Compared with standard-dose ziprasidone monotherapy, the combination strategy was associated with lower PANSS scores, reduced PANSS general psychopathology subscores, and lower Clinical Global Impression-Severity (CGI-S) ratings, with fewer QTc-related discontinuations reported in the combination arm [63,66].

Notably, sertraline has been reported to increase extracellular DA concentrations in the nucleus accumbens and striatum, which may partially align with its potential benefits in this context [67].

Fluvoxamine augmentation of clozapine has also been explored in patients with longstanding schizophrenia and poor prior treatment response. Available results suggest that low-dose clozapine combined with fluvoxamine can be effective and relatively safe and may not increase metabolic risk in the short term [68,69]. Clinical trials by Alireza Haji Seyed Javadi further indicated that fluvoxamine can improve negative symptoms and cognitive function in schizophrenia [70].

In addition, Ding Ning evaluated whether escitalopram could improve negative symptoms in schizophrenia. Over an 8-week trial with gradual titration up to 20 mg/day, the escitalopram group showed a greater decrease in negative-symptom scores than the placebo group. IL-6 levels were also lower after treatment, while C-reactive protein (CRP) was assessed, supporting a possible link between inflammatory modulation and negative-symptom improvement [71].

Interest has expanded to SNRIs as adjunctive options for stable-phase schizophrenia with persistent negative symptoms. Nikbakhat et al conducted an 8-week randomized double-blind trial in Iran. In the duloxetine arm, patients were treated with 60 mg/day duloxetine added to a flexible risperidone regimen (maximum 6 mg/day). while the control group received risperidone plus placebo. From week 4, the duloxetine add-on group showed greater improvement in negative symptoms on the PANSS, whereas no clear benefit was observed for positive symptoms or cognitive executive function [72].

Another SNRI, venlafaxine, has been reported to alleviate depressive symptoms among patients with schizophrenia and has shown a tentative association with verbal memory in serum level datasets, without clear evidence of aggravating the underlying psychotic disorder [73,74]. Other antidepressant classes have also been explored as adjuncts in schizophrenia. Sexual dysfunction is common with serotonergic antidepressants and may compromise adherence. Proposed mechanisms often involve increased serotonergic tone, with 5-HT2 related pathways frequently implicated [75,76].

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) that is often taken at night because of its sedative effect and sleep-related benefits. In a 6-week randomized double-blind placebo-controlled trial in patients with schizophrenia receiving stable antipsychotic treatment, add-on mirtazapine was associated with improved orgasmic functioning measured using selected items from the Udvalg for Kliniske Undersogelser Side Effect Rating Scale [77,78].

Mirtazapine may also be relevant for specific symptom clusters in schizophrenia. By antagonizing 5-HT2A and 5-HT2C receptors, it can enhance dopaminergic activity in certain brain regions and can help alleviate catatonic-like manifestations such as rigidity or mutism in selected patients [79]. It has also been reported to ameliorate akathisia, particularly when used adjunctively in patients receiving aripiprazole, although the supporting evidence remains limited [80]. For treatment-resistant depressive episodes, combining 2 antidepressants can yield better outcomes. A typical example is venlafaxine combined with mirtazapine, often referred to as “California rocket fuel.” Preclinical evidence suggests that this combination has more robust antidepressant effects without an apparent increase in female sexual dysfunction, although confirmation in clinical studies is still needed [81]. Animal studies have begun to examine venlafaxine and mirtazapine-based strategies in models linking schizophrenia- like and depressive phenotypes. In a mouse model of schizophrenia with major depressive disorder that incorporated dizocilpine (MK-801) and chronic stress, Zhuo Chuanjun et al compared clozapine and the mouse equivalent of electroconvulsive therapy alone and with venlafaxine and or mirtazapine, and the combination of electrical stimulation with venlafaxine and mirtazapine showed the most favorable behavioral improvement and prefrontal cortex-related signals among the tested regimens [82].

A study in Poland applied MK-801 to induce negative-symptom like behaviors in rats and examined combination strategies involving aripiprazole. The results suggested that MK-801 induced negative symptoms and that aripiprazole combined with escitalopram and mirtazapine improved these behaviors. Mechanistic inference in this line of work has pointed to potential involvement of 5-HT1A- and D1-related pathways [83,84]. Elsewhere, preclinical evidence also suggests that escitalopram combined with aripiprazole can influence medial prefrontal cortex function and glutamatergic transmission, which could be relevant to negative-symptom modulation [85]. For schizophrenia, reduced resting state functional connectivity of the prefrontal cortex has been reported [86]. This observation provides a neurobiological context for why multi-target approaches are sometimes discussed, although it does not itself constitute evidence the efficacy of specific drug combinations.

Treatment-resistant schizophrenia is generally defined as an inadequate response to at least 2 antipsychotics given at adequate doses and durations with reasonable adherence, and clozapine remains the cornerstone option when such criteria are met [87]. The examples above mainly address antidepressant augmentation for specific targets such as negative or affective symptoms, while a growing number of reports have explored multi-drug strategies in difficult cases. For instance, a case-based report described potential benefits of combining clozapine with cariprazine and fluoxetine in a patient with prominent negative symptoms (https://pmc.ncbi.nlm.nih.gov/articles/PMC9568255/). This observation aligns with broader but still-evolving, evidence that cariprazine augmentation of clozapine can relieve negative symptoms in some patients with inadequate clozapine response [88]. Preclinical work has also expanded beyond conventional SSRIs. In a sub-chronic MK-801 rat model, Bozkurt and colleagues reported that vortioxetine improved social behavior and cognitive performance and increased glutamate decarboxylase 67 (GAD67) and parvalbumin levels, supporting a mechanistic rationale for targeting negative and cognitive dimensions [89]. Clinically, an 8-week randomized double-blind trial found that vortioxetine as an adjunct to risperidone improved negative symptoms without a clear advantage for positive symptoms, suggesting a feasible option for selected patients [90].

Safety Considerations and Drug Interaction Risks in Combined Treatment

In clinical practice, antidepressant use may be accompanied by emotional fluctuations, and close monitoring for imminent suicidality is still warranted, particularly in younger patients during the early phase of treatment [91].

Therefore, concerns about the adverse effects of polypharmacy remain a significant issue for both clinical psychiatrists and patients [92]. Severe neuroleptic malignant syndrome is a rare but potentially fatal complication of antipsychotic treatment [93]. Earlier reports described higher incidence and mortality ranges, but more recent evidence suggests that the incidence is lower and that mortality has declined with improved recognition and supportive care [94,95].

Drug interaction-related seizure risk is another practical concern. The use of clozapine combined with bupropion has been reported to precipitate generalized seizures in case-based evidence, consistent with the fact that both agents can lower the seizure threshold [96,97].

For cardiac safety, escitalopram has a recognized association with QT interval prolongation, particularly at higher doses or in patients with multiple risk factors. Mechanistically, this effect is thought to be mainly related to inhibition of the cardiac human Ether-à-go-go-Related Gene (hERG) potassium channel, encoded by KCNH2, which reduces the rapid delayed rectifier potassium current and delays ventricular repolarization [98–100]. This hERG-related mechanism provides a biologically plausible basis for the dose- and risk factor-dependent nature of escitalopram-associated QT changes [101].

When antidepressants are added to antipsychotic regimens, pharmacokinetic interactions should be considered. Fluoxetine and paroxetine are strong cytochrome P4502D6 (CYP2D6) inhibitors, and available reports suggest that clozapine exposure rises in some patients during co-medication. In practice, this possibility is best handled through cautious dose titration, closer adverse effects surveillance, and therapeutic drug monitoring when accessible [102–105].

Beyond pharmacokinetic interactions, metabolic safety is another major concern in combined treatment. In the treatment of schizophrenia, the use of olanzapine has increased and its efficacy has been documented. However, it is strongly associated with metabolic adverse effects that may decrease patient adherence, even though it tends to produce fewer extrapyramidal symptoms than several alternatives [106,107].

A study explored the efficacy of sertraline and olanzapine combination in the treatment of psychotic depression. The experimental group was divided into 2 age groups: age 18 to 59 and age 60 and above. Older patients receiving sertraline combined with olanzapine experienced less weight and cholesterol increase than younger patients during acute and stabilization phases, whereas the younger group showed more pronounced overall weight gain [108]. Therefore, the metabolic adverse reactions of olanzapine may show age-related differences, and individual factors should be considered when combination therapy is planned. Metabolic syndrome remains a major global health issue; across adult populations, pooled estimates in the literature often are roughly 20% to 25%, but the reported burden shifts with diagnostic criteria and geographic context [109,110].

Sasváriová Michaela has suggested that the use of venlafaxine can exacerbate metabolic disorders in patients with metabolic syndrome and mental disorders [111]. Accordingly, in schizophrenia patients with metabolic abnormalities, laboratory results should guide treatment selection. In patients with hypertension, hyperlipidemia, or diabetes, closer monitoring is advisable if venlafaxine is combined with metabolically high-risk antipsychotics such as olanzapine or clozapine, rather than issuing a blanket avoidance statement [107].

Nguyen et al reported that adjunctive antidepressant use with aripiprazole was not associated with a clear increase in body weight [112]. In a related comparison of daily oral aripiprazole and monthly long-acting injectable aripiprazole, autonomic nervous activity was assessed using heart rate variability indices, and the long-acting formulation appeared to reduce impairment of sympathetic nervous activity relative to the oral regimen [113].

These observations suggest that when aripiprazole is combined with antidepressants the choice between oral and long-acting formulations may be guided by tolerability, autonomic safety signals, cost, and convenience, rather than efficacy considerations alone.

Recent studies increasingly highlight the importance of individualized treatment planning for patients with schizophrenia who present with depressive symptoms. Clinical decision-making should consider physical health comorbidities – such as metabolic vulnerability or cardiovascular risk – as well as the potential impact of antidepressant selection on clinical outcomes. This principle is consistent with contemporary guideline recommendations emphasizing a documented, comprehensive, and person-centered treatment plan for schizophrenia [9].

Because no single medication is universally effective, therapeutic choices are often shaped by inter-individual variation in drug sensitivity, tolerability, and biological factors, including genetic and epigenetic profiles. Recent work in people with affective disorders suggests that DNA methylation changes involving the SLC6A4 locus are associated with the heterogeneous SSRI response, supporting the plausibility of epigenetic-informed stratification in related clinical settings. Although direct evidence in schizophrenia remains limited, these findings provide a rationale for cautious, hypothesis-driven incorporation of genetic and epigenetic considerations into individualized-prescribing research agendas [114,115]. Reported adverse reactions involving aripiprazole – such as medication-induced hiccups – have been summarized in recent case-based reviews, with receptor-binding properties (including D3 and serotonergic pathways) proposed as plausible contributors. Such observations underscore the importance of close monitoring and timely dose adjustment, discontinuation, or switching when clinically significant adverse reactions emerge during SSRI antipsychotic co-treatment [116]. Overall, individualized strategies should focus on defined symptom targets, comorbidity-informed risk assessment, and active safety surveillance, rather than defaulting to routine antidepressant augmentation.

Future Directions

Although antidepressant augmentation may provide adjunctive benefits for negative symptoms, cognitive impairments, and comorbid depressive features in schizophrenia, the current evidence base is limited by methodological constraints. Many published studies have had small sample sizes, short treatment periods, and variable outcome measures, which reduces generalizability to broader clinical populations. Longer-term evidence on efficacy, safety, and functional recovery is particularly limited, even though these endpoints are central to chronic management and real-world decision-making.

Across the literature, a recurrent pattern is that reported benefits are more often observed for negative symptoms and depressive features than for positive symptoms. However, the magnitude and consistency of these signals vary across studies, in part because background antipsychotic regimens, outcome selection, and follow-up duration are not uniform. Future research would therefore benefit from symptom-specific and stratified designs that reflect the heterogeneity of schizophrenia and report results by clinically meaningful profiles, including predominant negative symptoms, cognitive deficits, and affective disturbances. Clearer alignment between the symptom domain of interest and the chosen endpoints, together with adequate follow-up, would help determine whether observed improvements represent durable clinical change rather than short-term scale variation.

In parallel, safety evaluation should be strengthened through more rigorous and standardized assessment of drug–drug interactions and adverse-effect profiles in combination treatment. Particular attention is needed when seizure liability, cardiovascular burden (including QT prolongation risk), or metabolic vulnerability may be heightened. More transparent monitoring procedures and more complete adverse event reporting would improve interpretability and support safer, more individualized use in routine care.

Conclusions

Adjunctive antidepressant use alongside antipsychotic medications may be a clinically relevant strategy for selected patients with schizophrenia who continue to experience persistent negative symptoms, cognitive deficits, or comorbid depressive disturbances. Across reported studies, SSRIs and SNRIs, as well as mirtazapine and vortioxetine, show generally favorable signals in specific symptom domains, with mirtazapine potentially contributing to quality-of-life improvements related to sleep and sexual function, and vortioxetine remaining of interest for cognitive and negative-symptom targets. In this context, the patterns of antidepressant augmentation discussed above are synthesized in Table 1, which summarizes agents that have shown relatively favorable signals across specific symptom targets together with key safety considerations reported in the literature. In parallel, Table 2 outlines antidepressants that are generally considered less suitable for first-line augmentation, highlighting recurrent concerns related to tolerability, pharmacokinetic interactions, and monitoring burden.

Nevertheless, antidepressant augmentation should not be viewed as a routine default. Selection should be driven by clearly defined symptom priorities, comorbidity-informed risk assessment, and proactive monitoring for pharmacokinetic interactions and adverse effects, particularly in clozapine-related or metabolically vulnerable contexts. Where evidence is limited, a cautious, time-limited trial with predefined outcomes may be preferable to open-ended polypharmacy.