The dilemma of polypharmacy in psychosis: is it worth combining partial and full dopamine modulation?

Abstract

Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of low-dose partial dopamine agonist (PDAs) add-ons to mitigate antipsychotic-induced metabolic adverse effects or hyperprolactinemia. However, clinicians are often concerned about using PDAs combined with high-potency, full dopaminergic antagonists (FDAs) due to the risk of psychosis relapse. We, therefore, conducted a literature review to find studies investigating the effects of combined treatment with PDAs (i.e. aripiprazole, cariprazine and brexpiprazole) and FDAs having a strong D2 receptor binding affinity. Twenty studies examining the combination aripiprazole – high-potency FDAs were included, while no study was available on combinations with cariprazine or brexpiprazole. Studies reporting clinical improvement suggested that this may require a relatively long time (~11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (~3 weeks). Patients with longer illness duration who received add-on aripiprazole on ongoing FDA monotherapy may be at greater risk for symptomatologic worsening. Especially in these cases, close clinical monitoring is therefore recommended during the first few weeks of combined treatment. These indications may be beneficial to psychiatrists who consider using this treatment strategy. Well-powered randomized clinical trials are needed to derive more solid clinical recommendations.

Aripiprazole: examining the clinical implications of D2 affinity

“…Prior studies have examined how adding Aripiprazole to another, more potent D2 antagonist can cause a relapse in psychotic symptoms; however, few studies have investigated the inverse relationship or mechanism. Those that have proposed mechanisms typically refer to Aripiprazole’s partial agonist activity as the causative factor, rather than an impediment to antipsychotic binding, which we have described (Adan-Manes and Garcia-Parajua, 2009; Lippi et al , 2022). While this interaction could be potentially problematic with oral formulations of these medications, it becomes particularly more so when using depot formulations, as seen in the above patient, as Ms. A did not respond to her previously effective dose of Paliperidone.…”

“…Aripiprazole has been proven effective in treating psychosis with the added benefit of fewer extrapyramidal, anticholinergic, or antihistaminergic side effects than FGAs (Stahl, 2020). It is thought to act as a "dopamine system stabilizer" by reducing dopamine in regions with overactive dopamine activity (mesolimbic system), while simultaneously increasing dopamine in regions with underactive dopamine activity (mesocortical system), demonstrating what Stahl coined as "Goldilocks actions" (Stahl, 2001;Lippi et al, 2022). Theoretically, this would explain Aripiprazole's ability to improve both the positive and negative symptoms of schizophrenia, as well as potentially enhance cognitive function.…”

Does a steroid dementia syndrome really exist? A brief narrative review of what the literature highlights about the relationship between glucocorticoids and cognition

“…29 A differential diagnosis between drug-induced and primary psychoses should be assessed in all older patients with polypharmacy. 30,31 The mean time of symptom onset is approximately 11.5 days. However, psychiatric manifestations may appear just 3-4 days after treatment initiation.…”

Patterns of antipsychotic prescription and accelerometer-based physical activity levels in people with schizophrenia spectrum disorders: a multicenter, prospective study

“…The use of APP in clinical practice may sometimes be justified also by the desire to improve the therapeutic response (Lahteenvuo and Tiihonen, 2021). However, even in this case, it is known that particular care must be taken when combining a partial dopaminergic agonist and a full D2 receptor antagonist, which may increase the risk of clinical relapse or worsening of psychotic symptoms ( Lippi et al , 2022 ). The relevant gap between evidence and routine practice, therefore, needs to be further investigated.…”