Strategies for Rational Prescribing in Schizophrenia

This educational piece examines the rationale and real-world drivers of polypharmacy in schizophrenia, including clinical complexity and system-level factors. It highlights the trade-offs between symptom control and cumulative treatment burden, emphasizing the risks associated with increased regimen complexity and the need for ongoing reassessment. The content underscores the importance of coordinated, individualized care to support rational prescribing decisions in routine practice.

Introduction

Moderator: Welcome, everyone, to today’s episode. In this discussion, we’ll examine rational prescribing in schizophrenia with a focus on opportunities to optimize care through thoughtful medication review, deprescribing, and integration of psychosocial supports. I’m Jenny Lamberts from Next in Neuro, and I’m joined by Kevin Williams, a clinician experienced in the complex management of schizophrenia.

Kevin Williams: Jenny, it’s great to be with you today!

Moderator: I’m pleased to be here today to discuss a topic that continues to challenge even experienced clinicians: rational prescribing in schizophrenia. This is an area that continues to evolve, yet many of the challenges, particularly around treatment complexity, remain deeply entrenched in everyday practice. Kevin, can you provide us with your perspective on this topic as a clinician?

Kevin Williams: Absolutely. You know, as clinicians, we often balance competing priorities: overall symptom control, safety, tolerability, and stability. Antipsychotics remain central to the treatment in schizophrenia, but may be layered with other medications for a number of reasons.¹ That sometimes means combining multiple antipsychotics. This is referred to as antipsychotic polypharmacy. You know, in some cases, clinicians may add medications to help manage comorbid symptoms such as anxiety, depression, or sleep disturbances¹, which would fall under broader psychotropic polypharmacy.² And of course, many patients are also receiving medications for comorbid medical conditions, which is broadly defined as the concomitant use of multiple medications and also contributes to the overall polypharmacy.² While there may be many potential reasons polypharmacy is initiated, one rationale tends to be the need to stabilize patients quickly during an acute crisis, such as hospitalization. And polypharmacy may also introduce new challenges for consideration, including drug-drug interactions and even the potential for adverse events.¹

Moderator: Yeah, you know, polypharmacy may increase the risk of side effects, necessitating safety considerations.^1,3,4

Kevin Williams: Exactly right. Because schizophrenia is a chronic, lifelong illness, long-term considerations, including relapse prevention, overall tolerability, and minimizing physical comorbidity tied to cumulative treatment exposure, are central to maintaining well-being.^5,6

That’s why rational prescribing requires a broader view; one that considers symptoms, side effects, psychosocial context, and long-term outcomes. Today, we’ll explore how clinicians might consider the overall approach to these strategies to inform treatment decisions, reduce unnecessary burden, and preserve coherence in the overall treatment strategy.

The Contemporary Landscape of Polypharmacy

Moderator: So perhaps we should begin with the reality we face: that antipsychotic polypharmacy does exist in clinical practice.^1,7-9

Kevin, does this align with your experience in real-world clinical practice?

Kevin Williams: Oh, yes, yes. There are various reasons why antipsychotic polypharmacy is used in routine practice, including but not limited to reducing hospitalization and managing challenging scenarios such as severe psychopathology.¹ Multi-agent antipsychotic regimens are used for roughly 10 to 20% of schizophrenia cases on an outpatient basis, and even up to 40% for inpatient cases.¹

And this includes more than just antipsychotics. Many clinicians may consider adding additional psychotropic medications to alleviate other symptoms such as anxiety or distress. They may also consider additional medications to manage side effects.⁷

Why Polypharmacy Persists

Moderator: So, knowing that, Kevin, can you talk a bit more about why polypharmacy persists in clinical practice?

Kevin Williams: That’s a good question. Part of it may be perceived clinically necessity. Patients with chronic, severe illness or multiple prior relapses often present with layered symptoms that challenge these streamlined strategies. Some observational work from Denmark, for example, shows that individuals with more complex disease presentations are more likely to receive multiple antipsychotics.¹⁰

Part of it simply reflects the practical realities of treatment. We know that adverse events play a major role in shaping attitudes toward medication, which in turn may influence adherence. When patients experience multiple side effects, it’s not uncommon for clinicians to adjust or add medications to manage those—sometimes creating a cycle of increasing complexity.⁷ For instance, additional treatments are sometimes added to help manage overall schizophrenia symptoms or other symptoms due to underlying conditions such as anxiety and trouble sleeping.^{7, 11,12}

Moderator: Well, that makes sense. But how about the recommendation to periodically review a patient’s medications and adjust them based on the patient's current needs?

Kevin Williams: It is definitely a good idea to regularly reassess patient regimens. You know, however, the reality of care coordination can make reassessment difficult in some cases. Maintaining patients on combination regimens often requires proactive integration with family medicine, specialists, case management, even social support to monitor and to ensure safe prescribing.¹¹ This highlights how fragmented care pathways can make it harder to routinely reassess and simplify regimens. Frequent transitions between inpatient, outpatient, and community settings create opportunities for regimens to expand without structured reassessment. Many US prescribing patterns reflect inadequate coordination across providers or a lack of dedicated deprescribing pathways.^13,14

Moderator: Well, you’ve painted a really clear picture of the complexity involved in schizophrenia management. Polypharmacy isn’t simply a clinical decision; it’s often a path-dependent outcome shaped by illness severity, system fragmentation, limited psychosocial resources, and time pressures in acute treatment settings.^1,10

Burden, Risks, and the Patient Experience

Moderator: And one area that’s often underestimated is the day-to-day impact of managing a complex treatment regimen. When patients are already navigating overall schizophrenia symptoms or social instability, even adding a single medication can feel overwhelming. What does the evidence tell us about this idea?

Kevin Williams: Well, across multiple studies, polypharmacy was consistently found to be associated with poor treatment adherence, which in turn leads to higher rates of recurrence and relapse within a few years of recovery from the first episode. It’s estimated that the non-adherence rate is 40-60% among patients with schizophrenia, and polypharmacy was found to increase the possibility of non-adherence roughly twice as much as compared to those receiving a single antipsychotic.^1,15,16

Moderator: We also know that treating patients with schizophrenia may involve therapy transitions. How do you balance polypharmacy against considerations related to switching or deprescribing medications?

Kevin Williams: Essentially, I try to remain mindful of the clinical nuance. Some patients who are transitioning therapies may become more vulnerable to relapse or treatment discontinuation during the switch.^1,11 Switching may occur: a US claims-based analysis of nearly 6500 patients showed that nearly one-fourth of patients on antipsychotics switched at least once to another antipsychotic.^17,18 And as a result, it is useful to have strategies to help patients navigate the transition.

Individualized strategies may be employed to help patients. For example, if a patient fears discontinuing a medication, introducing a psychosocial support such as cognitive behavioral therapy may help the patient transition more easily.¹⁵

Moderator: Okay, so what principles apply when evaluating whether or not to deprescribe a psychotropic medication?

Kevin Williams: The Clinical Pharmacology Task Force, a group of 45 psychopharmacology experts, recommends considering several factors when evaluating whether deprescribing may be appropriate, including whether a drug has failed to produce at least a partial response (and partial response is ≥25% reduction in overall symptomatology) or even clinically significant improvement in at least one core target symptom after a conventionally defined adequate trial.¹⁵

Of course, before even considering stopping a medication, a risk-benefit analysis should be conducted to better understand benefits versus lack of efficacy or benefits versus adverse events.¹⁵

Principles of Rational Prescribing

Moderator: Okay, so we've now mentioned this term “rational prescribing” several times. Kevin, can you tell us what this term means, and what it looks like in practice?

Kevin Williams: Well, I tend to frame it around a few core principles. First, I would like to clarify the therapeutic purpose of every medication. Why was another medication added? Was it meant to address the overall schizophrenia symptoms or mitigate a side effect? And also, was it intended only for the acute phase?

Then, after those questions are answered, I evaluate the cumulative burden, including efficacy, safety, and tolerability, and broader functional impact. As mentioned earlier, combination therapy may increase the probability of adverse events and drug–drug interactions. That’s why documenting the baseline symptom profile and clinical status before initiating another medication is truly essential.¹⁹ Without a clear record of why the combination was started, it becomes much harder to evaluate its impact on the patient.⁹ Also, I want to note it’s important to review the patient’s full antipsychotic and psychotropic drug history, ensuring that I’m looking at past trials, dosing adequacy, and tolerability that’s been properly assessed.¹

And a third principle is measurement-based care. Structured symptom ratings and side-effect monitoring reduce the possibility of unnecessary polypharmacy. This approach guides whether continuation, tapering, or modification of therapy may be clinically appropriate, and it helps identify the right timing for change.¹

Then I like to reassess regularly, especially during periods of stability. Some regimens that begin during a crisis remain in place simply because no one revisits them. Because the clinical rationale for polypharmacy can be poorly documented, the actual overall impact of continuing combination therapy may be unclear, highlighting the importance of reassessment once stability is achieved.^1,9

So, the goal is to ensure that whatever regimen we use actually serves the patient’s clinical needs.

Moderator: That framework is so helpful. One other consideration that arises is how to incorporate patient perspectives. What are your thoughts on that, Kevin?

Kevin Williams: Hm, well, it’s essential to incorporate patient perspectives. Patients’ experiences of side effects and treatment complexity may influence their engagement with medication. What may seem manageable from our perspective as clinicians may actually be an enormous burden to our patients. So, psychiatrists and clinicians overall need to consider the patient’s choice of treatment and psychosocial environment, and also include the patient’s family, significant others, and care partners in that decision.¹¹

In the United States, care fragmentation—which is when health services are delivered across multiple providers or settings without adequate coordination or communication—can be common. In this context, rational prescribing requires deliberate coordination. This includes communicating with inpatient teams, outpatient clinicians, case managers, and families to ensure that treatment decisions aren’t being made in isolation.¹³

Closing

Moderator: So, at its core, one could say that rational prescribing is about balance. Kevin, would you say you agree with that?

Kevin Williams: I do! Simplification for its own sake isn’t the goal. The goal is to identify an effective regimen that a patient can sustain, clinically and personally, and to adjust thoughtfully as their needs evolve. You know, ultimately, rational prescribing can help us reduce unnecessary burden while supporting patient goals.⁹ When we pair evidence-based decision-making with clear communication and collaborative care, it can help patients.

Moderator: And as the data remind us, there is a real opportunity to improve prescribing practices and reduce unnecessary complexity.

Well, Kevin, thank you so much for joining us today and for walking our listeners through these critical insights.

Kevin Williams: Yes, it was certainly my pleasure to collaborate on this episode. And thank you also to our listeners for joining us today!

References

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