The ARISE trial was a Phase 3 clinical study evaluating Cobenfy — a combination of xanomeline (a muscarinic receptor agonist) and trospium chloride (a peripheral anticholinergic) — as an adjunctive treatment for adults with schizophrenia who continued to experience symptoms despite taking an atypical antipsychotic.
What Is a Primary Endpoint, and Why Does It Matter?
In clinical trials, the primary endpoint is the most important outcome researchers are trying to affect — it’s how a drug’s success or failure is officially judged. In ARISE, the primary endpoint measured the change in symptom severity compared to placebo using a standardized scale for schizophrenia. Meeting this endpoint would have demonstrated clear, statistically significant symptom improvement attributable to Cobenfy.
The Outcome: No Statistically Significant Benefit
According to topline results, Cobenfy did not show a statistically significant improvement compared to placebo when added to atypical antipsychotics. This means the observed difference could have been due to chance and did not meet the pre-set threshold for success.
However, Cobenfy did show a numerical improvement — the group receiving the drug combination performed betterthan placebo in symptom reduction, just not to a statistically convincing degree.
Could Anticholinergic Effects Be to Blame?
One possible explanation for this outcome lies in the mechanism of action of both Cobenfy and many commonly used atypical antipsychotics.
Xanomeline is designed to activate muscarinic receptors in the brain (specifically M1 and M4), which may help regulate dopamine and reduce psychosis.
But many atypical antipsychotics — like olanzapine, clozapine, and quetiapine — also have anticholinergic properties, meaning they block these same receptors.
This sets up a pharmacological tug-of-war: Cobenfy tries to stimulate muscarinic activity, while the background antipsychotic may be dampening it. This conflict could blunt the therapeutic signal, explaining why the benefit didn’t reach statistical significance.
What This Means for the Future
The failure to meet the primary endpoint is a setback, but not the end of the road. The numerical improvements suggest a potential signal, and with refined trial design — perhaps using background medications with lower anticholinergic load — future studies may better reveal Cobenfy’s potential.
Additionally, this trial underscores the importance of considering mechanism compatibility in combination therapies. It’s not just about adding drugs — it’s about how they interact at the receptor level.
Conclusion
While the ARISE study didn’t deliver the result many hoped for, it raised critical questions that will shape future research. A deeper understanding of anticholinergic burden, drug synergy, and precision pharmacology is essential as we continue the search for more effective treatments for schizophrenia.
The FDA has officially ended the Clozapine REMS program—meaning no more mandatory registration, reporting, or ANC submissions to the REMS system! 🙌
What does this mean? ✅ Prescribers – No more REMS hurdles, but ANC monitoring is still recommended. ✅ Pharmacies – No REMS verification needed before dispensing. ✅ Patients – No more REMS-related delays in getting your medication!
This long-awaited change follows input from an FDA advisory committee and aims to reduce unnecessary barrierswhile keeping clozapine use safe and effective.
💬 What are your thoughts on this update? Drop a comment below! 👇
When it comes to bipolar disorder, the most commonly prescribed medication isn’t necessarily the most effective.Many clinicians default to prescribing quetiapine, valproate, or lamotrigine, yet lithium remains the gold standardfor long-term treatment.
So, why is lithium often overlooked? Despite decades of evidence supporting its unmatched efficacy in preventing relapse, reducing suicide risk, and stabilizing mood long-term, lithium is underprescribed due to concerns over side effects, monitoring requirements, and physician discomfort with its use.
🔹 What Do the RCTs Say About Lithium?
✅ BALANCE Trial (2010) – The landmark study comparing lithium vs. valproate vs. combination therapy found that lithium monotherapy was superior to valproate in preventing relapse into both manic and depressive episodes (Geddes et al., 2010).
✅ NIMH STEP-BD Trial (2005) – Among mood stabilizers, lithium significantly reduced suicide risk, a benefit not shared by other common treatments (Goodwin et al., 2003).
✅ Cade’s Legacy and Beyond – Multiple meta-analyses confirm that lithium reduces relapse rates and is the only mood stabilizer with strong anti-suicidal effects (Cipriani et al., 2005).
🚨 The Bottom Line?Lithium is STILL the most effective long-term treatment for bipolar disorder, yet it is often underutilized. Instead, newer and more expensive alternatives are frequently prescribed—even when they lack lithium’s robust evidence base.
Yes, lithium requires monitoring. Yes, it comes with side effects. But for patients with bipolar disorder, choosing the right medication can mean the difference between stability and relapse, life and death.
Let’s start prescribing based on data, not convenience. 🔥
Antipsychotic-induced weight gain remains a significant challenge in psychiatric practice, contributing to metabolic syndrome, decreased quality of life, and reduced medication adherence. This issue is especially concerning given the chronic nature of psychiatric illnesses requiring antipsychotic treatment. Among strategies to address this, metformin—an insulin sensitizer primarily used for type 2 diabetes—has garnered considerable interest. Below, we summarize the evidence from randomized controlled trials (RCTs) evaluating metformin’s efficacy and safety in mitigating weight gain associated with antipsychotic medications.
Evidence from Randomized Controlled Trials
Meta-Analyses and Systematic Reviews
Multiple meta-analyses of RCTs have shown that metformin effectively reduces weight gain in individuals receiving antipsychotics. Weight reductions of 2-3 kg over 12-16 weeks have been reported compared to placebo.
Beyond weight loss, improvements in metabolic parameters such as fasting glucose, insulin resistance, and lipid profiles have been observed.
Population-Specific Findings
First-Episode Psychosis (FEP): Studies indicate that metformin is particularly effective in individuals with FEP who experience rapid weight gain shortly after initiating antipsychotic therapy. Early intervention appears to yield more substantial benefits.
Chronic Schizophrenia: RCTs in populations with chronic schizophrenia have demonstrated similar weight-reducing effects, though results may be less pronounced compared to FEP patients.
Adjunctive Lifestyle Interventions
Combining metformin with lifestyle interventions, such as diet and exercise counseling, results in synergistic benefits. RCTs demonstrate that this combination is more effective than metformin or lifestyle changes alone.
Safety and Tolerability
Metformin is generally well-tolerated. The most common side effects are gastrointestinal (e.g., nausea, diarrhea), which tend to subside with continued use. Rarely, lactic acidosis—a serious adverse event—can occur, particularly in individuals with renal impairment. It is crucial to monitor kidney function periodically.
Practical Considerations
Dosing: Initiate metformin at a low dose (e.g., 500 mg once daily) to minimize gastrointestinal side effects, and titrate gradually to a typical maintenance dose of 1,000-2,000 mg per day.
Monitoring: Regularly assess weight, BMI, fasting glucose, and lipid profiles. Monitor renal function before and during treatment.
Patient Selection: Metformin may be particularly beneficial for patients who:
Have significant weight gain or metabolic disturbances from antipsychotic use.
Are early in their antipsychotic treatment course.
Have no contraindications, such as severe renal impairment.
Conclusion
Metformin offers a promising strategy for mitigating antipsychotic-induced weight gain, supported by robust evidence from RCTs. While not a standalone solution, it can play a critical role in a comprehensive approach to managing the metabolic side effects of antipsychotics. Clinicians should consider metformin’s inclusion in treatment plans for patients struggling with weight gain or metabolic dysfunction related to antipsychotic treatment.
In my practice, I see many patients who have been on high doses of antipsychotics for extended periods, particularly first-generation antipsychotics, which carry a higher risk of developing tardive dyskinesia (TD). While two FDA-approved treatments for TD exist, their high cost and limited availability can make access challenging in community mental health settings. This has led me to explore alternative treatments like amantadine. Like many of you, I wanted to understand the evidence supporting its use, so let’s take a closer look at what the research says about amantadine as a treatment option for TD.
The evidence for the use of amantadine in treating tardive dyskinesia (TD) has been explored in several small randomized controlled trials (RCTs), though it remains limited compared to other treatments.
Efficacy of Amantadine: Some studies suggest that amantadine, an NMDA receptor antagonist, may offer mild to moderate improvement in TD symptoms by modulating dopaminergic pathways. For instance, an early RCT (2007) tested amantadine in schizophrenia patients with TD and reported some improvements in abnormal involuntary movements compared to placebo. However, the sample size was small, and results were modest.
Comparative Effectiveness: Few trials directly compare amantadine to other TD treatments like VMAT-2 inhibitors (e.g., valbenazine, deutetrabenazine), which are the preferred treatment options due to stronger RCT evidence. Amantadine’s effects may be less pronounced, though some patients have reported partial symptom relief, especially when TD is not severe.
Safety Profile: In RCTs, amantadine is generally well-tolerated in TD patients, with few serious side effects. However, common side effects include dizziness, insomnia, and gastrointestinal issues, which may limit its use in certain patients, particularly those with cognitive or movement comorbidities.
Overall, while RCTs support some benefit of amantadine in TD, the effect size is generally moderate. VMAT-2 inhibitors are preferred based on stronger, more consistent RCT data, although amantadine may still be considered for patients who cannot tolerate or do not respond to these primary therapies.
The article “Deprescribing Antipsychotics in Patients with Schizophrenia: Findings from a Specialized Clinic” emphasizes a growing interest in reducing or discontinuing antipsychotic medications in patients with schizophrenia, particularly those stable on long-term treatment. While continuous antipsychotic use is common to prevent relapse, concerns about long-term side effects, such as metabolic give us pause and rise concerns.
Key Points:
Benefits of Deprescribing:
Reduction in side effects such as weight gain and metabolic syndrome.
Potential reversal of tardive dyskinesia.
Empowering patients by involving them in shared decision-making, improving adherence and satisfaction.
Risks:
The primary risk is relapse, with studies indicating relapse rates between 20-60% after discontinuation.
Relapse can lead to hospitalization, job loss, and disrupted relationships.
Strategies for Safe Deprescribing:
Individualized Tapering: Gradual reduction in dose is essential, tailored to the patient’s specific needs and history.
Relapse Prevention: Engaging support systems (family, mental health teams), monitoring for early signs of relapse, and incorporating psychosocial interventions.
Ethical Considerations: Balancing patient autonomy with the duty to minimize harm is a challenge. Encouraging patient participation respects autonomy while ensuring they are aware of risks.
Future Directions:
More research is needed on long-term outcomes of deprescribing, particularly in identifying which patients are the best candidates for safe withdrawal.
Clinical guidelines should better integrate recovery-oriented approaches with deprescribing efforts to strike a balance between risk mitigation and promoting patient empowerment
Antipsychotic Drugs and Cognitive Function: Key Findings from a Systematic Review and Meta-Analysis
Background: Cognitive impairment is a core feature of schizophrenia, often leading to significant functional disability. Antipsychotic medications are the main treatment for schizophrenia, but their impact on cognitive function remains debated.
Objective: This systematic review and network meta-analysis aimed to compare the effects of different antipsychotic drugs on cognitive function in patients with schizophrenia.
Methods: The review included randomized controlled trials (RCTs) that assessed cognitive outcomes in patients with schizophrenia treated with antipsychotics. A network meta-analysis was conducted to compare the cognitive effects across different antipsychotic drugs.
Key Findings:
Cognitive Improvement:
All antipsychotics studied showed modest cognitive benefits, though the effect sizes were small.
Second-generation antipsychotics (SGAs) generally performed better than first-generation antipsychotics (FGAs).
Among SGAs, lurasidone and amisulpride demonstrated the most pronounced cognitive improvements.
FGAs like haloperidol showed the least benefit for cognitive function.
Domains of Cognitive Improvement:
The drugs improved different cognitive domains, including working memory, processing speed, and executive functioning, though no single drug showed superiority across all domains.
Comparative Effectiveness:
In head-to-head comparisons, lurasidone and amisulpride were consistently ranked higher for cognitive improvement.
Olanzapine and risperidone also showed beneficial effects, though to a lesser extent.
Adverse Effects and Tolerability:
Cognitive improvements were often seen alongside side effects, with some drugs (e.g., olanzapine) associated with metabolic risks that may counterbalance cognitive benefits.
Limitations:
The analysis emphasized the small effect sizes, suggesting that while antipsychotics may slightly improve cognition, the changes may not be clinically meaningful in many cases.
Cognitive rehabilitation therapies may need to be paired with pharmacological treatment for more significant cognitive gains.
Conclusions: While antipsychotics can modestly improve cognitive function in schizophrenia, the benefits are relatively small, and no drug significantly outperforms others across all cognitive domains. Lurasidone and amisulpride may offer the greatest cognitive benefits, but additional interventions may be necessary to address cognitive deficits effectively.
In my practice, I encounter many cases of first-episode psychosis, a critical period that requires thoughtful and precise intervention. The decisions made during this time can set a patient on the path to long-term recovery or, unfortunately, towards a lifetime of challenges.
There are a few guiding principles I always adhere to:
Most antipsychotics can be effective, but it’s important to choose carefully.
Lower doses often suffice to achieve remission in first-episode psychosis. Starting with a medication that has a lower risk of cardiometabolic side effects and weight gain is crucial, especially for young patients. They shouldn’t be burdened with long-term physical side effects as they navigate their recovery.
Predicting whether a patient will experience a single episode or develop a chronic condition like schizophrenia is challenging. While family history and substance use, particularly cannabis, can provide clues, there is still uncertainty.
I believe that after 6-12 months of treatment, it’s worth considering tapering the antipsychotic to the lowest effective dose, with a careful eye on any signs of relapse. Unfortunately, what I often see is that both patients and clinicians overlook the subtle signs of relapse because they’ve mutually decided to discontinue the medication. By the time I see them again, the situation has worsened.
Early psychosis treatment requires a delicate balance between managing symptoms and minimizing long-term side effects, all while keeping a close watch for signs of relapse. Careful planning is key to setting patients on the best path forward.
Treating agitation is a big part of inpatient and emergency psychiatric treatment. In the emergency department agitation accounts for 2.6% of total patient encounters. Knowing which medications to use and how to use them is critically important. Today I’m going to discuss all the options for the treatment of acute agitation in clinical practice.
What is Agitation?
Agitation is an extreme form of arousal that is associated with increased verbal and motor activity that poses a threat to themselves and others. Agitation needs to be recognized immediately and addressed due to the risk of harm to the patient and others.
Verbal De-escalation is Always The First Step
Engaging the patient and attempting to elicit a reason for the agitation should always be attempted first. In many cases patients are hungry, tired, or overly stimulated by the busy inpatient or ED setting. If these interventions are unsuccessful and the patient remains agitated security staff lead by the physician should inform the patient that if the behavior continues medication will be administered for safety purposes.
Thinking About Medication
Sometimes using medication is unavoidable and is required to facilitate a medical evaluation. We need to be mindful of the potential adverse events associated with sedating medication. The most common adverse effects are hypoxia, airway obstruction, QTc prolongation, bradycardia, and hypotension. Patients over the age of 65, alcohol intoxication, and multiple medication administrations in a short period of time increases the risk of adverse events.
Routes of Administration
It’s always best to offer PO (oral) medication prior to using IM or IV medications. In the inpatient setting we do not allow IVs due to the potential risk of self-harm; IM medication is second route of administration commonly used. I will usually use risperidone 2 mg or olanzapine zydis 10 mg because it begins dissolving immediately once the person puts it in their mouth in both cases. Oral medications can be “cheeked” and will also take longer to start working. In general, it’s important to note the onset of PO medication will be slower. Antipsychotic medications and benzodiazepines are commonly used for sedation in acute agitation.
First Generation Dopamine Blocking Medications
These medications have been around for a long time and have a good safety profile when used to treat acute agitation. Some antipsychotics have the risk for more side effects due to their ability to lower seizure threshold, cause hypotension, and have an increased anticholinergic burden.
Haloperidol
This is the go-to antipsychotic for acute agitation. It works by blocking D2 receptors and can be given PO, IM, or IV. Typical dosing is 2.5 to 10 mg with a recommended maximum dose of 20 mg/day. The average time to sedation is 25-28 minutes and the mean total time sedated is 84-126 minutes. The main risk for haloperidol is EPS such as acute dystonic reactions. To avoid this situation, we usually combine Haldol with lorazepam or benztropine/diphenhydramine. Haldol is also well studied and relatively staff for those who are acutely intoxicated with alcohol.
Chlorpromazine
I will usually go to chlorpromazine when I need someone to sleep such as cases of mania with acute agitation. I find it to be a little more sedating and it can be combined with diphenhydramine. Doses can range from 25 mg to 200 mg depending on the level of severity. The maximum dose is 400 mg/day.
Second Generation Dopamine Blocking Medication
Second generation medications have the added advantage of lower risk for QTc prolongation, less sedation, and fewer extrapyramidal symptoms compared to the first-generation options.
Olanzapine
Olanzapine comes in PO, IM, and IV forms, and the typical starting dose is 10 mg. Olanzapine reaches peak concentration in 15-45 minutes and its half-life is 2-4 hours. The incidence of EPS is much lower than injectable haloperidol. There is very rare incidence of QTc prolongation. There is some evidence that 10 mg of olanzapine is more effective than 5 mg of haloperidol for sedation and that most patients are adequately sedated at 15 minutes after administration of 10 mg olanzapine compared to 5 mg and 10 mg of haloperidol.
It’s important to note that multiple studies have demonstrated adverse events when olanzapine is combined with benzodiazepines. Although the risk may be overstated it’s best to avoid this combination unless necessary. Olanzapine is highly anticholinergic and should be avoided in cases where anticholinergic overdose is suspected.
Ziprasidone
Ziprasidone is a second-generation medication that is available in either PO or IM formulations. The PO form of the medication has little utility in acute agitation, but the IM version can be useful. Time to onset of effect is usually 15-20 minutes and it reaches peak concentrations in 30-45 minutes. The duration of sedation is at least 4 hours. Ziprasidone carriers the highest risk of second-generation medications for QTc prolongation
Risperidone
Data for risperidone in acute agitation is limitted. It does have the advantage of coming as an oral disintegrating tablet. In most cases I would administer 2-4 mg depending on the severity of symptoms. It can be a good option for patients with psychotic agitation due to paranoid delusions. It’s a good option for elderly patients and pregnant patients who can take PO medication.
Benzodiazepines
Benzodiazepines are another good choice when it comes to rapid treatment of acute agitation. Benzodiazepines do carry the risk of creating a paradoxical reaction in the elderly, but it’s relatively rare and seen in only 1% of cases. Flumazenil (benzodiazepine blocker) can be used to counteract this paradoxical reaction if needed. There is risk for respiratory depression especially in those who are already on central nervous system depressants. If withdrawal is suspected from benzodiazepines or alcohol, this is the first line option for treatment.
Lorazepam
Lorazepam is available in IV, IM, and PO formulations. The typical dosing is 0.5-2 mg IM or PO. This medication can be given every 30 minutes up to a maximum dose of 12 mg/day. Lorazepam is longer acting than midazolam and has an average time to adequate sedation of 32 minutes.
Midazolam
Midazolam is available in IM formulation and the typical dosing begins at 2-5 mg. The average time to sedation is 13-18 minutes for the IM formulation. When given IM the total time of sedation is between 82-105 minutes. Midazolam offers the advantage over lorazepam because it’s onset of action is faster. Midazolam also works faster than haloperidol or ziprasidone. The duration of sedation is also shorter.
Medication Combinations
In most cases these medications will be used in combination to maximize their effects. The most well-known is the so called B52 which consists of Haloperidol 5 mg, Lorazepam 2 mg, and diphenhydramine 50 mg. The idea here being 50, 5, and 2 are the doses and B52 because it’s like the B52 bombers when it comes to sedation. I also often combine chlorpromazine and olanzapine with 50 mg of diphenhydramine in the IM formulations. For PO risperidone you can combine it with PO lorazepam and diphenhydramine if needed. With ziprasidone I will usually give this one alone without lorazepam or diphenhydramine.
Physical Restraints
The utilization of physical restraints may be necessary when safety is a major concern. In some cases, verbal de-escalation, and medication are not enough. The problem is physical restraints can lead to injury for both the patient and staff. Patients who continue to fight against the restraints can have a complication known as rhabdomyolysis where the muscles are literally breaking down from the person fighting against the restraints. Sedation should always be provided when physical restraints are used. What happens if a person is given high doses of sedating medications and placed in psychical restraints but remains agitated?
Special Cases
It’s rare but I have had two clinical scenarios where an individual was placed in restraints given multiple doses of medications and remained severely agitated. Due to concern for the patient’s safety and risk of rhabdomyolysis I had to transfer each of these cases to the medical floor for IV dexmedetomidine (Precedex) which is commonly used to sedate patients in the intensive care unit who are intubated. After a short course of Precedex treatment each patient’s agitation resolved. There is now a rapidly dissolving film of dexmedetomidine available for acute agitation in bipolar disorder and schizophrenia, so I guess I was ahead of the times when I made these clinical decisions.
Conclusion
Agitation is a complicated and multifactorial process that requires quick action. To maintain safety, agitation needs to be quickly identified and managed. Verbal de-escalation and comfort measures should always be the starting point. If medications are required there are several individual and combinations that can be selected based on the clinical situation. When all else fails physical restraints remain a possibility until medications have had time to reach peak concentrations and effectiveness.
It wasn’t that long ago when I was sitting in lectures as a first-year psychiatry resident. I learned about the first- and second-generation antipsychotic medications in detail. One commandment that was always preached in my training was to never combine two antipsychotic medications because there is no additional benefit. Today we are here to explore this idea and see if there is truly no additional benefit to using two antipsychotics and explore why there is so much antipsychotic polypharmacy in serious mental illness.
Since most guidelines discourage the use of multiple antipsychotic medications, why are many psychiatrists going against these guidelines? In most cases we are just trying to stabilize patients, get them better, and keep them out of the hospital as the goal is to provide most psychiatric care in the community. To reach these goals a single medication does not always produce the desired results.
Patients that end up on multiple antipsychotics have some unique characteristics. They tend to have more severe psychotic symptoms, are male, unemployed, and younger. Those with frequent inpatient admissions on involuntary status are also more likely to end up on two medications.
What To Do When a Single Medication Is Not Enough?
The use of multiple antipsychotics is an area of limitted research. However, there is a difference between rational polypharmacy and irrational polypharmacy.
We should start this discussion by saying a patient should be started on monotherapy titrated to an effective dose and continued on the medication for 6 weeks prior to making a change. If the first medications fails, then switching to another medication or long acting injectable is a reasonable next step. If after another 6 weeks of treatment the patient remains unstable and symptomatic the technical next step is to start clozapine. There are many reasons why clozapine may not be a good option for a particular patient including the strict requirements for weekly complete blood cell counts CBCs.
Assuming this process is followed and the patient is still symptomatic what’s the next step?
Consider Receptor Binding Profiles
This is the first step in prescribing two medications rationally. Most first-generation medications such as Haldol will bind tightly to D2 receptors and stay bound to the sites longer. Second-generation medications like quetiapine are known to bind to the receptors and quickly dissociate giving an on-off like effect. Tight binding and longer duration of binding can lead to extrapyramidal side effects (EPS), whereas quick on-off medications like quetiapine have limitted EPS risk.
You should also consider other receptors the medication may target such as histamine and muscarinic cholinergic receptors. It would be best to avoid combining two medications that have high antihistamine and anticholinergic activity.
Let’s look at some scenarios where antipsychotic polypharmacy makes sense.
Patients With Acute Agitation
This is a common problem on the inpatient unit. A patient is on a low-potency quick on-off medication like quetiapine but remains symptomatic and is engaging in dangerous behavior.
The addition of a higher potency, higher affinity medication like Haldol makes some sense here. This will control the acute agitation, can be titrated until the psychotic aggression is controlled, and can be stopped as soon as the patient is stable on quetiapine. We can see how the receptor binding profile makes this combination reasonable.
Clozapine Refractory Patients
What do you do when a patient is on the best antipsychotic medication but remains symptomatic?
We do have several lines of evidence that we can look at for this question. One option is to add low dose risperidone. This is a similar idea to adding Haldol to quetiapine. Clozapine has lower affinity for the D2 receptor than risperidone which has much higher affinity for D2 receptors. There were two placebo-controlled trials that support this combination. Before combining medications, I would suggest obtaining a clozapine level to make sure it’s therapeutic.
There are two more recent studies that compared multiple antipsychotic medication combinations and used rehospitalization as a measure of effectiveness. Both studies found a significant reduction in rehospitalization for patients receiving polypharmacy compared to those receiving monotherapy. The best outcome was achieved when clozapine was combined with aripiprazole.
Patient is On a Long Acting Injectable (LAI) but Remains Symptomatic at the Highest Dose
This is a common problem because the doses of LAIs are limitted. For example, the LAI aripiprazole (Aristida) is limitted to a maximum dose of 20 mg/day. The oral formulations of aripiprazole allow for a maximum dose of 30 mg/day. One strategy is to give the injection early. This will usually be done on week 3 for formulations that last 4 weeks. Another option is to add another medication with a different receptor binding profile such as the clozapine aripiprazole combination that was shown to reduce the risk of rehospitalization.
Treatment of Insomnia
The addition of low dose quetiapine to a medication like paliperidone is common in clinical practice. Once D2 receptor blockade has been maximized by reaching an effective dose of paliperidone, considering the addition of as need (PRN) quetiapine for its low potency and sedating properties is reasonable. The medication should be used PRN only and should be removed once the insomnia has resolved. Consider a sleep study if sleep apnea is possible and using other options such as short-term orexin antagonists, melatonin, and sedating antidepressant if appropriate.
Treatment of Antipsychotic Induced Side Effects
I know what you are going to say, adding a medication to treat a side effect of another medication doesn’t make sense. Let’s take an example to illustrate why this makes sense. If a patient is stable on risperidone and is discovered to have an elevated prolactin level you have an obligation to address it. The addition of low dose aripiprazole has been proven to reduce prolactin levels in these cases. Another possibility is using aripiprazole to reduce the metabolic burden of medications such as clozapine. There is much more limited data in this area and I would consider metformin a much better option to start with if antipsychotic induced weight gain is a problem.
In the process of Switching Medication the Patient Achieves Remission
This is another common clinical scenario. A patient didn’t respond to a medication, and you begin decreasing the dose of the first medication while titrating the new medicine. Then suddenly they are better. You don’t know why but they are better than they have ever been and now you are afraid to make any additional changes. Ideally you would finish the process and appropriately titrate the new medicine while discontinuing the ineffective medication. There is no good data to support inadequate dosing of two antipsychotics, and it’s best to continue your taper/titration and reevaluate after it’s complete.
Conclusion
There is still limited data to support the use of multiple antipsychotic medications although it is often seen in clinical practice. There are a few places where the addition of a second medication makes sense, and we can use receptor profiles to help us make rational decisions and avoid excess side effect burden.
