Category: medications

Clozapine in the Outpatient Setting: Why It Still Matters

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Drawing of large textbook with medications and written notes nearby.

Clozapine remains the most effective antipsychotic for treatment‑resistant schizophrenia, and recent Risk Evaluation and Mitigation Strategy (REMS) changes mean community-based providers are more likely to encounter patients starting or maintained on it, or be asked to co‑manage their care, given the shortage of mental health specialists in Washington. This overview focuses on what matters most in these care settings: when to think about clozapine, how monitoring has shifted, and the key safety pearls that will keep your patients out of trouble.

Clozapine is uniquely effective for patients with treatment‑resistant schizophrenia, typically defined as non‑response to at least two adequate antipsychotic trials from different classes over 4–6 weeks. About 30% of patients with schizophrenia meet this definition, yet U.S. prescribing rates are far below that, historically around 11% and declining, while countries like Australia approach 35% use among eligible patients.

The clinical benefit is not just symptom scores. Multiple meta-analyses indicate that clozapine reduces overall symptom burden, hospital bed days, and even mortality in comparison with the use of other antipsychotics. Surprisingly, given its substantial adverse metabolic effects, it even decreases deaths from ischemic heart disease in comparison to other antipsychotics. An influential publication by Tiihonen from 2009 following Finnish approximately 60,000 patients for 11 years indicated that clozapine had a 26% reduction in overall mortality.

REMS Changes: What’s Different Now

The most practice‑changing update is that the clozapine REMS program has been discontinued as of February 2025. Prescribers, pharmacies, and patients no longer need to enroll in a centralized registry managed by the FDA, and there is no longer a system‑level requirement to submit ANC values before dispensing.

However, the recommended Absolute Neutrophil Count (ANC) monitoring schedule in the prescribing information has not changed: weekly for 6 months, every 2 weeks for the next 6 months, then monthly indefinitely. The practical implication is a shift in responsibility—where pharmacists and a centralized database once served as a second set of eyes, the onus now falls almost entirely on the prescriber to ensure appropriate monitoring and interpretation of neutrophil counts.

For primary care clinicians asked to co‑sign labs, renew prescriptions, or cover during transitions of care, it is important to recognize that while administrative barriers are lower, the clinical risks of neutropenia and myocarditis remain, especially during the first 18 weeks and 4 weeks of therapy, respectively.

Neutropenia: Understanding the Real Risk

Early experience in Finland, where a cluster of agranulocytosis‑related deaths occurred in a single facility in 1975, cast a long shadow over clozapine’s reputation. Subsequent data suggested agranulocytosis occurs in approximately 0.4% of patients, with neutropenia rates somewhat higher, and around 550 deaths have been reported globally over decades. The highest risk period is during the first 6–18 weeks of treatment, after which risk falls sharply.

Large‑scale monitoring data from Australia and New Zealand (2.6 million ANC values) found that by 18 weeks, 0.9% of patients had a serious neutropenic event; from 25 to 50 weeks, only 16 additional events occurred, and from 50 to 100 weeks, only 20. Another long‑term Finnish study showed that after the first six months—when agranulocytosis risk was 36 times higher—risk in the following 2-3 overlapped with that seen with non‑clozapine antipsychotics. These findings underpin a major recent Delphi Consensus Guideline publication put out by an international group known as TRRIP or Treatment Response and Resistance in Psychosis Working Group suggesting that ANC monitoring could safely be reduced after 2–3 years in the future.

The FDA prescribing information for clozapine still suggests the following ANC monitoring frequency:

  • Weekly x first 6 months, Every 2 weeks for months 6-12 and Every 4 weeks thereafter.

However, the 2025 Delphi Consensus Guidelines suggest the following ANC monitoring frequency and many anticipate that the FDA will adjust the prescribing information to the following:

  • Weekly x first 18 weeks, Every 4 weeks from weeks 18-2 years, Annually thereafter.

For now, primary care pearls include:

  • Expect the most ANC events in the first 18 weeks-6 months; a sudden drop later in treatment is less common and more likely to be a minor neutropenic event but still warrants workup.
  • Treat fevers, sore throat, or infection‑like symptoms in a clozapine patient as a potential hematologic emergency until proven otherwise; checking an ANC promptly is appropriate.
  • Be aware that other countries (EU, Australia, New Zealand, Netherlands, Finland) often monitor weekly for 18 weeks then move to monthly, reflecting their interpretation of the early‑risk data.

During the COVID‑19 pandemic, UK and VA systems experimented with extending monitoring intervals (for example, every 12 weeks) and did not see increased neutropenia or hospitalizations, and patients on extended schedules were 31–49% less likely to discontinue clozapine. These real‑world data support a more flexible, individualized risk–benefit conversation, particularly for stable long‑term patients struggling with frequent lab visits.

Myocarditis: The Under‑Recognized Early Threat

Myocarditis is at least as important as neutropenia from a mortality standpoint and may warrant more vigilance from non‑psychiatric clinicians. Approximately 539 myocarditis‑related deaths have been reported worldwide, like agranulocytosis, but myocarditis carries a much higher case fatality rate—up to 50%, compared with about 2% for agranulocytosis.

Key clinical pearls for myocarditis:

  • Timing: Most cases occur in the first 3–4 weeks of treatment, rarely beyond 8 weeks.
  • Risk factors: Younger age (under 40) and aggressive titrations appear to increase risk.
  • Presentation: Symptoms are non‑specific and easily misattributed—fever, flu‑like illness, fatigue, malaise, tachycardia, and hypotension, followed by rising CRP, troponin, and eosinophilia.

A practical approach, especially in primary care settings co‑managing new starts, is to:

  • Monitor daily for non‑specific symptoms during the first month; patient and family education is critical.
  • Add weekly CRP and troponin for at least the first 4 weeks (up to 8 weeks in higher‑risk patients).
  • If CRP is 50–100 mg/L, increase monitoring and consider slowing the titration.
  • If CRP exceeds 100 mg/L or troponin is more than twice the upper limit of normal, stop clozapine and involve cardiology urgently.

From a primary care perspective, any new chest discomfort, disproportionate tachycardia, or “viral” picture in a newly initiated clozapine patient should trigger a low threshold for ECG, troponin, CRP, and cardiology consultation.

Titration, Levels, and What Providers Need to Know

Traditional inpatient titration starts at 25 mg/day and increases by 25 mg increments to reach roughly 300 mg by day 14. Emerging myocarditis data support slower up‑titration strategies, such as reaching 275 mg by week 4 (NHS example) or 100 mg by day 17 in Dutch protocols, with Dutch populations showing some of the lowest myocarditis rates.

Therapeutic drug monitoring is increasingly used to optimize dosing:

  • A clozapine level of at least 350 ng/mL is usually needed for meaningful antipsychotic response.
  • Literature now suggests a practical “target range” of 350–600 ng/mL; older upper limits of 1000 ng/mL are being revised down by many labs to 600 ng/mL based upon meta-analysis showing higher NNT for higher levels.
  • Many patients do well at 600–1000 ng/mL if they are clinically stable and not experiencing dose‑related adverse effects such as seizures, myoclonus, or severe sedation.

For outpatient care, the main use of levels is during:

  • Non‑response (“Is this a pharmacologic failure or just subtherapeutic exposure?”).
  • Suspected toxicity (for example, sedation, confusion, new seizures, especially around infections, changes in smoking or drug interactions).

Though you may not initiate clozapine in your practice, it may help to know that an apparently “high” dose may be entirely appropriate if corresponding levels and the patient’s clinical status support it.

High‑Yield Drug and Disease Interactions

Clozapine is highly sensitive to CYP1A2 activity and systemic inflammation, which means common primary care issues can destabilize levels. Priority interactions include:

  • Tobacco smoking: As few as 5 cigarettes per day can decrease clozapine levels by 30–50% via CYP1A2 induction; stopping smoking during a hospitalization or quit attempt can rapidly increase levels at the same dose.
  • Fluvoxamine: A strong inhibitor that can cause large level increases; sometimes used intentionally by specialists to boost levels but risky without close monitoring.
  • Estrogen‑containing oral contraceptives and high caffeine intake: Moderate CYP1A2 inhibition; case reports describe patients needing up to a 50% dose reduction after starting oral contraceptives.
  • Acute infection (for example, pneumonia, sepsis): Inflammatory cytokines suppress CYP enzyme production, leading to lower levels of CYP enzymes and higher clozapine levels; in one inpatient series, up to 60% of patients with infection required a clozapine dose reduction of 50% or more.

The clinical takeaway is that any change in smoking status, hormone therapy, caffeine consumption, or major infection should prompt you to consider what this is doing to the clozapine level and whether a dose adjustment or level check is needed.

How Health Care Providers Can Add Value

Even if you are not initiating clozapine yourself, you play a central role in keeping patients safe and maximizing benefit:

  • Reinforce adherence to ANC monitoring and help interpret results, especially early in therapy.
  • Maintain a high index of suspicion for myocarditis for the first 4 weeks and neutropenia in the first 18 weeks of treatment.
  • Actively manage smoking cessation, infections, and interacting medications with an eye on clozapine levels and side effects.
  • Collaborate with psychiatry on individualized monitoring schedules for stable, long‑term patients who may safely tolerate less frequent lab visits.

Many patients who have cycled through repeated hospitalizations and failed multiple antipsychotics can achieve durable stability on clozapine—holding jobs, living independently, and staying out of the hospital for decades. With the REMS barrier removed, outpatient care provider involvement will be increasingly important to ensure that more of these patients can access and safely remain on this uniquely effective medication.

References:

  • Northwood K, Myles N, Clark SR, et al. Evaluating the epidemiology of clozapine associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand:  a retrospective cohort study. Lancet Psychiat. 2024; 11:  27-35.
  • Rubio JM, Kane JM, Tanskanen A, et al. Long term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics:  a nationwide cohort and case-control study in Finland. Lancet Psychiat. 2024; 11:  443-50.
  • Siskind D, Northwood K, Pillinger T, et al.  Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment:  consensus guidelines from a global Delphi panel. Lancet Psychiat. 2025; 2, 77-85.

Jennifer Jepsen, PharmD, BCPS

Jennifer Jepsen is a Clinical Pharmacist within Harborview Medical Center. She has specialized in inpatient psychiatric hospital practice and has worked at Harborview, Western State Hospital and Navos. She has also worked within a Collaborative Drug Therapy Agreement as a prescribing pharmacist within an outpatient mental health clinic as well as a pharmacogenetic lab. She is a board-certified pharmacist in pharmacotherapy with interests in pharmacogenetics and geriatrics. 

Treatment of Adults with Opioid Use Disorder

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Do you have patients who are misusing opiates? Do you wonder if you can manage prescribing medications for opioid use disorder (MOUD) or have questions about what to prescribe? Drug overdose deaths in the United States are at an all-time high, with most caused by opioid use, namely fentanyl. The good news is that effective medication treatments for opioid use are available, and in case you didn’t know, Washington providers can call the Psychiatry Consultation Line at 877-927-7924 to consult with our psychiatrists about using these treatments with your adult patients.

It’s critical for more clinicians to explore whether they can prescribe MOUD; in 2019, only 18% of people with opioid use disorder (OUD) received MOUD in the prior year. What are the MOUD options for your patients living with OUD?

Methadone 

The three FDA-approved MOUD options are methadone, buprenorphine and naltrexone. Methadone is a full mu-opioid agonist that has been exhaustively studied and shown to be safe and effective for patients with OUD, particularly when dosed above 60 mg per day. Because of the time involved in titration, achieving a dose of methadone that alleviates cravings and protects patients from overdose can take weeks. Despite the efficacy data, methadone is the most tightly regulated MOUD, and it is only accessible through DEA-approved treatment facilities. Many counties in Washington have no methadone clinics, leaving those with OUD only two MOUD options: naltrexone and buprenorphine.

Naltrexone

Naltrexone, particularly in the form of the 380 mg per month, long-acting injectable is another option for patients. As a full mu opioid blocker, initiation of naltrexone requires full withdrawal from opioids. Starting naltrexone prior to completion of opioid withdrawal can result in precipitated withdrawal. Many patients are unable to achieve full cessation and thus studies have shown higher dropout rates with naltrexone for OUD compared to buprenorphine.

Buprenorphine

Buprenorphine is the third FDA-approved MOUD with evidence similar to methadone in terms of treatment outcomes. In years past, prescribing buprenorphine required at least 8 hours of training and an x-waiver. As of January 2023, this requirement was dropped and anyone with a standard DEA registration number can prescribe buprenorphine. Unlike methadone, buprenorphine can be prescribed in an office-based setting, making it more accessible for patients.

As a partial agonist with a high binding affinity for the mu-opioid receptor, buprenorphine is a very safe option for OUD. Even at maximum doses, patients do not experience respiratory depression with the medication alone. Further, doses of buprenorphine, which protect patients from overdose, can be achieved quickly in one or two days. Given the pharmacologic properties of buprenorphine, patients must be in some degree of opioid withdrawal prior to initiating buprenorphine, as it can otherwise precipitate opioid withdrawal. Typically, it is recommended for patients to achieve a clinical opioid withdrawal scale (COWS) score of 8 or more prior to initiating buprenorphine. Though precipitated withdrawal is not necessarily dangerous, patients feel extremely uncomfortable and can have negative connotations with buprenorphine, reducing their likelihood of continuing the medication in the future.

Thankfully this outcome is a relatively rare occurrence. In one recent study less than 1% of patients experienced precipitated withdrawal when dosed with buprenorphine after achieving a COWS score greater than 8. Techniques for initiating buprenorphine varies significantly, ranging from “low dose induction,” the practice of giving small doses of buprenorphine with gradual increases over time to “standard induction,” giving 4 mg -12 mg of buprenorphine in the first day, to “high dose inductions” initiating higher doses of buprenorphine, 16 mg to 32 mg quickly following emergence of withdrawal symptoms.

Buprenorphine Treatment Guidelines

Regardless of the initiating dose, the goal of treatment is to achieve a dose of buprenorphine that eliminates opioid withdrawal, significantly reduces or eliminates craving to use opioids, and blocks the effects of illicit opioids to the degree that the patient has significantly reduced, or better yet, stopped use of illicit opioids all together. If patients have cravings to use, evidence of withdrawal from opioids, or continue using illicit opioids, increasing the dose of buprenorphine should be considered. The current maximum dose is 32mg daily.

Previous guidelines have suggested that doses of buprenorphine beyond 24 mg may not be necessary, but these recommendations were based primarily on data associated with patients using heroin. In the current era where the illicit opioid market is dominated by fentanyl, patients may well require higher doses of buprenorphine. Typically, buprenorphine has been dosed once daily, but for some, 2-4 doses spread throughout the day are preferred. Buprenorphine has multiple formulations for the treatment of OUD which include sublingual, buccal, implantable, and long-acting subcutaneous injectable versions.

There are no clear data on the length of time patients with OUD should remain on MOUD. However, after cessation of medications, rates of return to use of opioids is high, so most experts recommend ongoing maintenance therapy with buprenorphine or methadone. For more information on treatment of patients with MOUD, please see the resources below. And please call the PCL at 877-927-7924 if you are a Washington provider who would like to consult about your adult patients with mental health and/or substance use care needs.

Author

Jonathan Buchholz, MD
Director, Addictions Psychiatry Fellowship; Medical Director of Inpatient Psychiatry, VA Puget Sound

Dr. Buchholz specializes in working with individuals experiencing co-occurring mental health and substance use disorders, a process that reminds him of the amazing resiliency that lies within us all.

Related Resources

Practice-Based Guidelines: Buprenorphine in the Age of Fentanyl
Provides practical clinical practice-based guidance, based on available research combined with emerging clinical experience, on the use of buprenorphine in the treatment of individuals using fentanyl and other highly potent synthetic opioids.

Linking People with Opioid Use Disorder to Medication Treatment
This prevention resource presents strategies that can help state, local, and tribal leaders and healthcare professionals link persons living with OUD to evidence-based care. Strategies are based on the best available evidence.

Medications for Opioid Use Disorder
The Executive Summary of this Treatment Improvement Protocol provides an overview on the use of the three Food and Drug Administration-approved medications used to treat opioid use disorder—methadone, naltrexone, and buprenorphine—and the other strategies and services
needed to support recovery.

Providers Clinical Support System-Medications for Opioid Use Disorders
A program funded by the Substance Abuse and Mental Health Services Administration (SAMHSA) and created in response to the opioid overdose epidemic. PCSS-MOUD’s goal is to provide evidence-based practices to improve healthcare and outcomes in the prevention of those at risk and treatment for individuals with an opioid use disorder (OUD).

10 Tips for Prescribing in the Perinatal Period

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Psychiatric disorders are common during pregnancy and postpartum. For example, rates of perinatal depression and anxiety are 15-20%. Twenty percent of people with postpartum depression have a bipolar spectrum disorder. In addition, many people have pre-existing psychiatric conditions and are already taking psychotropic medications when they become, or are planning to become, pregnant. The overall goal of treatment during pregnancy is to use the lowest number and dosages of medications possible, while effectively treating the underlying psychiatric disorder(s).

Although the Perinatal PCL receives questions about diagnoses, non-medication treatments, and resources and referrals, many calls are about prescribing and the effects of medications during pregnancy and lactation. Here, we provide some general guidelines about prescribing during the perinatal period and some resources to find information about risks of specific medications.

What are some general guidelines about prescribing during the perinatal period?

1. Consider risks during pregnancy whenever prescribing medication for someone of childbearing potential.
About 50% of pregnancies are unplanned. Considering, and informing people of childbearing potential about, risks of their medication(s) during pregnancy helps to maximize prescribing of safer medications and avoid patients’ suddenly discontinuing needed medication if they find out they are pregnant.

2. Make any medication changes before pregnancy if possible.
This minimizes the number of exposures for the baby and maximizes stability for the parent. Changing a newer medication with less data regarding safety in pregnancy to an older medication with more safety data can be done before pregnancy, if desired. Making this change once the patient is already pregnant involves exposing the baby to two medications instead of one and potentially causing worsening of the parent’s psychiatric condition during pregnancy.

3. Ideally, the patient should be psychiatrically stable for at least 3 months before trying to conceive.
Although this is not always possible, it decreases the risk of relapse and exposure of the baby to risks of untreated/undertreated psychiatric illness.

4. Avoid polypharmacy whenever possible.
Prescribing the fewest medications possible to effectively treat the patient’s psychiatric disorder reduces exposures for the baby. Reviewing the need for each medication is especially important when someone is taking multiple medications and/or more than one medication in a class (e.g., two or more antidepressants, two or more antipsychotics, multiple antianxiety/hypnotic medications, etc.).

5. Avoid Depakote.
Depakote (valproic acid) is a commonly prescribed mood stabilizer for patients with bipolar disorder. Depakote is a known teratogen (rate of malformations elevated in all dosage ranges and 25% at doses above 1450 mg/day) and is associated with significantly decreased IQ in children exposed in utero.

6. Optimize non-medication treatments.
At all times, and especially during the perinatal period, we want to maximize the use of evidence-based non-medication treatments such as psychotherapy. Even if someone requires medication for effective treatment of their condition, non-medication treatments can help minimize numbers and dosages of medications and increase effectiveness of treatment.

7. Remember that an untreated/undertreated psychiatric disorder also poses risks to the parent and the baby.
Untreated/undertreated psychiatric disorders pose significant risks for parents and babies. For example, perinatal depression is associated with higher rates of preterm birth, low birth weight, problems with attachment and bonding, and increased rates of psychiatric disorders in childhood and adolescence. For this reason, it is important to treat psychiatric disorders effectively during the perinatal period.

8. If you are thinking of stopping your patient’s psychotropic medications because they are pregnant, please call us first.
Discontinuing medications abruptly can precipitate relapse (another exposure for the baby and risk for the parent). Also, stopping some medications can cause withdrawal symptoms that are potentially dangerous (e.g., benzodiazepines) or unpleasant (e.g., antidepressants). We would be happy to help you sort out which medications to discontinue and safe tapering schedules.

9. Prescribing during the perinatal period requires a risk-risk discussion.
Informed consent during the perinatal period involves collaborating with the patient in discussing and weighing risks of medication for the fetus/baby, risks of the psychiatric disorder, and possible alternative treatments.      

10. Use a patient-centered and team approach.
In addition to collaborative decision-making with, and support of, the patient, this includes involving family members and communicating with other care providers. It is important to educate the partner and/or family members about the risks and benefits of treatment as well as warning symptoms of relapse. Communication with obstetric and pediatric providers minimizes the patient’s hearing conflicting opinions and being confused and concerned.   

The Perinatal PCL is a free, state-funded, provider-to-provider consultation line like the Psychiatry Consultation Line (PCL) but focused on behavioral health disorders and symptoms during the perinatal period (pregnancy and the first 12 months postpartum). We are available at 877-725-4666 or by email at ppcl@uw.edu, weekdays 9-5. Like PCL, we also offer scheduled consultations.

Any healthcare provider in Washington State can call us with any behavioral health-related questions about a patient/client who is pregnant, planning pregnancy, postpartum, or who has pregnancy-related complications (e.g., infertility, pregnancy loss). Perinatal PCL is staffed by University of Washington perinatal psychiatrists, an addiction psychiatrist with expertise in the perinatal period, and our program coordinator, who is trained in social work. We offer psychiatric consultation and local perinatal mental health resources. For more information about Perinatal PCL, and to access our online Perinatal Mental Health Care Guide, please visit our website.

Author

Deb Cowley, MD
Board-certified psychiatrist at UWMC-Roosevelt
UW professor of Psychiatry and Behavioral Sciences
Medical director, Perinatal PCL

Dr. Cowley has expertise evaluating and treating women who have mental health issues during pregnancy and postpartum, and throughout their life cycle, including premenstrual and menopause-related psychiatric symptoms. Her clinical interests include anxiety disorders, depressive disorders, obsessive compulsive and related disorders, panic disorder, postpartum depression, evidence-based medicine, maternal mental health and women’s health.

Related Resource

Management of Psychotropic Drugs During Pregnancy
Psychiatric conditions (including substance misuse disorders) are serious, potentially life threatening illnesses that can be successfully treated by psychotropic drugs, even during pregnancy. This review presents an up to date and careful examination of the most rigorous scientific studies on the effects of psychotropic drugs in pregnancy.

Other Resources

InfantRisk for Healthcare Providers
This collection of apps is for healthcare providers and parents about the safety of medications during pregnancy and breastfeeding. 

LactMed
This database of drugs and other chemicals provides information about the safety of exposure during breastfeeding.

Reprotox
This database of medications highlights their effects during pregnancy, breastfeeding, and development. (Requires subscription.)

MotherToBaby
These fact sheets are for parents regarding risks of drugs (including non-prescribed drugs) during pregnancy and breastfeeding. 

Perinatal Support Washington
This non-profit organization provides a warm line, support groups, peer support, resources, and therapy referrals to support emotional wellbeing for new parents. 

Treatment of Adult Patients with Obsessive-Compulsive Disorder

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The lifetime prevalence of obsessive-compulsive disorder (OCD) amongst adults in the United States is 2-3%. While most providers can list the most common symptoms of OCD, the diagnosis is rare enough that it may have been a while since you got an update on useful screening tools and treatment recommendations. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) is a good place to start, and you can find this document online (it is now under copyright so no longer available on the Resources page of the PCL website). The Y-BOCS contains a list of symptoms that can be helpful for making the diagnosis, as well as a rating scale that can be used to track treatment efficacy.

There are a wide range of obsessions and compulsions that can be seen in OCD and thus the symptom checklist on the third page of the Y-BOCS document can be very helpful when trying to establish the diagnosis. Moreover, the rating scale on the first two pages not only helps with establishing the diagnosis but is also useful for tracking the improvement seen with treatment.

The first-line treatment for adults with OCD is cognitive behavioral therapy (CBT) with exposure and response prevention. When medication is added to CBT, the usual first choice is an SSRI. Though an 8-week trial of an SSRI is adequate for some behavioral health diagnoses, patients with OCD may see better results from SSRIs at 16 weeks. Moreover, some patients with OCD require SSRI dosing that is titrated up toward the higher end of the usual dosage spectrum. This might mean, for example, a final daily sertraline dose of 150-200mg, rather than 50-100mg, if the patient can tolerate the higher dose. 

For patients who have not responded to one or two different SSRI trials, clomipramine is sometimes trialed. SSRIs and clomipramine are not used together since the combination increases the risk of serotonin syndrome. In terms of efficacy, some clomipramine studies suggest this medication is superior to SSRIs in OCD. However, clomipramine is a tricyclic antidepressant and thus has more side effects than SSRIs, with anticholinergic side effects especially intolerable for some patients. Tricyclics also have a higher risk of cardiac side effects, even at normal doses, and are more lethal on overdose than SSRIs.

Atypical antipsychotics have some data as an augmentation strategy for patients who have a partial response to SSRIs or clomipramine. Lamotrigine and topiramate have a small amount of data for augmentation in refractory cases, as well. Clonazepam and lorazepam, on the other hand, do not generally demonstrate efficacy in studies of augmentation or monotherapy for OCD.

If you are considering using a medication for OCD, please first review your own reference material for full details on indications, side effects, dosing, monitoring requirements, and drug interactions. For reference, we most often use Micromedex, UpToDate, or Epocrates. Additionally, there are free databases available to Washington providers at HEAL WA.

If you would like more information on the spectrum of medications for OCD, please call the Psychiatry Consultation Line (877-WA-PSYCH / 877-927-7924) and one of our psychiatrists would be happy to review the data with you.

Author

Ryan Kimmel, MD
Professor, University of Washington School of Medicine, Department of Psychiatry and Behavioral Sciences
Chief of Psychiatry, University of Washington Medical Center
Medical Director, Psychiatry Consultation Line


Learn More

UW Psychiatry and Addictions Case Conference series (UW PACC)*

OCD: Diagnosis and Treatment
Presenter: Deborah Cowley, MD
The objectives of this presentation are to: 1) review the diagnosis of OCD and related disorders; 2) discuss the epidemiology, differential diagnosis, and comorbidity; and 3) discuss treatment of OCD and related disorders. 

*The UW Psychiatry and Addictions Case Conference series (UW PACC) is a free, weekly teleconference that connects community providers with UW Medicine psychiatrists and addictions experts. Sessions include both an educational presentation on an addictions or psychiatry topic and case presentations where providers who participate receive feedback and recommendations for their patients.

Antipsychotic-associated Metabolic Syndrome

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When providers reach out to the PCL program with questions about antipsychotics, we often attach a PCL developed document that outlines a schedule for monitoring metabolic side effects. While we follow this monitoring schedule for all antipsychotics, there are certain second-generation antipsychotics that are more notorious than others.

Olanzapine and clozapine, for example, are associated with the most weight gain. On the other end of the spectrum, ziprasidone and aripiprazole are associated with the least. Beyond the long-term cardiovascular risks, tracking the metabolic syndrome is also important because patients are understandably reluctant to continue taking medications that cause weight gain. 

While there have been studies to suggest that metformin may have a modest, short-term benefit for olanzapine-associated weight gain, there is also data that switching from olanzapine to aripiprazole or ziprasidone can result in the loss of some of the weight gained while on olanzapine. There is a risk of decompensation when switching from one antipsychotic to another and the decision to switch is thus ultimately based on a variety of patient-specific factors. There are not yet any published, placebo-controlled trials on the use of semaglutide or tirzepatide for antipsychotic-associated weight gain.

Antipsychotics can also cause glucose dysregulation and lipid disturbance. These abnormalities can arise even in patients who are not gaining weight, which is why we monitor fasting labs as a matter of course. For a useful way to visualize the spectrum of antipsychotics in terms of their metabolic side effects, I’d recommend looking at Figure 3 of Pillinger’s article on antipsychotics in Lancet Psychiatry 2020; 7: 64-77. In this “heat map,” red are the worst offenders and yellow the least, though you can see that no antipsychotic is wholly innocent.

If you would like more information on the spectrum of antipsychotic side effects, please call the Psychiatry Consultation Line (877-WA-PSYCH) and one of our psychiatrists would be happy to review the data with you.

Author

Ryan Kimmel, MD
Professor, University of Washington School of Medicine, Department of Psychiatry and Behavioral Sciences
Chief of Psychiatry, University of Washington Medical Center
Medical Director, Psychiatry Consultation Line

New Generic Option for Treating Bipolar

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Within the last few months, a generic formulation of Latuda (lurasidone) has become available. Should you consider prescribing it for adult Bipolar I Depression?

Previously, this medication cost >$1,200/month and was thus out of reach for most patients and/or required insurance pre-authorization. Now that the price of lurasidone has fallen dramatically, it is worth comparing this medication to quetiapine, which is also generic and also has an FDA indication for adult Bipolar I Depression.

There aren’t very many head-to-head trials, but in meta-analyses of monotherapy for adult Bipolar I Depression, both lurasidone and quetiapine appear to be efficacious. Several published treatment algorithms consider both medications to be first-line options as monotherapy for this indication. In other studies, lurasidone has demonstrated efficacy for adult Bipolar I Depression when used as an adjunct to lithium or divalproex and, indeed, Latuda garnered FDA-approval for adjunct use for this indication.

FDA package inserts are available on the FDA approved drugs site. Package inserts contain a lot of useful information and are likely underutilized in our era of quick, app-based, medication references. When comparing the data reported in the package inserts for lurasidone and quetiapine, lurasidone appears to have a lower incidence of the antipsychotic-associated metabolic syndrome (weight gain, new-onset diabetes, new-onset hyperlipidemia, etc.). Lurasidone, at least at low doses, is also felt to be less sedating than quetiapine. However, when compared to quetiapine, lurasidone appears to have a higher incidence of parkinsonism, akathisia, and other D2 blockade-mediated side effects. For more details on the side effects of these medications, including information on the Black Box warnings, QTc prolongation, monitoring of the metabolic syndrome, and other adverse effects, please refer to your own medication reference material or the free sites available via HEAL WA.

Another important difference between lurasidone and quetiapine is that lurasidone needs to be taken with a >350 calorie meal. This dramatically increases the absorption of lurasidone. However, food insecurity is a problem experienced by many people in our society, and it is important to ask your patients if they have regular access to a >350 calorie dinner.

Lurasidone dosing is usually initiated at 20mg/day. Though the FDA max dose is 120mg/day, some studies of adult Bipolar I Depression suggest that high-end dosing does not necessarily increase efficacy but might increase the risk of side effects. The mean (SD) lurasidone dose was 64.1 (14.4) mg in a 24-week open label study authored by Ketter et al for the journal Depression and Anxiety. Thus, rather than automatically pushing the lurasidone dose to the top end, it could be useful to first give the patient a good trial in the middle of the dosing range.

If you would like more information on the treatment of adult Bipolar I Depression, please call the Psychiatry Consultation Line (877-WA-PSYCH) and one of our psychiatrists would be happy to review the options with you.

Author

Ryan Kimmel, MD
Professor, University of Washington School of Medicine, Department of Psychiatry and Behavioral Sciences
Chief of Psychiatry, University of Washington Medical Center
Medical Director, Psychiatry Consultation Line


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Bipolar Disorder – Screening and Diagnosing in Primary Care
UW Psychiatry and Addictions Case Conference series (UW PACC)*
Presenter: Joseph Cerimele, MD, MPH
The objectives of this presentation are to describe1) the clinical epidemiology of individuals with bipolar disorder in primary care settings; 2) techniques to improve the recognition of bipolar disorder in primary care patients; and 3) clinical characteristics of patients with bipolar disorder in primary care. 

*The UW Psychiatry and Addictions Case Conference series (UW PACC) is a free, weekly teleconference that connects community providers with UW Medicine psychiatrists and addictions experts. Sessions include both an educational presentation on an addictions or psychiatry topic and case presentations where providers who participate receive feedback and recommendations for their patients.

Lack of Evidence: Gabapentin in Bipolar Disorder

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Illustration of a medical provider standing beside a large prescription form, surrounded by various medications, representing professional care and prescribed treatment.

When it comes to treating adults with bipolar disorder, gabapentin appears to be everything you’d want in a medication…except for efficacy.

Prescribers wish that gabapentin had utility in bipolar disorder because gabapentin isn’t a P450 substrate, is renally excreted, and is generic and thus relatively affordable. Unfortunately, gabapentin does not demonstrate efficacy in randomized trials for bipolar disorder and current treatment guidelines do not emphasize its use. Despite of the lack of evidence, reviews of gabapentin prescribing patterns in the United States show that this medication is still being used with alarming frequency for bipolar disorder.

There are now five medications with specific, FDA approval for acute bipolar depression. Moreover, there are at least a dozen medications with FDA approval for acute mania. Many of these options are available in generic formulations.

Instead of reaching for gabapentin as a potential intervention for bipolar disorder, please call the Psychiatry Consultation Line (877-WA-PSYCH) and one of our psychiatrists would be happy to review treatment options that have better evidence.

You can also call the PCL for advice regarding differential diagnosis, non-pharmacologic interventions, and treatment monitoring. In complicated clinical scenarios, discussing a patient’s care with a colleague can help you formulate a more comprehensive treatment plan.  

The PCL is a free resource for healthcare providers in Washington State to consult with a psychiatrist about their adult patients with mental health or substance use conditions. Learn more at pcl.psychiatry.uw.edu.

If you are considering using a medication for bipolar disorder, please first review your own reference material for full details on indications, side effects, dosing, monitoring requirements, and drug interactions. For reference, we most often use Micromedex, UpToDate, or Epocrates. Additionally, there are free databases available to Washington providers at HEAL WA.


Author

Ryan Kimmel, MD
Professor, University of Washington School of Medicine, Department of Psychiatry and Behavioral Sciences
Chief of Psychiatry, University of Washington Medical Center
Medical Director, Psychiatry Consultation Line


Learn More

Managing Bipolar Depression in Primary Care
UW Psychiatry and Addictions Case Conference series (UW PACC)*
Presenter: John S. Kern, MD
The objectives of this presentation are to 1) recognize the predominant role of depressive episodes in the morbidity associated with bipolar disorder; 2) summarize the outcomes of the SPIRIT study; and 3) apply an orderly approach to the care of bipolar depression.

*The UW Psychiatry and Addictions Case Conference series (UW PACC) is a free, weekly teleconference that connects community providers with UW Medicine psychiatrists and addictions experts. Sessions include both an educational presentation on an addictions or psychiatry topic and case presentations where providers who participate receive feedback and recommendations for their patients.

Mirtazapine in major depressive disorder in adults

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Illustration of a sad-looking person sitting alone while a large hand offers medication, symbolizing treatment options for depression.

Mirtazapine garnered FDA approval as an antidepressant in 1997. It has been generic for so long that it no longer has an advertising budget and thus you won’t see commercials for it on late-night television. Mirtazapine impacts serotonin and norepinephrine systems in the brain but is not a reuptake inhibitor. While SSRIs are generally considered first-line in major depressive disorder, mirtazapine is a medication worth remembering in certain situations. 

Mirtazapine does not inhibit P450 enzymes and thus can be useful in depressed patients who have complex medical histories and are on complicated (and ever changing) medication regimens. 

Mirtazapine does not cause sexual dysfunction greater than placebo, making it a potentially useful alternative for patients with depression and intractable, SSRI-associated, sexual dysfunction. Sexual side effects are seen in as many as 50% of patients on SSRIs and are frequently cited by patients as a reason for medication discontinuation.

Per the original package insert, 17% percent of patients taking mirtazapine experienced appetite stimulation. “Weight gain” is often all that prescribers remember about mirtazapine. It is true that this medication has a higher risk of weight gain than SSRIs, that this issue needs to be discussed with patients, and that weight needs to be closely monitored. However, it is also notable that only a minority of patients have this side effect. On the other hand, for patients who experience a profound loss of appetite as a feature of their depression, the potential for appetite stimulation with mirtazapine might be seen as an advantage. 

Mirtazapine is a strong antihistamine and, indeed, the original package insert notes that 54% of patients on mirtazapine reported sedation, compared to only 18% for placebo. This side effect can represent a hindrance or a benefit, depending on the specific features of the patient’s depression and on the degree of sedation. For example, psychiatrists sometimes use mirtazapine as an augmentation strategy for patients who have had a partial response to SSRIs and whose depressive symptoms include prominent initial insomnia. It should be noted that oversedation can impair performance and thus this side effect needs to be monitored by the patient and the prescriber.

Unlike the SSRIs and SNRIs, mirtazapine’s only FDA indication is for major depression. In the intervening 25 years since its FDA approval, the bulk of mirtazapine’s positive data remains for its use in major depression. There is some mixed data (variable strength of study and variable results) in generalized anxiety disorder and social anxiety disorder. However, we do not usually consider mirtazapine as a first- or second-line agent for monotherapy in anxiety disorders.

If you are considering using mirtazapine, please refer to your own reference material for full prescribing information regarding medication dosing, risks, benefits, side effects, monitoring requirements, and drug interactions.  We most often use Micromedex, UpToDate, or Epocrates.  Additionally, there are free databases available to Washington State providers at HEAL WA. You can also call the Psychiatry Consultation Line (877-927-7924) for clinical advice on using mirtazapine in the treatment of major depressive disorder in adults as well as assessment, treatment decisions and monitoring of mental health conditions in general. Even in complicated clinical scenarios, discussing a patient’s care with a colleague can lead to a path forward.

Author
Ryan Kimmel, MD
Professor, University of Washington School of Medicine, Department of Psychiatry and Behavioral Sciences
Chief of Psychiatry, University of Washington Medical Center
Medical Director, Psychiatry Consultation Line

Learn More
UW Psychiatry and Addictions Case Conference series (UW PACC)*

Treatment Resistant Depression
Presenter: Mark Duncan, MD
The objectives of this presentation are to 1) discuss pros and cons of treatment guidelines, 2) walk through cases to determine best options, and 3) Improve confidence in decision making around treatment resistant depression.

Using Stimulants to Augment Depression Treatment
Presenter: Ramanpreet Toor, MD
The objectives of this presentation are to review evidence of psychostimulant use in the treatment of depression.

*The UW Psychiatry and Addictions Case Conference series (UW PACC) is a free, weekly teleconference that connects community providers with UW Medicine psychiatrists and addictions experts. Sessions include both an educational presentation on an addictions or psychiatry topic and case presentations where providers who participate receive feedback and recommendations for their patients.

Non-stimulants for adult ADHD

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Cartoon of a person at a laptop with a cloud of racing, random thoughts around them, illustrating distraction and an overactive, wandering mind.

While the data on the efficacy of stimulants in adult ADHD is robust, we have had numerous calls to the PCL program from providers seeking information on medications that have a lower misuse and abuse potential.

Atomoxetine has an FDA indication for adult ADHD. Atomoxetine is often thought of as the first-line medication for adult ADHD in patients with a history of substance use disorder. There are several studies that demonstrate an improvement in quality of life ratings, for example, with longer term use in patients with ADHD. Atomoxetine selectively inhibits norepinephrine reuptake and medications with this mechanism of action convey a risk of psychosis and mania, especially in patients with a personal or family history of bipolar disorder or psychosis. Like many medications with an antidepressant-like mechanism of action, atomoxetine has a black box warning for increased suicidality in children, adolescents and young adults.

Bupropion does not have an FDA indication for ADHD, though there are meta-analyses that suggest it has some utility. Bupropion is FDA-approved for major depressive disorder. The symptom of poor concentration can be magnified when patients with ADHD experience a major depressive episode. For some of these patients, bupropion might help both disorders. Providers should keep in mind, however, that bupropion is not effective for anxiety disorders. Moreover, some patients with anxiety disorders find that bupropion worsens their anxiety symptoms. Like atomoxetine, bupropion has a black box warning for suicidality in patients under the age of 25. Bupropion can also cause mania and psychosis, particularly in patients with a personal or family history of bipolar disorder or psychosis. Bupropion can increase the risk of seizure and is contraindicated in patients with eating disorders.

While guanfacine has an FDA indication for pediatric ADHD, it does not have an FDA indication for adult ADHD. Some authors are pessimistic about its utility in adult ADHD. Overall, the data is mixed and there have only been a few controlled studies, though research is actively being done and the efficacy (or lack thereof) of guanfacine in adult ADHD may be more clearly articulated in the next few years. Guanfacine is an alpha-2 agonist that is used to treat hypertension and thus it has a unique side effect profile compared to atomoxetine or bupropion.

If you are considering using any of the medications discussed above, please first review your own reference material for full details on side effects, dosing, adjustment in the setting of renal or hepatic impairment, cautions/contraindications, monitoring requirements, and safety in pregnancy and lactation. We most often use Micromedex, UpToDate, or Epocrates. Additionally, there are free databases available to Washington State providers at HEAL WA. You can also call the Psychiatry Consultation Line (877-927-7924) for clinical advice on using these medications in the treatment of adult ADHD as well as assessment, treatment decisions and monitoring of mental health conditions in general. Even in complicated clinical scenarios, discussing a patient’s care with a colleague can lead to a path forward.

Author
Ryan Kimmel, MD
Professor, University of Washington School of Medicine, Department of Psychiatry and Behavioral Sciences
Chief of Psychiatry, University of Washington Medical Center
Medical Director, Psychiatry Consultation Line

Learn More
UW Psychiatry and Addictions Case Conference series (UW PACC)*

Cognitive Behavioral Therapy (CBT) for adult ADHD: does ADHD need therapy (pdf)
Presenter: Kristen Lindgren, PhD, ABPP
The objectives of this presentation are to 1) review diagnostic criteria for ADHD, 2) understand the Role of CBT in the Treatment of adult ADHD, and 3) describe how combined medication and CBT can benefit adults with ADHD

Treating ADHD in SUD patients: how do I treat patients with ADHD and SUDs without making them addicted to stimulants? (pdf)
UW Psychiatry and Addictions Case Conference series (UW PACC)*
Presenter: Robert Sise, MD, MBA, MPH
The objectives of this presentation are to 1) review general considerations in diagnosis of adult ADHD, 2) explore multimodal treatment for adult ADHD with co-occurring SUDs, 3) discuss risks and benefits of pharmacotherapy, and 4) explore how ADHD treatment should be coordinated with SUDs treatment.

*The UW Psychiatry and Addictions Case Conference series (UW PACC) is a free, weekly teleconference that connects community providers with UW Medicine psychiatrists and addictions experts. Sessions include both an educational presentation on an addictions or psychiatry topic and case presentations where providers who participate receive feedback and recommendations for their patients.

Treating Generalized Anxiety Disorder with buspirone

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Illustration of a person holding their head in their hands as a storm of tangled thoughts swirls around them, representing anxiety and mental overwhelm.

A common question to the Psychiatry Consultation Line is around treatment of Generalized Anxiety Disorder (GAD) in patients with a history of substance use disorders and for whom a Selective Serotonin Reuptake Inhibitor has not been effective. First-line treatments for Generalized Anxiety Disorder include Cognitive Behavioral Therapy (CBT), Serotonin Reuptake Inhibitors (SRI), or a combination of both. In cases where adjunctive CBT and multiple trials of SRIs have failed, buspirone can be given some consideration.

In 1980s-era, double-blind studies of GAD, buspirone’s efficacy was shown to be similar to benzodiazepines. An important difference between benzodiazepines and buspirone is that it takes buspirone longer to start working. Buspirone requires a multi-week or multi-month trial to assess efficacy. Compared to benzodiazepines, buspirone is less likely to cause sedation and, importantly, is not associated with the development of tolerance or dependence. Common side effects of buspirone include dizziness, nausea, and headache.

The FDA max dosing is 60mg/day and while some patients require a high dose, average therapeutic doses are in the range of 20 to 45 mg/day. Buspirone has a short half-life and some patients benefit from TID dosing.

Please refer to your own reference material for full prescribing information regarding medication dosing, risks, benefits, side effects, monitoring requirements, and drug interactions. We most often use Micromedex, UpToDate, or Epocrates. Additionally, there are free databases available to Washington State providers at HEAL WA.

Author
Ryan Kimmel, MD
Professor, University of Washington School of Medicine, Department of Psychiatry and Behavioral Sciences
Chief of Psychiatry, University of Washington Medical Center
Medical Director, Psychiatric Consultation Line

Learn more
UW Psychiatry and Addictions Case Conference series (UW PACC)*

How do I address emerging anxiety during substance use recovery?
Presenter: Mark Duncan, MD
The objectives of this presentation are to 1) discuss characteristics between a substance induced anxiety disorder and a primary anxiety disorder, and 2) to talk through different treatment options for anxiety symptoms.

CBT for Anxiety (CBT-A): What can I do with my patient instead of giving them a PRN benzodiazepine?
Presenter: Patrick Raue, PhD
The objectives of this presentation are to 1) understand the CBT model of anxiety symptoms, 2) describe how to give the “treatment pitch” to patients, and discuss the difference between treatment with exposure vs. anxiety management strategies, 3) understand how to develop and work on an exposure hierarchy with patients and 4) describe anxiety management strategies that use physical and cognitive approaches.

Anxiety: fast facts and skills for the primary care physician
Presenter: Ryan Kimmel, MD
A brief overview of diagnosing and treating anxiety in primary care.

*The UW Psychiatry and Addictions Case Conference series (UW PACC) is a free, weekly teleconference that connects community providers with UW Medicine psychiatrists and addictions experts. Sessions include both an educational presentation on an addictions or psychiatry topic and case presentations where providers who participate receive feedback and recommendations for their patients.