News – Psychiatry Consultation Line

Clozapine in the Outpatient Setting: Why It Still Matters

Posted on October 1, 2026

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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.

PCL Satisfaction Survey Feedback, 2025-2026

Posted on October 1, 2026

Every summer, we ask community providers who’ve consulted the PCL over the past year to share their feedback and improvement ideas through an anonymous survey. In 2026, we received survey responses from providers in 22 counties across Washington. Thank you all for your time and thoughtful feedback.

Of those who responded to the survey,

100% were satisfied or very satisfied with the time it took to connect to the PCL psychiatrist
99% were satisfied or very satisfied with the recommendations they received
98% said they would use the PCL again and would recommend the service to their colleagues
97% indicated the consultation helped them care for a specific patient
94% said the consult would help in the care of future patients

PCL Improvement Ideas

Can PCL consult notes be uploaded to Epic?

Since we no longer collect patient identifiers like name and date of birth, this is not possible.

It would be great if the PCL shared treatment algorithms or simple handouts as part of consultations.

PCL psychiatrists routinely share standardized scales and screeners with callers, and most of these tools are also posted on the PCL website Resources page except for those that require a clinical review with the psychiatrist. Also, we are only able to share screeners that do not have copyright protection. We do not maintain patient-facing materials because these would be very challenging and resource intensive to develop and maintain for the entire state. Our partners at ScalaNW have a robust library of patient care algorithms regarding medications for substance use conditions.

Can I consult with the same psychiatrist when calling back on the same patient?

Given the number of psychiatrists who cover the PCL, we can’t guarantee the same psychiatrist is available for repeat consultations. However, several years ago the PCL database was improved to automatically retrieve previous notes to allow the psychiatrist on duty an opportunity to review earlier recommendations, thus creating more care continuity.

Can the PCL offer psychotherapy supervision?

Unfortunately, even though many of the PCL psychiatrists have training and experience in psychotherapy, this is not something the PCL can offer on a consistent basis as not all our psychiatrists have experience with all the various types of therapy. Thus, our website notes this in our FAQs and in-scope/out-of-scope content.

It would be helpful to provide info for complex patients on establishing with a long-term psychiatrist.

We have a similar guide for our department’s Family and Caregiver Support and Training (FACTS) Program. Click here to access the “Choosing a mental health provider” page of the FACTS website. A reminder that nearly half of Washington’s counties do not have a practicing psychiatrist but telehealth has helped improve access for some patients. It can also be challenging to find providers who accept Medicare.

Enhancing Behavioral Health for Dementia Care: A Multi-Modal Approach to Neuropsychiatric Symptoms

Posted on August 6, 2026

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Primary care and mental health providers are the frontline for managing the complex interplay between physical health and neuropsychiatric symptoms (NPS). Whether it is the subtle onset of depression in an older adult or the disruptive agitation of a patient with advancing dementia, the burden on the patient, their caregivers, and the healthcare system is profound. This article provides a concise guide to non-pharmacologic strategies, medication safety, and recent therapeutic updates to help streamline your psychiatric consultations for the care of those with dementia.

1. The Foundation: Non-Pharmacologic Management

Before reaching for the prescription pad, non-pharmacologic interventions should be the first-line approach, particularly for depression, anxiety, and agitation. These strategies are not only evidence-based but also avoid the polypharmacy risks inherent in psychiatric medications.

For Depression: Focus on Behavioral Activation. Encourage patients and caregivers to schedule small, manageable activities that once brought them joy. Even a 10-minute daily walk can significantly impact mood. Walking outside in the morning can also provide light exposure which can help with circadian rythms which can help promote regular sleep-wake cycles. Where and when available, engaging in adult day programs or senior centers that provide dementia support groups or programming can be helpful for structure. Socialization is one of the main pillars of care for those with dementia.

For Anxiety: Implement Structured Relaxation. Teach simple diaphragmatic breathing or “box breathing” during the visit and provide written instructions/online resources to practice/review. Caregivers may need to cue them to do the breathing or suggest “let’s do some breathing together.” Referral to Cognitive Behavioral Therapy (CBT) remains the gold standard for long-term anxiety management but may need to be modified for those with cognitive impairment and also may not be readily available to all patients. Where cognitive impairment is still mild, this can still be effective with modifications. Identify other calming environmental changes (check temperature, use of white noise or calming music, or distracting with a conversation or activity can be helpful). What is calming should be individualized to that specific person.

For Agitation/Aggression: Use Environmental Modification. Identify triggers—such as loud noises, poor lighting, or “sundowning” patterns. Use nightlights to help with sundowning. Maintain a consistent daily routine. Using “validation therapy” (acknowledging the patient’s feelings rather than correcting their reality) can de-escalate aggressive outbursts. Avoid confrontation. Avoid overscheduling and allow adequate rest between activities. Acknowledge and respond to requests. Educate caregivers about dementia by providing resources for education and support. Identify sources of pain, constipation, need to use the bathroom, hunger, or thirst. Urinary retention and constipation from medications and dental issues are common underrecognized contributors to behavior.

2. Medication Review: Protecting Cognition

Polypharmacy is a quiet thief of cognitive function. Many common medications possess anticholinergic properties that can induce or worsen “pseudo-dementia.” A partial list of common contributors:

Drug Class	Examples to Review	Impact on Cognition
Antihistamines	diphenhydramine, hydroxyzine	Confusion, sedation, increased fall risk.
TCAs	amitriptyline, nortriptyline	High anticholinergic burden; worsens memory.
Benzodiazepines And “Z drugs:	lorazepam, alprazolam, zolpidem, zaleplon, eszopiclone	Paradoxical agitation, amnesia, and gait instability.
GI Agents	hyoscyamine, dicyclomine	May cause acute delirium in the elderly.

The American Geriatrics Society’s has a list of medications (the Beers list) that can impact cognition and contribute to things like falls. These medications are recommended not to be used in geriatric patients. Remember that it’s not always a single agent causing the issue but rather the synergy of multiple agents with cognitive side effects. Never abruptly stop medications; provide instructions for taper and discontinuation. Regularly review and encourage patients and families to keep an updated list of all medications they take, who prescribes them, and include supplements and over the counter medications. It is especially important to carefully review lists during transitions like a move or discharge from a hospitalization. For those in facilities, regularly review the Medication Administration Record (MAR) not just the orders list; the MAR documents scheduled medications but also how often as needed medications are being given and efficacy, which is especially important if as needed psychotropic medications are being prescribed. Assessing from documentation whether a specific target symptom is improved with as needed medication administration is paramount so that ineffective medications are not given indefinitely.

3. Updates in Pharmacotherapy: Brexpiprazole and Pimavanserin

In 2026, the landscape for managing agitation associated with dementia shifted toward more targeted agents with improved safety profiles compared to traditional antipsychotics.

Brexpiprazole: Originally an adjunct for MDD and schizophrenia, brexpiprazole is now FDA-approved for agitation associated with Alzheimer’s dementia. It acts as a partial agonist at D2 and 5-HT1A receptors. Unlike older agents, it has lower intrinsic activity at dopamine receptors, which may reduce the risk of extrapyramidal symptoms (EPS).
Pimavanserin: This is a selective serotonin inverse agonist (SSIA) targeting 5-HT2A receptors. It is notably the only medication FDA-approved for Parkinson’s disease psychosis. Its lack of dopamine D2 blockade is critical because it treats hallucinations and delusions without worsening motor function.
Both medications are new and therefore can be quite expensive, often necessitating prior authorization/review of prior failed medications or justification for use.

The Role of Medications for the Treatment of Dementia

While not primary treatments for agitation, Acetylcholinesterase Inhibitors (AChEIs) like donepezil and NMDA receptor antagonists like memantine should be optimized. AChEIs can subtly improve apathy and anxiety, while memantine may help reduce the “overflow” of glutamate that contributes to irritability and aggression in moderate-to-severe cases.

4. Other antipsychotics: Considerations for Use and the “Black Box”

Antipsychotics (e.g., quetiapine, risperidone, haloperidol, aripiprazole) are frequently used off-label in primary care and in psychiatry for management of neuropsychiatric symptoms in dementia. Common reasons for use include:

Acute Safety: When a patient is a danger to themselves or others.
Severe Psychosis: Distressing hallucinations or paranoid delusions.
Refractory Agitation, Inconsolable or persistent distress, or difficulty receiving care: When non-pharmacologic and first-line agents fail

FDA Black Box Warning: All antipsychotics (both typical and atypical) carry a “Black Box” warning regarding an increased risk of death in elderly patients with dementia-related psychosis. Most deaths are cardiovascular (heart failure, sudden death) or infectious (pneumonia) in nature. Informed consent with family and caregivers is mandatory before initiation.

Be aware of the particular risks of using many antipsychotic medications in those with dementia with Lewy bodies or dementia due to Parkinson’s disease as they can be exquisitely sensitive to extrapyramidal side effects. Quetiapine, pimsvanserin, or sometimes clozapine are first line agents where antipsychotic medications are needed. Brexpiprazole may be another option given its potentially lower propensity for EPS.

5. Supporting the “Invisible Patient”: The Caregiver

Caregiver stress is often an underrecognized contributor to symptoms in patients with dementia. When a caregiver’s mental health fails, the patient’s institutionalization can become imminent and crisis-driven so it’s important to check in regularly.

Screening: Use the Zarit Burden Interview or simply ask: “How are you holding up?”
Depression in Caregivers: Caregivers have significantly higher rates of clinical depression than the general population. PCPs should treat the caregiver as an essential component of the patient’s “care ecosystem.”
Resources: Emphasize respite care. Encourage them to utilize local Area Agency on Aging resources to prevent burnout.

Managing psychiatric symptoms in dementia requires a delicate balance between behavioral interventions and careful medication management. Prioritizing non-pharmacologic strategies, reviewing cognitive-impairing drugs, and staying updated on new developments in pharmacotherapy are central management strategies for individualized dementia care.

Resources:

UW Medicine Project ECHO Dementia (virtual)
Free case-based learning for primary care providers hosted by dementia specialists at the UW; meets every other Friday; CME/CNE credit available.

Dementia Road Map
The DSHS Health Care Providers and Community Organizations page hosts clinical tools from the Dementia Action Collaborative, including the Dementia Road Map, a free guide for newly diagnosed patients and families.

Washington Association of Area Agencies on Aging
Connects adults with dementia and their families with local long-term care, community resources, and specialized caregiver support.

The Memory Hub, UW Medicine Memory and Brain Wellness Center
Offers education, support groups, and resources for patients and their care partners, including virtual or phone appointments with a Memory Navigator.

Alzheimer’s Association Washington State Chapter, Education and Resources
Free on-demand webinars and live programs on Alzheimer’s and dementia and a 24/7 Helpline for patients and families.

American Geriatrics Society Beers Criteria® Alternatives Panel, & Steinman, M. A. (2025). Alternative treatments to selected medications in the 2023 American Geriatrics Society Beers Criteria®. Journal of the American Geriatrics Society, 73(9), 2657–2677. https://doi.org/10.1111/jgs.19500

Brody, H., & Heath, A. (2023, July). Nonpharmacologic approaches to adverse behaviors associated with dementia. Practical Neurology. https://practicalneurology.com/diseases-diagnoses/alzheimer-disease-dementias/nonpharmacologic-approaches-to-adverse-behaviors-associated-with-dementia/32015/

Imbimbo, C., Cotta Ramusino, M., Leone, S., et al. (2025). Emerging pharmacological approaches for psychosis and agitation in Alzheimer’s disease. CNS Drugs, 39(2), 143–160. https://doi.org/10.1007/s40263-024-01133-9

Whitney Carlson, MD

Dr. Carlson is a board-certified psychiatrist and geriatric psychiatrist in the UW Medicine Department of Psychiatry and Behavioral Sciences. She graduated from the University of Iowa College of Medicine, completed her Psychiatry Residency at the University of Michigan and a Geriatric Psychiatry Fellowship at the University of Washington. Dr. Carlson is the medical director of the Geriatric Psychiatry Services Clinic at Harborview Medical Center and is one of the primary faculty on the Psychiatry Consultation Line (PCL). Her clinical interests include aging in chronic mental illness, mood disorders, nursing home psychiatry/consult liaison psychiatry, ethics, and palliative care.

Back to Basics: A Refresher on Treating Major Depressive Disorder

Posted on January 12, 2026

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Major Depressive Disorder (MDD) remains one of the most common and impactful conditions seen in primary care. While many of us treat depression daily, it is valuable to periodically revisit the foundational principles of diagnosis and initial treatment to ensure we are offering the best possible care.

This article highlights key takeaways and “clinical pearls” from a recent presentation on the initial treatment of MDD. For those interested in a deeper dive, a link to the full transcript is provided at the end of this article.

Diagnosis: Beyond the Checklist

The DSM-5 criteria for a Major Depressive Episode are familiar to most: five or more symptoms present for at least two weeks, representing a change from previous functioning. One of the symptoms must be either depressed mood or loss of interest/pleasure (anhedonia).

However, beyond the checklist, pay attention to functional impairment. Is the patient calling in sick to work? Withdrawing socially? Spending excessive time in bed? These behavioral changes are often the most reliable indicators of severity.

The PHQ-9 as a Clinical Tool The PHQ-9 is not just a screener; it maps directly to DSM-5 criteria and can support your diagnosis. It is also the standard for measurement-based care to track symptoms and response to treatment over time. Initially, the total score helps stratify severity and guide treatment selection:

5-9 (Mild): Consider psychotherapy or behavioral activation first.
10-14 (Moderate): Psychotherapy, medication, or both are reasonable initial options based on patient preference.
15-19 (Moderately Severe) & 20+ (Severe): Combination treatment (medication + psychotherapy) is often the gold standard.

Don’t Forget the Differential Before initiating treatment, rule out common mimics:

Medical causes: Hypothyroidism (TSH), anemia (CBC), vitamin deficiencies (B12, Folate, Vitamin D), and obstructive sleep apnea (OSA). Treating OSA can often resolve depressive symptoms entirely.
Substance use: Alcohol and cannabis are frequent contributors.
Bipolar Disorder: Screening for mania/hypomania is critical before starting an antidepressant. Use the Mood Disorder Questionnaire (MDQ) to reduce the likelihood of triggering a manic episode. The MDQ can be self-administered or administered with a provider. If the MDQ is negative, you can feel reassured that the likelihood of triggering a manic episode is unlikely. However, if it is positive, you will need to review the results to clarify the diagnosis as false positives are common.

Initial Treatment Selection

For mild to moderate depression, psychotherapy (CBT, Behavioral Activation) is as effective as medication and has lasting benefits. For more severe cases, or when therapy is inaccessible, pharmacotherapy is indicated.

Choosing an Antidepressant Most first-line agents (SSRIs, SNRIs, Bupropion, Mirtazapine) have comparable efficacy across the population. Therefore, selection should be driven by:

Side Effect Profile: Leverage side effects to the patient’s advantage.
- Insomnia + Weight Loss? Consider Mirtazapine (sedating, increases appetite).
- Low Energy + Smoking + No anxiety? Consider Bupropion (activating, helps cessation, may worsen anxiety).
- Sexual Dysfunction Concern? Bupropion and mirtazapine have a lower risk than SSRIs and SNRIs
Prior Response: If it worked before (for the patient or a family member), try it again.
Comorbidities:
- Chronic Pain? Duloxetine (SNRI) has an FDA indication for certain kinds of pain.
- Anxiety? SSRIs are generally preferred.

Initiating and Monitoring Treatment

Start Low and Go Slow: Minimize initial side effects to improve adherence. Titrate every few weeks until you reach a therapeutic dose or see a response.

The 4-6 Week Rule: An adequate trial is typically 4-6 weeks at a therapeutic dose.

No response? Switch to a different medication (different SSRI or different class).
Partial response? Consider augmentation (e.g., adding Bupropion, Mirtazapine, or a second-generation antipsychotic like aripiprazole).

Duration of Treatment: For a first episode, continue treatment for 6-12 months after remission to prevent relapse. For recurrent or severe episodes, long-term maintenance may be necessary.

Clinical Pearls & FAQs

Anxiety Spike: Warn patients that anxiety may briefly worsen when starting an antidepressant. This prevents early discontinuation.
Sexual Side Effects: Patients rarely volunteer this information, but it is a common reason why patients stop the medication without telling their provider. Ask directly. If present, consider switching to Bupropion or adding it as an adjunct.
Pharmacogenomics: Tests like GeneSight are not a “magic bullet” for initial selection. They help guide dosing based on metabolism but do not predict efficacy. Reserve them for treatment-resistant cases or those with unusual side effects. Most insurances will not pay for gene-drug interaction tests unless the patient has failed at least two antidepressant trials.
Exercise as Medicine: For mild-moderate depression, exercise can be as effective as medication. Use behavioral activation (“Just walk to the mailbox today”) to help patients overcome the inertia of depression.
Cannabis Use: Daily cannabis use can mimic or worsen depression. While we can’t force patients to quit, encouraging a “tincture of time” off the substance can clarify the diagnosis. Note that substance-induced depression often resolves without antidepressants once substance use stops.

When to Refer to Psychiatry (if/when available) or call the UW Psychiatry Consultation Line (PCL)

Primary care is the ideal setting for uncomplicated depression. Consider referral if:

Diagnosis is unclear (e.g., suspected bipolar or schizoaffective disorder).
Treatment resistance (failed 2+ medication trials).
High safety risk (active suicidal ideation, psychosis).
Complex comorbidities (severe substance use, personality disorders).

If a referral to psychiatry is not possible, you can always call the PCL for free clinical advice about your adult patients with mental health and/or substance use conditions. Prescribing providers can call any time, 24/7, and non-prescribing providers can call Mon-Fri, 8 a.m. – 5 p.m. (excluding holidays). 877-WA-PSYCH/877-927-7924 We are here to help!

To see Dr. Duncan’s complete UW PACC presentation on this topic, click on this link: Initial Treatment of MDD

Mark Duncan, MD

Dr. Duncan, trained in both family medicine and addiction psychiatry, practices at the intersection of mental health and primary care. He is the co-medical director for the University of Washington Psychiatry and Addiction Case Conference (UW PACC), a weekly online learning collaborative to help community providers across the state improve their psychiatric and addiction clinical skills. Dr. Duncan is one of the PCL’s core weekday faculty where his unique expertise in primary care and psychiatry is available to healthcare providers across Washington.