Jose Crossier is a board‑certified psychiatric‑mental health and family nurse practitioner (PMHNP‑BC) and a paid consultant of Alkermes, Inc. The following is Jose’s perspective and does not represent the perspective of all healthcare professionals. The information included is not a substitute for professional medical advice. Always exercise your professional judgment. Intended for U.S. audiences only.
Bipolar I disorder (BD‑I) is a serious mental health condition marked by intense shifts in mood, energy, and activity levels.1 The condition affects an estimated 1% of adults in the United States2 and is clinically characterized by distinct mood episodes, with polarity tending to alternate over time between periods of mania or hypomania and depression. Manic or hypomanic symptoms can include elevated mood, increased energy, decreased need for sleep, and increased or faster speech. Depressive symptoms may include intense sadness, loss of interest in activities once enjoyed, feelings of guilt, fatigue, and suicidal ideation.1
Research shows that the presentation of bipolar disorder varies phenotypically and genetically, with differences in symptom expression and illness course. For patients, this means that their experience is highly variable, and symptoms do not always follow neatly defined mood states. Each person may experience and express symptoms differently, and patterns can shift over time. This heterogeneity can make accurate diagnosis and treatment planning difficult as patterns of mood changes and responses to treatment are highly individualized.1,3-5
Further, approximately one‑third of people living with BD‑I experience mixed features during mood episodes, in which symptoms of mania and depression occur simultaneously.6 When these occur, clinical assessment becomes even more nuanced. Because mixed episodes are common yet can be challenging to identify in routine clinical practice, understanding how they present and approaches for treatment is an important part of caring for people living with BD‑I.7
Defining mixed episodes and mixed features
In recent years, the clinical understanding of mixed episodes has evolved in response to changes in diagnostic criteria. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM‑5‑TR) moved away from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM‑IV) definition of a “mixed episode” and introduced the “mixed features” specifier. This change allows clinicians to diagnose a primary mood episode—manic, hypomanic, or depressive—while also recognizing the presence of symptoms from the opposite mood pole during the same episode, without requiring that full criteria for both a manic and a major depressive episode be met. Under this new definition, episodes with mixed features are characterized by the simultaneous presence of both manic or hypomanic and depressive symptoms.8
A mixed presentation may occur when a patient meets full criteria for a manic or hypomanic episode while also experiencing at least three depressive symptoms, or when a patient meets criteria for a depressive episode with at least three manic or hypomanic symptoms.6 Certain symptoms, including irritability, distractibility, and psychomotor agitation, are excluded from the DSM‑5‑TR mixed features criteria as they commonly occur in both manic and depressive episodes.9
To qualify as mixed features under DSM‑5‑TR, these symptoms must be observable by others, represent a clear change from the patient’s usual baseline, and not be attributable to the physiological effects of a substance or another medical condition.6
Why mixed features can be easy to miss
Mixed presentations can be difficult to recognize because patients are more likely to seek care during depressive episodes and may report depressive symptoms without disclosing co‑occurring manic or hypomanic features.6,10,11 Depressive symptoms are often more distressing to patients and therefore more likely to be raised in clinical encounters, contributing to under‑identification of episodes with mixed features despite their frequency in BD‑I.6,10
In addition, similar to the variability in symptom presentation inherent in BD‑I, episodes with mixed features may differ in presentation from one patient to another and can change over time within the same individual.12 For example, a patient may present with mostly depressive symptoms at one visit but may later present with more manic symptoms, or vice versa. When symptoms overlap or don’t present in expected ways, mixed features can be easy to overlook.11 Rating scales like the Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HAM‑D), which measure manic and depressive symptom severity respectively, can help round out the overall picture of what a patient is experiencing.13,14
BD‑I is associated with a substantial disease burden and a clinical course marked by recurring mood episodes over time, making accurate assessment throughout the patient’s diagnosis and treatment journey especially important.1 Mixed features can add another layer of complexity, as overlapping manic and depressive symptoms may affect patient experience and response to treatment. It’s critical to understand that when episodes with mixed features go unrecognized, patients may not receive care that fully reflects the complexity of their symptoms.15
The nurse’s role in recognizing episodes with mixed features
I’ve found that nurses and advanced practice providers, including nurse practitioners and physician assistants, often develop close, trusting relationships with patients and are in a unique position to notice changes in mood and the emergence of mixed presentations. In my practice, these providers frequently see patients at different times of day, across care settings, and in moments outside of formal assessments, allowing subtle shifts in behavior, energy, or sleep patterns to become more apparent over time.
When that happens, I like to ask a few questions, which can go a long way in helping to clarify what the patient is really experiencing. Questions like, “When you’re feeling this low, do you ever notice your thoughts speeding up?” or “How has your energy been, even on days when your mood feels down?” frequently open space for patients to share symptoms they may not initially think to mention. Check‑ins about sleep, irritability, or drive also can help surface overlapping features that may point toward an episode with mixed features.
Having a sense of how episodes with mixed features can present in everyday practice enables nurses to flag concerns earlier and bring more context into conversations and considerations around treatment. This shared understanding helps support care plans that reflect what patients are actually living with, not just how their symptoms fit into a single diagnostic category.
Treatment considerations for adults experiencing BD‑I with mixed features
Clinical practice guidelines recommend maintenance treatment for BD‑I due to its recurrent nature, highlighting the role of ongoing management in supporting stability over time. Pharmacotherapy is a central component of this care, both in helping with acute symptoms of BD‑I and delaying time to symptom relapse.4
One treatment option I consider for adults living with BD‑I who are experiencing manic or mixed episodes is LYBALVI® (olanzapine and samidorphan). LYBALVI is a once‑daily, oral tablet that combines olanzapine, an atypical antipsychotic, and samidorphan, an opioid receptor antagonist. LYBALVI is indicated for the treatment of adults with BD‑I for acute treatment of manic or mixed episodes as monotherapy and as an adjunct to lithium or valproate, or as a maintenance monotherapy treatment, or for the treatment of adults with schizophrenia. LYBALVI also is the only branded oral atypical antipsychotic with a maintenance indication for BD‑I. It is important to note that LYBALVI has a boxed warning for increased mortality in elderly patients with dementia‑related psychosis and is not approved for the treatment of patients with dementia‑related psychosis. Please see additional Important Safety Information below and full Prescribing Information, including Boxed Warning, for LYBALVI.16
The efficacy and safety of LYBALVI for adults living with BD‑I is based on adequate and well‑controlled studies of orally administered olanzapine in patients with BD‑I, including those experiencing manic or mixed episodes. In a randomized, double‑blind, placebo‑controlled study, adults meeting DSM‑IV criteria for a manic or mixed episode who had responded to an initial open‑label treatment phase of approximately 2 weeks, on average, of olanzapine 5 mg/day to 20 mg/day were randomized to continue olanzapine at the same dose (n=225) or switch to placebo (n=136) and observed for relapse. During the randomized phase, approximately 50% of patients in the olanzapine group discontinued by Day 59, compared to 50% of patients in the placebo group who discontinued by Day 23. Relapse during the double‑blind phase was defined as an increase in YMRS or HAM‑D 21 total score to ≥15 or being hospitalized for mania or depression.16 In the randomized phase, patients receiving olanzapine maintenance monotherapy demonstrated a significantly longer median time to symptomatic relapse, including hospitalization, compared with placebo (174 days vs 22 days, respectively; p<0.001).17
The efficacy of LYBALVI for the acute treatment of manic or mixed episodes was established in short‑term, placebo‑controlled studies of olanzapine monotherapy, including a 3‑week trial (n=67) and a 4‑week trial (n=115). In these studies, the primary endpoint was change from baseline in YMRS total score. In the 3‑week study, olanzapine was superior to placebo in the reduction of the YMRS total score. In an identically designed 3‑week study conducted concurrently, olanzapine demonstrated a similar treatment difference, but did not achieve statistical superiority to placebo, potentially due to sample size and site variability. In the 4‑week study, olanzapine monotherapy was superior to placebo in reduction of mania.16
In these short‑term trials, the most common adverse reactions, with an incidence ≥5% and at least twice the rate of placebo, were somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, and tremor.16
Taken together, these findings support the role of olanzapine‑based therapies in treating mixed episodes of bipolar Ⅰ disorder and provide clinicians with important information as they navigate treatment decisions with their patients in real-world clinical practice.
Supporting patients through complex symptoms
BD‑I with mixed features can be difficult to identify and complex to treat given its heterogeneous nature and the individualized expression of disease from one patient to the next.12 Understanding how mixed features can present is an important part of caring for people living with BD‑I.15 In my experience, nurses are central to picking up on early signs, such as shifts in sleep patterns, energy that doesn’t match mood, or behavior that just feels different. By recognizing these patterns, understanding what mixed symptoms may look like in practice, paying attention to those details, and asking a few extra questions, I have found nurses can help patients receive care that reflects their unique experience. Additionally, nurses can support care by reinforcing patient education, monitoring changes in mood and side effects over time, and helping patients and families recognize when to talk to their healthcare provider. LYBALVI is one FDA‑approved treatment option for adults living with BD‑I, including mixed episodes. By considering all available medications and working closely with patients and the rest of the care team, nurses can play an important role in supporting thoughtful, individualized care.
IMPORTANT SAFETY INFORMATION AND INDICATIONS
Boxed Warning: Elderly patients with dementia‑related psychosis treated with antipsychotic drugs are at an increased risk of death. LYBALVI is not approved for the treatment of patients with dementia‑related psychosis.
Contraindications: LYBALVI is contraindicated in patients who are using opioids or are undergoing acute opioid withdrawal. If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products.
Cerebrovascular Adverse Reactions in Elderly Patients with Dementia‑Related Psychosis, including stroke, transient ischemia attack, and fatalities. See Boxed Warning.
Precipitation of Severe Opioid Withdrawal in Patients who are Physiologically Dependent on Opioids: LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids, which can lead to an opioid withdrawal syndrome, sometimes requiring hospitalization. LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Prior to initiating LYBALVI, there should be at least a 7 day opioid‑free interval from last use of short‑acting opioids, and at least a 14‑day opioid‑free interval from the last use of long‑acting opioids. Explain the risks associated with precipitated withdrawal and the importance of giving an accurate account of last opioid use to patients and caregivers.
Vulnerability to Life‑Threatening Opioid Overdose: Attempting to overcome opioid blockade with high or repeated doses of exogenous opioids could lead to life‑threatening or fatal opioid intoxication, particularly if LYBALVI therapy is interrupted or discontinued, subjecting the patient to high levels of unopposed opioid agonist as the samidorphan blockade wanes. Inform patients of the potential consequences of trying to overcome the opioid blockade and the serious risks of taking opioids concurrently with LYBALVI or while transitioning off LYBALVI. In emergency situations, if a LYBALVI‑treated patient requires opioid treatment as part of anesthesia or analgesia, discontinue LYBALVI. Opioids should be administered by properly trained individual(s) and patient should be continuously monitored in a setting equipped and staffed for cardiopulmonary resuscitation. Patients with a history of chronic opioid use prior to treatment with LYBALVI may have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued. Advise patients that this decreased tolerance may increase the risk of opioid overdose if opioids are resumed at the previously tolerated dosage.
Neuroleptic Malignant Syndrome, a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and close monitoring.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a potentially fatal condition reported with exposure to olanzapine, a component of LYBALVI. Symptoms include a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinue if DRESS is suspected.
Metabolic Changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Any patient treated with LYBALVI should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required anti‑diabetic treatment despite discontinuation of the suspect drug. Measure weight and assess fasting glucose and lipids when initiating LYBALVI and monitor periodically.
Tardive Dyskinesia (TD): Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood it will become irreversible increases with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses, or after discontinuation. Given these considerations, LYBALVI should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. If signs and symptoms of TD appear, drug discontinuation should be considered.
Orthostatic Hypotension and Syncope: Monitor orthostatic vital signs in patients who are vulnerable to hypotension, patients with known cardiovascular disease, and patients with cerebrovascular disease.
Falls: LYBALVI may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls, and consequently, fractures or other injuries. Assess patients for risk when using LYBALVI.
Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases): Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count or history of leukopenia or neutropenia. Discontinue LYBALVI if clinically significant decline in WBC occurs in the absence of other causative factors.
Dysphagia: Use LYBALVI with caution in patients at risk for aspiration.
Seizures: Use LYBALVI with caution in patients with a history of seizures or with conditions that lower the seizure threshold.
Potential for Cognitive and Motor Impairment: Because LYBALVI may cause somnolence, and may impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including motor vehicles, until they are certain that LYBALVI does not affect them adversely.
Body Temperature Dysregulation: Use LYBALVI with caution in patients who may experience conditions that increase core body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).
Anticholinergic (Antimuscarinic) Effects: Olanzapine, a component of LYBALVI, was associated with constipation, dry mouth, and tachycardia. Use LYBALVI with caution with other anticholinergic medications and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications.
Hyperprolactinemia: LYBALVI elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin‑elevating compounds.
Risks Associated with Combination Treatment with Lithium or Valproate: If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for a description of the risks for these products.
Interference with Laboratory Tests for Opioid Detection: LYBALVI may cause false positive results with urinary immunoassay methods for detecting opioids. Use an alternative analytical technique (e.g., chromatographic methods) to confirm positive opioid urine drug screen results.
- Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache
- Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, and tremor
- Bipolar I Disorder, Manic or Mixed Episodes, adjunct to lithium or valproate (olanzapine): dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia
Concomitant Medication: LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Concomitant use of LYBALVI is not recommended with strong CYP3A4 inducers, levodopa and dopamine agonists. Reduce dosage of LYBALVI when using with strong CYP1A2 inhibitors. Increase dosage of LYBALVI with CYP1A2 inducers. Use caution with diazepam, alcohol, other CNS acting drugs, or in patients receiving anticholinergic (antimuscarinic) medications. Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling.
Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with LYBALVI. Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYBALVI during pregnancy.
Renal Impairment: LYBALVI is not recommended for patients with end‑stage renal disease (eGFR of <15 mL/minute/1.73 m2).
To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
INDICATIONS
LYBALVI is indicated for the treatment of:
- Schizophrenia in adults
- Bipolar I disorder in adults
- Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate
- Maintenance monotherapy treatment
Jose Crossier, MSN, PMHNP-BC, FNP-BC, is a double board-certified nurse practitioner in family and psychiatric-mental health with over 15 years of experience in healthcare. He provides comprehensive, patient-centered psychiatric care across the lifespan. His clinical approach integrates evidence-based medicine with a holistic framework, emphasizing individualized treatment and patient-centered outcomes. His professional focus is on improving quality of life through structured, compassionate, and outcomes-driven mental health care.References
1 American Psychiatric Association. What Are Bipolar Disorders? American Psychiatric Association. Accessed March 10, 2026. https://www.psychiatry.org/patients-families/bipolar-disorders/what-are-bipolar-disorders
2 Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication [published correction appears in Arch Gen Psychiatry. 2007 Sep;64(9):1039]. Arch Gen Psychiatry. 2007;64(5):543-552. doi:10.1001/archpsyc.64.5.543
3 McGrouther CC, Rangan AV, Di Florio A, Elman JA, Schork NJ, Kelsoe J; for the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium. Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar‑disorder. ArXiv. 2024:arXiv:2405.00159v2
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5 Fountoulakis, K. N., Fountoulakis, N. K., & Antoniadis, D. (2025). Challenges in the development of treatment guidelines for bipolar disorder. Frontiers in psychiatry, 16, 1564004. https://doi.org/10.3389/fpsyt.2025.1564004
6 Diagnostic and Statistical Manual of Mental Disorders, DSM-5-TR. American Psychiatric Association; 2022.
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8 American Psychiatric Association. Highlights of changes from DSM-IV-TR to DSM-5. 2013. https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/DSM/APA_DSM_Changes_from_DSM-IV-TR_-to_DSM-5.pdf. Accessed January 9, 2026.
9 Stahl SM, Morrissette DA, Faedda G, et al. Guidelines for the recognition and management of mixed depression. CNS Spectr. 2017;22(2):203-219. doi:10.1017/S1092852917000165
10 Calabrese JR, Hirschfeld RM, Frye MA, Reed ML. Impact of depressive symptoms compared with manic symptoms in bipolar disorder: results of a U.S. community-based sample. J Clin Psychiatry. 2004;65(11):1499-1504. doi:10.4088/jcp.v65n1109
11 Goldberg JF, Perlis RH, Bowden CL, et al. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2009;166(2):173-181. doi:10.1176/appi.ajp.2008.08050746
12 Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. doi:10.1111/bdi.12609
13 Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429-435.
14 Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23(1):56-62.
15 American Psychiatric Association. (2013). Mixed Features Specifier. https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/DSM/APA_DSM-5-Mixed-Features-Specifier.pdf.
16 LYBALVI [prescribing information]. Waltham, MA: Alkermes, Inc.
17 Tohen M, Calabrese JR, Sachs GS, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psych. 2006; 163(2):247-256.
ALKERMES® is a registered trademark of Alkermes, Inc. LYBALVI® is a registered trademark of Alkermes Pharma Ireland Limited, used by Alkermes, Inc., under license.
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LYB‑003532‑1
