Samidorphan Sadness: does the addition of samidorphan to olanzapine have pro-depressive effects?

Abstract

Olanzapine–samidorphan (Lybalvi) combines the antipsychotic olanzapine with the opioid receptor modulator samidorphan to mitigate olanzapine-associated weight gain. While clinical trials have supported comparable efficacy and improved metabolic outcomes relative to olanzapine alone, data on mood effects remain limited. We report the case of a 40-year-old man with no prior psychiatric history who was psychiatrically hospitalized, and developed clinically significant dysphoric and depressive symptoms shortly after transitioning from a new prescription of olanzapine monotherapy to olanzapine–samidorphan. His depressive symptoms, including anhedonia, amotivation, and fatigue, resolved rapidly upon resumption of olanzapine alone, with no recurrence over six months of follow-up. The temporal association and symptom resolution following discontinuation suggest a possible causal relationship. Samidorphan’s pharmacologic profile, as a μ-opioid receptor antagonist and partial κ-agonist, may underlie this effect, as κ-receptor activation has been linked to dysphoria and anhedonia. Although large-scale studies of samidorphan have not demonstrated consistent pro-depressive effects, individual susceptibility related to opioid receptor signaling may exist. This case highlights the need for clinical vigilance regarding emergent depressive symptoms in patients prescribed olanzapine–samidorphan, particularly those with prior mood vulnerability. Further investigation is warranted to clarify the neurobiological mechanisms and potential risk factors for mood disturbance associated with samidorphan-containing formulations.

Background:

Olanzapine (Zyprexa) is a second-generation antipsychotic approved for treatment of schizophrenia in adults and adolescents ages 13 years and older; acute manic or mixed episodes of bipolar I disorder, as well as bipolar I disorder maintenance in patients 13 years and older; and as adjunct to lithium or valproic acid treatment in adult patients with bipolar I disorder (U.S. Food and Drug Administration, 2025a). It is also available in several combined formulations, including as olanzapine-fluoxetine (Symbyax) for depression associated with bipolar I disorder in people 10 years and older and treatment-resistant depression in adults (U.S. Food and Drug Administration, 2025b). In 2021, olanzapine-samidorphan (Lybalvi) was approved for management of schizophrenia, bipolar I disorder manic or mixed episodes as monotherapy or adjunct, as well as bipolar I maintenance monotherapy in adults, and has seen increasing clinical adoption (U.S. Food and Drug Administration, 2025c). Samidorphan, an opioid antagonist and partial agonist, was added to olanzapine with the intention of mitigating one of the most concerning and common side effects of olanzapine: weight gain and metabolic derangements (Lee et al., 2025).

Generally, samidorphan works by blocking certain opioid receptors in the brain that are involved in reward signaling and appetite regulation. By reducing endogenous opioid activity, samidorphan is thought to attenuate olanzapine-associated increases in appetite and weight gain. However, because opioid signaling is also involved in mood and motivation, altering this system may have unintended neuropsychiatric effects in some individuals.

Evidence has supported the use of olanzapine-samidorphan, showing no significant decreases in efficacy but potential improvement in managing drug-induced weight gain compared to olanzapine alone (Gupta and Singh, 2024; He et al., 2025; Rehan et al., 2022). However, little is known about the impact of samidorphan on mood or affective states.

In this case report we describe the case of a patient who developed significant depressive symptoms when switched from olanzapine alone to olanzapine-samidorphan, and hypothesize regarding the potential psychopharmacological explanations for this phenomenon. Written informed consent was obtained from the patient for his case to be published, and details surrounding his identify have been disguised to protect anonymity.

Case Report:

Mr. A is a 40-year-old man with no formal medical or psychiatric history, no prior manic or depressive episodes, active tobacco use disorder (vaporized), several-year engagement in psychodynamic psychotherapy, who presented to the Comprehensive Psychiatric Emergency Program (CPEP). He described grandiose delusions, rumination, and functional impairment at work in the setting of 3 days without sleep, and collateral concern for bizarre behavior. His spouse reported a several-day history of not sleeping, blurting out unusual words, appearing disoriented to time, and bizarre behaviors, including taking a taxi to the hospital without alerting her. The patient was admitted to inpatient psychiatry on involuntary status for symptoms of psychosis and possible mania, and was initiated on olanzapine and lithium to manage his acute symptoms.

On the inpatient unit, the patient reported additional symptoms of recent increased goal-directed activities, distractibility, impulsivity, grandiosity, insomnia, flight of ideas, referential thinking, and talkativeness over the preceding weeks and several months of increased mood lability. A CT head without contrast was obtained, which was unremarkable. Baseline assessment included an unremarkable lipid panel, normal glucose levels, and a BMI of 30. No family history of psychiatric disorder, substance use, or psychosocial stressors were identified. He improved throughout his admission, and was discharged with the diagnosis of Brief Psychotic Disorder, and was prescribed lithium 300mg by mouth twice daily and olanzapine 10mg by mouth at bedtime. He was referred internally to the integrated outpatient services department at time of discharge.

On evaluation as an outpatient 1-week post-discharge, he presented as calm, cooperative, and pleasant, and both he and his spouse reported the hospitalization had been beneficial. The Young Mania Rating Scale (YMRS) and the Positive and Negative Syndrome Scale (PANSS)-6 were administered, with scores of 2 and 7, respectively. Further laboratory testing was performed to rule-out organic causes of his symptoms, including inflammatory markers (C-reactive protein), a full thyroid function panel, and a heavy metal panel, all of which were unremarkable.

Over the course of his outpatient treatment, Mr. A voiced concerns about the long-term effects of his medications. He expressed a preference to taper lithium, which given unclear diagnosis and rapid resolution of symptoms on subtherapeutic dosing, was deemed appropriate. His lithium dose was slowly decreased over the course of 2 months, during which time Mr. A’s scores on the PANSS-6 and YMRS both remained unremarkable (6 and 0, respectively).

Olanzapine monotherapy was planned to continue for approximately one year before attempting to decrease/discontinue the medication. Mr. A did not experience any significant side-effects, with the exception of increased appetite and increased sleep (8–10 hours/night). Side effects of olanzapine were discussed, including the potential significant metabolic side effects. Mitigation strategies were explored, and approximately 2–3 months after discharge, Mr. A decided he would like to transition his medication from olanzapine to olanzapine-samidorphan (Lybalvi) 10mg-10mg at bedtime.

Two weeks after transitioning to olanzapine-samidorphan, the patient notified his outpatient psychiatrist via telephone of rapid-onset of dysphoric and depressive symptoms that emerged over several days. During this period, the patient reported persistent low mood, marked anhedonia, apathy, amotivation, reduced energy, and impaired concentration. He denied diurnal variation, changes in appetite or weight, psychomotor agitation or retardation, feelings of guilt or hopelessness, anxiety or irritability, and suicidal ideation. Sleep duration remained stable compared to baseline on olanzapine (8–10 hours nightly), without insomnia or hypersomnia. No psychotic or manic symptoms were endorsed. Symptoms were distressing and functionally impairing but did not include suicidal thoughts or behaviors. Standardized depression rating scales were not obtained during the symptomatic period, as symptoms emerged and largely resolved between scheduled visits and were assessed via telephone contact.

No recent psychosocial stressors, medical illness, or other medication changes were reported by the patient or by collateral sources. He requested an earlier follow-up appointment, and requested to change his medication back to olanzapine (without samidorphan) 10mg at bedtime beforehand. After switching back to olanzapine, he reported that all depressive symptoms remitted rapidly (within 1–2 days after changing the medication). A detailed CARE-style clinical timeline highlighting medication changes, symptom onset, dechallenge, and objective mood ratings is provided in Table 1. Based on the Naranjo Adverse Drug Reaction Probability Scale, the score was 6, indicating a probable adverse drug reaction (+2 for effects appearing after drug administered, +1 for reaction improving when drug was discontinued, +2 for lack of alternative causes, +1 for effects being confirmed by objective evidence) (Naranjo et al., 1981). Repeat evaluation yielded YMRS score of 0, a PANSS-6 score of 6, and a Montgomery and Asberg Depression Rating Scale (MADRS) of 5. No suicidal ideation was endorsed at any point during assessment. He subsequently continued olanzapine monotherapy with no return of symptoms for over 6 months.

Table 1.

Clinical Timeline of Medication Changes and Symptom Emergence

Time Point	Event	Medication Status	Objective Ratings	Clinical Notes
Day 0	Presentation to CPEP	None	--	Insomnia x 3 days, grandiosity, psychosis
Day 1	Inpatient admission	Olanzapine and lithium initiated	--	Involuntary admission
Hospital Days 2–6	Inpatient treatment	Olanzapine + lithium	--	Progressive symptomatic improvement
Hospital Day 7	Discharge from inpatient unit	Lithium 300mg twice daily; olanzapine 10mg at bedtime.	--	Discharge Dagnosis: Brief Psychotic Disorder
1 week after discharge	Initial outpatient follow-up	Lithium 300mg twice daily; olanzapine 10mg at bedtime.	YMRS = 2 PANSS-6 = 7	Calm, cooperative. No mood or psychotic symptoms.
3 weeks post-discharge	Begin lithium taper	Olanzapine continued. Lithium decreased to 450mg total daily dose.	YMRS = 0 PANSS-6 = 6	No recurrence of any symptoms.
6 weeks post-discharge	Continue lithium taper	Olanzapine continued. Lithium decreased to 300mg total daily dose.	YMRS = 0 PANSS-6 = 6	No recurrence of any symptoms.
10 weeks post-discharge	Complete lithium taper	Olanzapine continued. Lithium discontinued	YMRS = 0 PANSS-6 = 6	No recurrence of any symptoms.
12 weeks post discharge	Medication change	Switched from olanzapine 10mg olanzapine-samidorphan 10/10mg	YMRS = 0 PANSS-6 = 6	Change driven due to metabolic concerns.
Days 3–7 after olanzapine-samidorphan initiation	Symptom onset	Olanzapine-samidorphan 10/10mg	N/A (symptoms reported via telephone; no in-person assessment)	Emerging low mood, anhedonia, and apathy reported by patient.
Days 8–13 after olanzapine-samidorphan start	Peak depressive symptoms	Olanzapine-samidorphan 10/10mg	N/A (symptoms reported via telephone; no in-person assessment)	Fatigue, amotivation.
Day 14 after olanzapine-samidorphan initiation	Discontinue olanzapine-samidorphan	Switched back to olanzapine monoproduct.	N/A (symptoms reported via telephone; no in-person assessment)	Patient-initiated contact to request medication change.
1–2 days after switch	Symptom resolution	Olanzapine 10mg	MADRS = 5 YMRS =0 PANSS-6 = 6	Rapid remission of depressive symptoms.
6-month folow-up	Stability maintained	Olanzapine 10mg	--	No recurrence of mood or psychotic symptoms.

Discussion

The addition of samidorphan to this patient’s medication regimen was associated with a rapid and significant emergence of depressive symptoms. This observation may be explained, at least in part, by samidorphan’s unique pharmacological profile in the central nervous system. Samidorphan is a synthetic analogue of naltrexone, exhibiting high-affinity μ-opioid receptor antagonism, as well as partial agonist effects at κ-opioid receptors and weaker activity at δ-opioid receptors (Peckham et al., 2018; Sun et al., 2019). Given these mixed receptor effects, the net behavioral impact of samidorphan likely reflects the balance of opioid receptor signaling rather than activity at a single receptor subtype.

Early studies of μ-opioid receptor antagonists, particularly naltrexone, raised concerns about potential pro-depressive effects resulting from opioid receptor blockade (Miotto et al., 2002). The rationale was that activation of opioid receptors is associated with euphoria and a sense of well-being, so their antagonism might induce dysphoria and depressive symptoms (Crowley et al., 1985). However, subsequent studies largely failed to demonstrate significant pro-depressive effects with naltrexone (Dean et al., 2006; Jelen et al., 2022). This suggests that μ-opioid receptor antagonism alone is unlikely to account for clinically meaningful depressive symptoms in most individuals.

While μ-opioid receptor antagonism alone may not be sufficient to induce depressive symptoms, the combined effects of samidorphan’s activity at the κ-opioid receptor may be clinically relevant (Borbély et al., 2022). The κ-opioid receptor is increasingly recognized for its role in modulating mood and anxiety, particularly symptoms such as anhedonia and low mood (Dinoff et al., 2020; Mansoori et al., 2025; Puryear et al., 2020; Wong et al., 2024). κ-opioid receptor agonism inhibits dopamine release both directly and indirectly, resulting in anhedonia, aversion, and depressive symptoms (Jelen et al., 2022; Margolis and Karkhanis, 2019; Santino and Gentilucci, 2023). Unlike naltrexone or buprenorphine, which are κ-opioid receptor antagonists, samidorphan’s partial agonist activity at the κ-opioid receptor may exert clinically meaningful effects in susceptible individuals, particularly when combined with μ-opioid receptor antagonism that reduces endogenous opioid tone (Jelen et al., 2022; Peckham et al., 2018). Figure 1 summarizes the hypothesized opioid receptor–mediated pathways through which samidorphan may contribute to depressive symptoms.

Figure 1.

Samidorphan is a high-affinity μ-opioid receptor antagonist with partial κ-opioid receptor agonist activity. μ-opioid receptor antagonism may reduce endogenous opioid tone, while partial κ-opioid receptor activation has been associated with reduced mesolimbic dopamine signaling, dysphoria, and anhedonia in preclinical and human studies. The combined effect of altered opioid receptor signaling may contribute to depressive symptoms in susceptible individuals. Alternative explanations, including illness course, sleep disruption, and psychosocial factors, are also plausible and are not excluded. All mechanisms depicted are hypothetical and intended to be hypothesis-generating. Other receptors acted upon by olanzapine, including 5HT-2C and histaminergic receptors, are not depicted in this figure.

Abbreviations: D2 = Dopamine D2 receptor; 5HT-2A = Serotonin 2A receptor; μ-OR = μ-opioid receptor; κ-OR = κ-opioid receptor; δ-OR = δ-opioid receptor. Dotted arrows represent partial agonism. Solid lines represent antagonism.

Importantly, the proposed κ-opioid receptor–mediated mechanism remains speculative and should be interpreted as hypothesis-generating. Partial agonism at the κ-opioid receptor may produce variable behavioral effects depending on endogenous opioid tone, receptor density, downstream signaling pathways, and individual neurobiological vulnerability. As such, the same pharmacologic action may be clinically neutral in some individuals while producing dysphoric or anhedonic effects in others.

The potential for samidorphan to exacerbate mood symptoms has broader implications, particularly in light of recent clinical trials investigating buprenorphine-samidorphan (ALKS 5461) for treatment-resistant depression (Peckham et al., 2018). Importantly, buprenorphine and samidorphan have distinct and partially opposing opioid receptor profiles: buprenorphine is a partial μ-opioid receptor agonist and κ-opioid receptor antagonist, whereas samidorphan lacks μ-opioid agonist activity and exhibits partial κ-opioid receptor Although results from ALKS 5461 trials were mixed, and in late 2018 the FDA Advisory Committees voted against its approval due to insufficient evidence of benefit (Riblet et al., 2023), these findings highlight the complexity and context-dependence of opioid modulation in mood disorders rather than supporting a uniform antidepressant or pro-depressant effect. A 2020 meta-analysis of six studies (N=1,242) found no significant difference between buprenorphine and placebo for treatment-resistant depression; notably, five of these studies used the buprenorphine-samidorphan combination (Dinoff et al., 2020). A more recent meta-analysis of 11 studies (N=1,699) by Riblet et al. reported a small but statistically significant benefit of buprenorphine-samidorphan on depressive symptoms (Riblet et al., 2023).

Alternative explanations for the depressive symptoms observed in this case must also be considered. These include the natural affective course following a first psychotic or manic episode, delayed mood symptoms emerging during recovery, sleep disruption related to medication changes, psychosocial factors not fully captured during assessment, and placebo or nocebo effects related to expectations about medication side effects. Although the symptom cluster included prominent dysphoria, anhedonia, and apathy, available data do not support a diagnosis of a full major depressive episode, and the presentation is more accurately characterized as an acute dysphoric syndrome temporally associated with medication exposure. Additionally, although the olanzapine dose remained unchanged, the act of medication transition itself could theoretically contribute to transient neurochemical or circadian effects. However, the rapid onset of depressive symptoms following initiation of olanzapine-samidorphan, coupled with equally rapid resolution within 1–2 days of dechallenge and absence of recurrence during prolonged follow-up, argues against these alternative explanations as the sole contributors to the observed clinical course.

This case highlights important clinical implications as psychiatry increasingly adopts a patient-centered approach, particularly in the management of antipsychotic-induced metabolic side effects. Olanzapine has long been associated with significant weight gain and metabolic disturbances, often limiting its use despite its robust efficacy. The introduction of olanzapine-samidorphan was intended to address these concerns by mitigating weight gain, thereby aligning with patient preferences and improving long-term adherence (McIntyre et al., 2023; Pham et al., 2022). However, this case underscores the need for careful monitoring of mood symptoms when initiating samidorphan, as its unique opioid receptor profile may introduce mood-related risks in a subset of patients, including the potential for depressive symptomatology. Adverse events that have been reported for olanzapine-samidorphan have thus far largely matched those of olanzapine alone (Lee et al., 2025; Rehan et al., 2022). No formal cases of severe depression from olanzapine-samidorphan have been published and altered mood/anxiety were reported as rare events during samidorphan clinical trials (Chaudhary et al., 2019).

As this report is of a single patient’s case, causality cannot be established, and other underlying variables may have contributed to his presentation. The rapid onset of depressive symptoms following initiation of olanzapine-samidorphan and their resolution within 48 hours of dechallenge (Table 1) supports a temporal association consistent with a probable adverse drug reaction. Overall, his experience highlights the importance of close patient monitoring, and could generate hypotheses for future pharmacovigilance and mechanistic studies.

Conclusion

Further research is needed to clarify the risk factors and mechanisms underlying mood changes with olanzapine-samidorphan considering the known effects of opioid signaling on mood, equivocal clinical effect of ALKS 5461, and complex pharmacology of both olanzapine and samidorphan. Clinicians should closely monitor for emergent mood changes, especially in patients with a history of depression or other risk factors, and engage in shared decision-making that balances both the metabolic benefits and possible neuropsychiatric risks of this combination therapy. Additionally, future studies should investigate whether samidorphan’s partial κ-agonist activity contributes to individual mood vulnerability in clinical populations