by Amro H. Mohammad, MD, PhD; Marie-Pier Lecours, MD, PhD; Emmanuel Adams-Gelinas, BSc; Arshia Kakkar, MD; and Anthi Stefatos, MD, FRCPC

Dr. Mohammad, Mr. Adams-Gelinas, and Dr. Kakkar are with the Faculty of Medicine and Health Sciences at McGill University in Montreal, Quebec, Canada. Dr. Lecours is with Hôpital Pierre-Boucher in Longueuil, Quebec, Canada. Dr. Stefatos is with the Department of Psychiatry at McGill University in Montreal, Quebec, and the Department of Psychiatry, Integrated University Health and Social Services Center of the West Island of Montreal (CIUSSS ODIM) in Pointe-Claire, Quebec, Canada.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors declare no conflicts of interest relevant to the content of this article.

Innov Clin Neurosci. 2025;22(1–3):54–57.

Abstract

Introduction: Premarketing clinical trials of azithromycin (AZT) computed a 0.8-percent incidence rate of neurological symptoms, such as headaches and vertigo. Postmarket surveillance reported on psychiatric reactions to AZT that included aggression, agitation, anxiety, delirium, and hallucinations. Nonetheless, these observations do not provide further insight on patient characteristics, disease course, and medical intervention. Methods: We report the case of an 18-year-old male patient with no prior medical or psychiatric history who developed profound religious delusions and unusual behavior hours after taking a one-time AZT dose of 1,000mg for a confirmed sexually transmitted Chlamydia trachomatis infection. Results: The patient presentation and clinical history satisfied criteria for a manic episode with psychotic features lasting for at least one week. As per The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, the patient was diagnosed with medication-induced manic episode with psychotic features. At presentation, the patient received an intramuscular injection consisting of haloperidol 10mg and diphenhydramine 50mg, followed by olanzapine 10mg, diazepam 20mg, and lorazepam 5mg orally on account of his severe agitation. The patient was then maintained on olanzapine 30mg and lorazepam 5mg for six days. Lorazepam was then titrated down to 4mg for two days, then to 3mg in the outpatient setting. The patient demonstrated relative improvement in both the inpatient and outpatient settings, with no relapse despite eventual discontinuation of psychotropic medication. Conclusion: We report, to our knowledge for the first time, that AZT monotherapy might induce a manic episode with psychotic features in adolescent patients with no psychiatric medical history.

Keywords: Azithromycin, macrolide, manic episode

The widespread use of antibiotics in the clinical setting and at point of care warrants a thorough understanding of the psychotropic effects of certain antimicrobial agents, such as azithromycin (AZT). Medication-induced manic episodes in adolescents with no psychiatric history prompts an understanding of risk factors and ways to reverse psychosis. Studies that link neuropsychiatric adverse effects and antimicrobial use were examined.¹ However, only a few studies investigated the central nervous system effects of macrolides;^1–4 to date, these have been mainly linked to adults and the elderly population with many comorbidities. The benefit of AZT as adjunct therapy in patients with schizophrenia who were seropositive for Toxoplasma gondii (T. gondii) was tested but with inconsistent results.^5–7 This is in part due to the differences in patient populations and varying concurrent medications, but more specifically to the inconsistent efficacy of AZT against T. gondii and to the complexity the interactions between T. gondii, immune response, and dopamine release.⁸ This is the first report, to our knowledge, to describe a manic episode with profound psychotic features in an adolescent patient shortly following the initiation of AZT monotherapy for the treatment of a Chlamydia trachomatis sexually transmitted infection (STI). 

Methods

Study approval. Patient records at the emergency unit and outpatient Lakeshore General Hospital (LGH) were used by the patient’s treating team to write this case report. The patient could not be reached for consent beyond the follow-up period described in this study. Alternatively, the authors sought an evaluation by the Committee on Access to Information and Protection of Personal Information (ATIP Committee) and by the director of professional services of the Integrated University Health and Social Services Center of the West Island of Montreal (CIUSSS ODIM), under which the jurisdiction of the LGH falls. The study was assigned EC-2023-001 case number. After careful evaluation of the case report in the form presented here on January 22, 2024, the ATIP Committee found this study in its current format to be in adherence with the privacy impact agreement to communicate patient information for the purpose of publication on February 1, 2024. The applicant for this case study has obtained all confidentiality undertakings from individuals with access to personal information. The aforementioned information can be validated with the Department of University Affairs, Teaching and Research government branch and the commission d’accés á l’information du Quebec (recherche.comtl@ssss.gouv.qc.ca). 

Patient information. De-identified patient information. We report on an 18-year-old male patient (JJ, pseudo-initials), who could not be reached after multiple attempts for patient consenting. JJ was single and lived with his mother and a sibling. The family immigrated to Canada many years ago. The sister had a history of major depressive disorder (MDD) and severe panic attacks and was currently taking antidepressants. There was no other psychiatric family history; however, there was no information about the father of the patient. JJ had no past medical or psychiatric history. JJ’s baseline personality was described by family members as introverted, nontalkative, and nonreligious. After leaving school at a young age, JJ received training as a skilled laborer. JJ left his job 10 days after receiving treatment for an STI. During his short stay at the psychiatric unit, JJ reported that his new job was as a “dog sitter.” JJ used 1g of cannabis every day for one year prior to presentation. JJ denied drinking alcohol and smoking cigarettes. JJ used psilocybin once five months prior to his medical encounter discussed in this study. Table 1 details the patient’s timeline of events. 

Primary concerns and symptoms of patient. JJ had no prior psychiatric illness or substance use disorder history until he began using cannabis one year prior to presentation. He presented to the emergency unit after a three-week history of disruptive behavior. He quit his job during those three weeks and started talking more and sleeping less. JJ had strong religious delusions. The mother reported that JJ exhibited this unusual behavior the morning after taking a prescribed single 1,000mg oral dose of AZT monotherapy for a diagnosed Chlamydia trachomatis STI. At the time of taking the AZT, JJ’s symptoms were limited to penile irritation, frequent urination, and dysuria. There were no constitutional symptoms, such as fever, chills, or costovertebral angle tenderness. There was no change in JJ’s cannabis use and no new drug use. Additionally, JJ had no comorbidities and was not taking any other prescribed medications. He was brought in by the police after he showed aggressive behavior at home. 

Clinical findings, outcomes, and patient perspective. Day 0: Emergency room encounter. Our assessment relied on the Positive and Negative Syndrome Scale (PANSS) for schizophrenia.⁹ At presentation, JJ’s vital measurements were within normal range. There were no signs of head trauma, nuchal rigidity, or focal neurological deficits. Furthermore, there were no signs of sepsis or metabolic shift that could explain the ongoing psychotic episode, such as fever, fatigue, nausea, weight loss, joint pain, or cardiopulmonary distress. JJ had not slept in 72 hours. He was oriented to person only and showed intense mood lability. JJ demonstrated noncatatonic abnormal motor behavior with unpredictable agitation. He showed intense mood swings with a reactive affect congruent to mood, which was euphoric. Speech volume of patient was loud with pressured speech. Thought process was extremely disorganized with profound derailment and flight of ideas. JJ’s thought content included grandiose and religious delusions, as he believed he was “Jesus.” There was no evidence for response to internal stimuli. Suicidal ideation could not be assessed, but the patient demonstrated heteroaggressive behavior toward staff. Negative symptoms were absent. General symptoms included intense apparent anxiety, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, and poor impulse control. Patient perspective could not be elicited. JJ’s toxicology screen was remarkable for cannabis use only. JJ received an intramuscular injection of haloperidol 10mg and diphenhydramine 50mg to manage his agitation. JJ also received olanzapine 10mg, diazepam 20mg, and lorazepam 5mg orally as one dose. 

Day 1: Inpatient. JJ was continued on a daily oral dose of olanzapine 30mg and lorazepam 5mg. At night, JJ had better sleep than before, as stated by the family. His vital signs remained within the normal range. There were no signs of focal neurological deficits. JJ was now alert and oriented to person, place, and time. He remained overly friendly but not hostile. His motor function remained agitated but to a lesser magnitude. He reported feeling “good,” and his affect was congruent with mood, which was normal. Speech was relatively coherent. Answers were related to the questions asked, but his thought process was still disorganized with frequent derailment but less flight of ideas. Thought content carried religious, grandiose, and paranoid delusions. Patient did not seem to respond to internal stimuli. There was also marked difficulty in abstract thinking with lack of spontaneity and flow of conversation. There were no suicidal or heteroaggressive ideations. JJ remained anxious but to a lesser extent. His general symptoms were now limited to anxiety, guilt feeling, unusual thought content, and lack of judgement and insight. 

Days 2–4: Inpatient. While still receiving the daily oral dose of olanzapine 30mg and lorazepam 5mg, JJ’s sleep continued to improve. Vital signs also remained within a stable range. There were also no signs of focal neurological deficits. JJ remained alert to person, place, and time. His attitude became less malleable and passive, relative to his excessive friendliness on the first day. He also became emotional when probed about family ties and relationship with father. Motor behavior was progressively becoming less agitated and more predictable. The patient reported a positive mood, but affect was becoming progressively less congruent with mood, as the patient’s affect was becoming more blunted. His speech remained coherent with answers that were related to the questions asked but with more succinct answers. His thought process was progressively more organized. However, with more probing, thought content proveed to remain delusional with religious reference. There were no suicidal or heteroaggressive ideations. The patient’s anxiety lessened during this period. However, JJ started displaying more guilt and uncooperativeness. There was an improvement in the patient’s judgement, but his insight remained poor. 

Days 5–9­: Inpatient. The patient’s sleep and appetite were fair, considering the inpatient setting. As a result, the lorazepam dose was decreased to 4mg while maintaining olanzapine 30mg. Vital signs also remained within normal range, and there were no signs of focal neurological deficits. JJ became increasingly frustrated with his involuntary stay in hospital. His affect was blunted. Motor behavior was grossly normal. He became more emotionally withdrawn. His thought process remained coherent and was more organized with no evidence of derailment or flight of ideas. JJ was increasingly reluctant and agitated toward disclosure of thought content, which contained religious delusions. Thought content also included plans of returning to work and school and of supporting his family. There were no suicidal or heteroaggressive ideations. His general symptoms were limited to moderate insight. Given the objective improvement in symptoms and the absence of acute safety concerns, he was discharged from the inpatient unit with close follow-up with the Early Psychosis Intervention team. 

Day 13: Outpatient (first follow-up). JJ was dressed appropriately and well-groomed. He was accompanied by his mother. JJ and his mother emphasized the patient’s adherence to medication (daily dose of olanzapine 30mg and lorazepam 3mg). There was no evidence of abnormal vital signs or neurological abnormalities. Patient reported feeling better, but his affect was blunted and incongruent with mood, which was reported as normal. Motor behavior was grossly normal with no evidence of dystonia. His speech remained coherent. His thought process was more organized with no evidence of derailment or flight of ideas. JJ became increasingly agitated toward questions about his religious beliefs. However, his mother reported by phone some delusional thought content at home. There were no suicidal or heteroaggressive ideations. Judgement and insight were improved. 

Day 27: Outpatient. JJ was well-groomed and accompanied by his mother. He reported going to the gym and losing weight. The patient had returned to school. He admitted to continued cannabis use (1–2g/week). JJ and his mother emphasized the patient’s adherence to medication (daily dose of olanzapine 30mg and lorazepam 3mg). There was no evidence of abnormal vital signs or neurological abnormalities. He was markedly less agitated than the previous follow-up. The patient reported a positive mood, and his affect was broad and congruent with mood. Motor behavior and speech were grossly normal. Thought content was organized. There was no evidence of delusional thought content during the interview. JJ’s thought content revolved around upcoming plans. Judgement and insight continued to show improvement.

Day 52: Outpatient. JJ was well-groomed and accompanied by his mother. He had recently returned from an overseas trip in which he suddenly discontinued olanzapine and lorazepam medication against medical advice. The patient refused a maintenance dose of olanzapine. Instead, olanzapine 10mg was to be taken orally as needed. The patient denied using cannabis during his trip and reported good sleep quality. The patient’s mother reported no unusual behavior since the patient’s return. The patient was calm, pleasant, and nonirritable. Thought content was organized and contained no suicidal or heteroaggressive ideations. The patient remained religiously preoccupied but with no clear delusions. The patient also denied experiencing hallucinations. Insight was partial. 

Day 75: Outpatient. JJ was sleeping and eating well and reported no issues with concentration. The patient remained off olanzapine medication and had not taken olanzapine as needed. The patient continued the recreational use of cannabis 1 to 2 times per week. The patient remained religiously preoccupied when discussing his hospital stay, but he did not identify as Jesus. However, the patient admitted to feeling special and being able to “make one woman walk when she could not” during his hospital stay. The patient expressed his discomfort toward visiting the hospital because “demon-occupied doctors” might keep the patient against his will. Despite these thoughts, the patient maintained a euthymic mood without thoughts of self-harm or violence. The patient was socializing more with friends and experiencing nightlife again without developing negative feelings toward nonreligious individuals, as he had during the acute episode. Patient started working to pay off his credit card debt. 

Diagnostic assessment. As per The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria, the formal diagnosis made was a probable AZT-induced manic disorder with psychotic features, as JJ presented with delusions, expansive mood, logorrhea, grandiosity, flight of ideas, and psychomotor agitation soon after exposure to AZT. AZT, along with other similar medications in the macrolide family, was reported to cause comparable neuropsychiatric symptoms in other patients.^2–4,10 The delusions exhibited by JJ are not better explained by a psychotic disorder that is not medication-induced. The delusions did not precede the onset of AZT use, and there was no history of nonmedication-related psychotic episodes in this patient. Also, a delirious state as a cause of psychotic symptoms was ruled out. The delusions exhibited by JJ caused clinically significant distress and impairment in social and occupational areas of function in his life. Finally, despite discontinuation of antipsychotic medication, the patient remained in remission months after the first presentation. 

Discussion 

JJ’s event timeline (Table 1) and work up at presentation strongly support an association between JJ’s use of AZT and his episode of mania with psychotic features. His family described a stark difference between his baseline personality and his state with grandiose and religious delusions following AZT treatment. Furthermore, JJ’s clinical presentation upon taking AZT excluded symptoms that could indicate a septic state (ie, fever, night sweats, nausea, fatigue, joint pain, lymphadenopathy, sore throat, skin rashes, or costovertebral angle tenderness). Moreover, history of present illness indicated no neurological symptoms to suggest a meningeal or encephalopathic cause of psychotic symptoms. Furthermore, a hyperactive delirious state was ruled out based on the absence of laboratory readings to suggest a metabolic imbalance and the patient’s intact awareness and working memory. Prior to AZT treatment, the patient had typical localized urethritis symptoms that included dysuria, frequent urination, and penile discharge. Also, there was no evidence to suggest erroneous dosing of AZT or patient misuse. 

The patient’s cannabis use might have had confounding effects on the presumed association between AZT use and his manic episode. Indeed, self-reported cannabis use has an independent effect on psychosis age of onset after controlling for alcohol use and misuse of other drugs.¹¹ Our report cannot exclude a multifactorial cause of the patient’s manic episode. However, the onset of mania with severe psychotic features only hours after the administration of AZT and the current absence of recurrent psychotic or manic episode despite continued cannabis use reinforce a potential cause-and-effect relationship between AZT administration and manic episode occurrence. 

It was reported that a single dose of AZT 1,000mg is equally as efficacious as a seven-day course of AZT for treatment of genital Chlamydial infections.¹² This efficacy is in part owed to the rapid distribution of AZT from blood to tissues. Indeed, a single 500mg dose of AZT increases plasma concentrations of AZT to 0.45mg/L within two hours due to a rapid distribution from blood to tissue that is maximized with a long half-life of four days.¹³ Therefore, with approximately 5.5 half-lives required to clear AZT, AZT might, in theory, explain JJ’s presentation 20 days after taking the 1,000mg AZT dose. Furthermore, brain concentrations of AZT persisted for several days after administration and long after the blood level of AZT decreased, with a considerable ability to cross the blood brain barrier.¹³ Based on the pharmacokinetics of AZT,^14,15 we can expect that JJ’s one-time 1,000mg dose significantly increased the availability of AZT within the brain, with possible long-term effects. 

Although our report documents neuropsychiatric connections to AZT administration in the adolescent population, AZT was previously shown to be associated with neurological manifestations in two pediatric patients with no comorbidities.⁴ In Schiff et al,⁴ AZT was reported to cause severe and prolonged complex neuropsychiatric symptoms in two previously healthy brothers (6 and 15 years of age). The two brothers were administered a weight-adjusted dose of AZT monotherapy after an episode of follicular tonsilitis.⁴ Within 12 hours after their exposure to AZT for the first time and while being afebrile, both patients experienced recurring visual and auditory hallucinations. Both patients also endured neurological symptoms, such as headaches, visual deficits, and complex partial seizures. While the patient in our study had no visible neurological deficits, both Schiff et al⁴ and our observations indicate that AZT treatment could result in neuropsychiatric symptoms. Interestingly, the two brothers improved within weeks. They did not experience similar neuropsychiatric episodes without antipsychotic or anticonvulsant medications.⁴ These observations suggest that AZT was the cause of the neuropsychiatric symptoms, rather than a provocative agent to an underlying psychiatric pathology. 

As per the DSM-5 diagnostic assessment, JJ met the criteria for an AZT-induced manic episode with psychotic features diagnosis. Nonetheless, at the time of writing this study, it is unclear if JJ had only reached partial remission with the possibility of a second manic or psychotic episode, given the persistence of religious preoccupations at 75-day follow-up. Alternatively, JJ might currently be in full remission, as he was not actively exhibiting symptoms at 75 days but still lacked insight into the delusions during his hospital stay. Adding another variable to the analysis is the fact that JJ was started on antipsychotic medication three weeks after the onset of mania and upon his arrival to the emergency unit. Thus, it is also unclear if the improvement was solely due to the antipsychotic medication effect, the natural remission course after cessation of AZT, or both. Furthermore, JJ’s genetic background might contribute to the risk for bipolar type I disorder and vulnerability to the neuropsychiatric side effects of any medication, including AZT. This was corroborated with JJ’s sister’s MDD diagnosis and that relatives of patients with BPD are more likely to be affected with MDD than BPD.¹⁶ 

Conclusion

Our report documents, for the first time to our knowledge, a manic episode with psychotic features induced by AZT use in an adolescent patient. Our study also emphasizes the need for more scrutiny in the use of antibiotics in special patient populations and documents the course of AZT-induced manic episode after counseling and medical intervention.

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