Isoniazid‐induced mania and the history of antidepressant drugs: Case report and literature review

Isoniazid is the first-line antimicrobial drug for the treatment of tuberculosis, a leading cause of death worldwide. In rare, but likely under-reported cases, isoniazid is associated with the emergence of secondary manic and or psychotic symptoms, requiring an immediate drug discontinuation. Awareness of isoniazid´s psychiatric side effects is particularly relevant given the significant worldwide rates of latent tuberculosis. A 46-year-old Caucasian male was involuntarily hospitalized in a Portuguese psychiatric unit due to manic and psychotic symptoms. The symptoms started abruptly 1 week prior to the hospitalization (Figure 1) and comprised irritability, psychomotor agitation, restlessness, purposeless activity, euphoric mood, affect lability, verborrhea and pressured speech, flight of ideas, grandiose and messianic delusions, disinhibition, verbal aggressiveness, total insomnia, excessive money spending, and the conception of several extravagant and unreasonable plans for the future. His medical history included latent tuberculosis (TB; diagnosed 10 years prior), ankylosing spondylitis (AS), and high blood pressure. The patient had no previous personal or familiar psychiatric history. At the time of the admission, his medication comprised omeprazole (20 mg/day), losartan + hydrochlorothiazide (100 + 25 mg/day), sulfasalazine (500 mg/day) and indomethacin (75 mg). Isoniazid preventive therapy (300 mg/day) had been started 1 month prior to admission, as part of etanercept's initiation protocol of AS biological treatment. However, the emergence of significant psychiatric symptoms led the physicians of his local isoniazid dispensary to withdraw the drug 3 days prior to his hospitalization. Despite this, the symptoms persisted and their severity, impact on social and daily function, as well as absolute lack of insight led to the patient's involuntary admission. It is important to point out that the patient received treatment with isoniazid when he was first diagnosed with latent TB 10 years prior. The treatment was interrupted after 2 months due to unforeseen delays in the availability of etanercept. No neuropsychiatric adverse reactions were recorded at that time. On admission, hematological and biochemical laboratory findings were normal, and head CT showed no abnormalities. After the exclusion of potential medical causes, the patient was provisionally diagnosed with secondary psychotic mania induced by isoniazid. The discontinuation of isoniazid did not resolve the patient's psychiatric symptoms and, due to their severity, it was deemed necessary to start olanzapine (titrated to 15 mg/day). After 2 weeks of treatment with olanzapine, his symptoms did not improve. The patient continued to exhibit elevated mood, disinhibition, messianic and grandiose delusions, and psychomotor agitation, which led to the administration of sodium valproate (titrated up to 1000 mg/day). His condition steadily improved over the course of the following 2 weeks, leading to his discharge after a 34-day hospitalization with a complete resolution of the psychiatric symptoms. He maintained ambulatory treatment with olanzapine (10 mg/day) and sodium valproate (1000 mg/day) and commenced rifampicin (600 mg/day) for latent tuberculosis 1 month later after discharge. There was no recurrence of the aforementioned symptoms during the 6-month follow-up period. We reported a case of mania induced by isoniazid preventive therapy. Several commonly prescribed drugs have been associated with secondary mania, such as isoniazid and sulfasalazine. In this case, sulfasalazine for AS treatment had been started 2 months prior to the hospitalization, but we are convinced that sulfasalazine's contribution to the emergence of maniac and psychotic symptoms was unlikely. Sulfasalazine-induced mania is rare. According to data collected from an ongoing FDA phase IV clinical study,1 only 31 people (0.05%) from a pool of 67,897 who reported side effects from sulfasalazine-developed mania. Moreover, the reported cases occurred mainly among males within the age range of 20–29, who have been taking the drug for 1–6 months. Only one case of mania was reported within the age range of our patient (40–49).1 More importantly, manic and psychotic symptoms resolved even without the discontinuation of sulfasalazine. On the other hand, isoniazid-induced mania, although rare, is more frequent than sulfasalazine-induced mania, and its emergence is usually reported within the first month of treatment.1, 2 In addition, the discontinuation of isoniazid along with psychopharmacological treatment led to symptomatic remission. Finally, a comprehensive revision of the literature surrounding isoniazid and its mechanisms of action is also consistent with a diagnosis of isoniazid-induced mania. Isoniazid, first discovered in 1912, has been used since 1951 as a first-line drug in the treatment and prevention of TB.3 Although isoniazid is an effective treatment for TB, the disease continues to figure among the leading causes of death worldwide.2-4 Risk factors for tuberculosis activation include immunosuppressed individuals,2 and preventive treatment should be delivered in such cases (e.g., patients on etanercept therapy).2 Despite its effectiveness as a first-line agent in TB, isoniazid has several recognized adverse effects, including peripheral and central (rare) nervous system toxicity.2, 4 Psychiatric symptoms, such as insomnia, irritability, psychosis, and mania, are rare events, although their actual incidence rate is unestablished. The data available is mostly based on case reports.2, 4 A consultation of the WHO's adverse drug reactions (ADR) database (VigiBase) suggests that only a small fraction of isoniazid's ADRs correspond to psychiatric symptoms (3.2% of reports, n = 1639). Of those, 1.6% (n = 26) refer to manic symptoms and 18.7% (n = 307) refer to psychotic symptoms. Our patient is the first reported case of suspected manic and psychotic adverse reactions with isoniazid in Portugal. Manic-like adverse reactions with isoniazid were first noticed by doctors working in specialized sanatoriums after the introduction of the drug and its metabolite, iproniazid, for TB treatment.3 In fact, 1950s descriptions of isoniazid trials in terminal TB patients included surprising reports of improved mood, vitality, and sociability, despite the fact that the reporting patients were dying.3 Media reports at the time stated that patients were “dancing in the halls, they had holes in their lungs”.3 These unexpected “antidepressant” effects of isoniazid and iproniazid led to their use in clinical drug trials with psychiatric patients. In 1957, some literature reports showed remarkable improvement in 70% of depressive patients treated with iproniazid.3 Due to hepatotoxicity, both isoniazid and iproniazid's use as antidepressants were suspended in 1961.3 Nevertheless, isoniazid effectiveness still justifies its current use as first-line treatment in TB.2 Moreover, the serendipitous finding of antitubercular drugs' antidepressant effects was the first step in understanding the neurobiological basis of psychiatric conditions and led to the foundation of psychopharmacology. The association of isoniazid's antidepressant effects with its monoamine oxidase inhibitor properties (previously described in 19523) eventually led to the development of the first class of antidepressants: irreversible and non-selective MAO inhibitors. A literature review on isoniazid-induced mania and psychosis shows that these symptoms may develop in patients from all age groups, with or without a psychiatric history, in multiple or single-drug anti-tuberculosis regimens, at various isoniazid dosages, and with or without pyridoxine supplementation (at various dosages).2, 4 Psychiatric symptoms' latency of onset varies from 1 day to 10 months following isoniazid introduction, often precluded by a prodromal phase (e.g., headaches, dizziness, irritability, anxiety, and insomnia) and an abrupt onset of symptoms.2, 4 Several clinical syndromes may occur, including psychosis or, less commonly, mania (with/without psychotic symptoms).4 Most cases either resolve or dramatically improve without additional treatment besides the withdrawal of isoniazid; the duration of symptoms after withdrawal varies from 1 day to 120 days (most cases less than 2 months).2 The introduction of atypical antipsychotic drugs, mood-stabilizing agents, and/or benzodiazepines can be considered in some cases.4 Several mechanisms have been proposed to explain the emergence of manic and/or psychotic symptoms in individuals treated with the drug. First, mania could result from isoniazid's weak MAO inhibition, causing increased monoamine levels.3-5 Second, it could be consequential to a vitamin B6 deficiency, resulting from isoniazid's inhibition of pyridoxine phosphorylation, and thus decreased production of pyridoxal-5-phosphate (the biologically active form of vitamin B6).5 Additionally, isoniazid interacts with vitamin B6 in the tissues to form a pyridoxal-isoniazid complex, which increases its urine excretion.5 Moreover, isoniazid metabolites also bind to pyridoxal-5-phosphate, thus inhibiting the enzymes depending on it, and resulting in a functional B6 deficiency.4, 5 Vitamin B6 is a cofactor of the enzymes involved in the synthesis of several neurotransmitters (most importantly GABA); as such, its deficiency results in GABA depletion,2, 5 which has been associated with the emergence of manic and psychotic symptoms. Third, isoniazid contributes to oxidative stress through increased production of ROS and decreased glutathione.4, 5 This has been shown to reduce NMDA receptor density in the hippocampus,4 which may contribute to the development of psychotic symptoms (in line with the NMDA receptor hypofunction hypothesis of schizophrenia).5 However, pyridoxine supplementation does not appear effective in preventing or treating mania/psychosis secondary to isoniazid and is strictly recommended for the prevention/treatment of peripheral neuropathy.4, 5 The insufficient knowledge about the pathophysiology of psychiatric disorders such as mania, adds to the complexity and difficulty in pinpointing the association between manic or psychotic symptoms and the mechanism of action of a specific drug. Another aspect to consider is whether isoniazid-induced mania is more likely to occur in individuals with latent bipolar disorder or if it is more likely to exacerbate previously diagnosed cases (similar to what is reported for antidepressant-induced mania). In our case, the patient's improvement was mostly noticeable after the introduction of a mood stabilizer (sodium valproate), which could support this hypothesis. Nevertheless, further study is necessary on this topic. The authors have no conflicts of interest to declare. The datasets analyzed for the purpose of the current study are available in the public domain VigiBase repository, at http://www.vigiaccess.org.