Remission of Persistent Methamphetamine-Induced Psychosis After Electroconvulsive Therapy: Presentation of a Case and Review of the Literature

Mr. A, a 37-year-old openly homosexual software engineer, had a graduate education, stable employment, a comfortable suburban house, and supportive parents. He reported no family history of psychiatric disorder in any first-degree relative, although he had one second-degree relative, a paternal uncle, with bipolar disorder. His own past psychiatric history had been benign except for a mild depressive episode in college for which he received 6 weeks of counseling. However, by his late 20s, Mr. A became frustrated by loneliness and what he called social and sexual "inhibition," which kept him from pursuing both romantic and sexual partnerships. In an effort to remedy these self-perceived deficits, he turned to drugs. In 2003, at age 32, he began infrequently smoking methamphetamine, but he quickly increased his frequency of smoking and the amount of methamphetamine that he smoked because he felt that the drug enhanced his sex life. During the same period, about three times a month, he drank as many as five alcoholic drinks per occasion. He also reported occasional use of 3,4-methylenedioxyamphetamine (MDMA; "Ecstasy"), gamma-hydroxybutyrate (GHB), marijuana, and alkyl nitrites. Methamphetamine was his drug of choice, however, and he reported that by 2005 he was smoking it daily.

In August 2006, Mr. A first developed auditory hallucinations, which he attributed to conversation among his neighbors. In November 2006, a single voice emerged and became nearly constant. He identified it as the voice of his former roommate; it told him that he was a "terrible person" who had "had sex with over 300 men" and spread to them syphilis and HIV. The voice told him to jump out of an eighth-floor window of a hotel; he went to the window but did not jump. At about the same time that he began to hear hallucinations, Mr. A developed paranoid delusions, believing, for example, that a tan sport utility vehicle was the police or that the FBI was following him. Also starting in November 2006, he began to experience depression with erratic sleep, ruminative thoughts, difficulty concentrating, poor appetite with weight loss, and suicidal ideation.

Alarmed by these experiences, Mr. A stopped all illicit drug use in February 2007, although he still occasionally used alcohol in the same amount and frequency described above. Nevertheless, the auditory hallucinations and persecutory delusions persisted, and his depression worsened. He rarely left his apartment, and when he did leave his apartment for work, he "sat around all day unable to function." Fearing the loss of his job in June 2007, he first sought mental health treatment at a local clinic, where he was evaluated and immediately referred for admission to McLean Hospital. Although the extent of his psychosis was not immediately apparent on admission, he was soon transferred to a psychotic disorders unit after disclosing that he was experiencing command auditory hallucinations.

Results of initial medical evaluations, including physical examination, routine laboratory studies, serology for syphilis and HIV, neurological evaluation, and noncontrast brain MRI, were normal. Mr. A was not taking any medications at the time of admission, and he reported that his last alcoholic drink was 10 days earlier. His only medical problems, ulcerative colitis and genital herpes, were not active. He was started on olanzapine, which was titrated up to a dose of 20 mg/day by hospital day 3, but no improvement was seen in his mood or psychotic symptoms after 2 weeks. On hospital day 17, Mr. A's case was presented at a departmental case conference; the discussant (H.G.P.) noted that from a purely phenomenological standpoint, the clinical picture was one of agitated psychotic depression, and he therefore recommended ECT as a treatment likely to be effective. Mr. A was started on right unilateral ECT on hospital day 18. He showed some improvement even after the first ECT treatment, and by the sixth treatment, on hospital day 30, he was euthymic and completely free of psychotic symptoms. He was discharged on hospital day 32 on olanzapine, at 20 mg/day, and planned maintenance ECT. However, Mr. A attended only one additional session of ECT, and because of sedation with olanzapine, he was switched by his outpatient psychiatrist to bupropion, 150 mg/day, and aripiprazole, 15 mg/day.

As an outpatient, Mr. A continued to be essentially asymptomatic. Whereas before admission he had been unable to fulfill most of his obligations at work because of cognitive impairments, after ECT he returned to his full baseline level of social and occupational functioning. He adopted a "sober lifestyle," did not drink or use drugs, and attended 12-step groups, although he had no sponsor. Five months later, in December 2007, he resumed smoking methamphetamine "sporadically" in the setting of the same perceived social isolation and dissatisfaction with his sex life. He spent hours viewing pornography on his computer and smoked methamphetamine to facilitate meeting sexual partners and to enhance sexual experience. Although he also occasionally used alkyl nitrites and GHB at that time, he denied use of alcohol, marijuana, and Ecstasy. Over the next 2 months, his methamphetamine smoking steadily increased, and during that time his auditory hallucinations returned, although he did not initially find them problematic. He curtailed his use of methamphetamine in February 2008. By May 2008, however, he was feeling "lonely" and "disconnected" from the majority of his friends who were actively smoking methamphetamine; he reverted to smoking methamphetamine daily for a period of 3 weeks and during that time developed florid auditory hallucinations and persecutory delusions nearly identical to those that he had at the time of his first admission. He was readmitted to McLean Hospital in June 2008.

Mr. A was started on quetiapine, 200 mg/day, at admission, and he started a second course of right unilateral ECT on hospital day 3. After only four treatments, his symptoms resolved entirely, and both the patient and his parents reported that he was back to his baseline of functioning. On hospital day 11, he was discharged after his fifth ECT session with instructions to take quetiapine, 200 mg/day, and with a complement of aftercare supports, including continued psychopharmacological management, psychotherapy, referral to substance abuse group for homosexual men with methamphetamine addiction, referral to a 12-step program, and five maintenance ECT treatments over the next 3 weeks.

Three months after discharge, Mr. A continued to be free of psychotic symptoms, maintaining his baseline level of social and occupational functioning and remaining abstinent from methamphetamine.

Mr. A, a man with no premorbid history of schizophrenia or other psychotic disorders, developed auditory hallucinations and paranoid delusions starting 2–3 years after he began regularly smoking illicit methamphetamine. The latency from his first methamphetamine smoking to the onset of psychosis is comparable to the mean latency of 1.7 years (SD=2.0) from first use to onset of psychosis recently reported for 42 methamphetamine smokers in Japan (18). Mr. A's psychotic symptoms persisted for approximately 5 months even after stopping methamphetamine use—a phenomenon often reported in previous studies of illicit methamphetamine users, as described below (11, 13–15, 19, 28, 29). An initial trial of an atypical antipsychotic showed little benefit—a problem also previously reported in the treatment of methamphetamine psychosis (14, 15). However, Mr. A's psychotic and affective symptoms appeared to respond quickly to ECT and remained in remission until he resumed smoking methamphetamine. Reexposure to methamphetamine produced a rapid recurrence of the psychotic symptoms—an observation also consistent with the prior literature (29–31). These symptoms again appeared to respond to a brief course of ECT.

How common are psychotic symptoms with methamphetamine use? Such symptoms are almost certainly rare with ordinary therapeutic doses; methamphetamine is pharmacologically similar to other amphetamines (32, 33), and amphetamines are widely prescribed for conditions such as attention deficit hyperactivity disorder, with very little risk of psychosis (34, 35). By contrast, illicit use of methamphetamine, especially in supratherapeutic doses taken by nonoral routes of administration, may produce psychotic symptoms more frequently. For example, a recent Australian study of 277 non-treatment-seeking illicit methamphetamine users with no prior diagnosis of schizophrenia or other psychotic disorders found that 51 (18%) had "clinically significant" psychotic symptoms (36). Similarly, a recent U.S. study of 42 cocaine-dependent and 43 methamphetamine-dependent individuals, screened to exclude patients with other axis I disorders, reported psychotic symptoms of at least some type in at least 60% of both groups (37).

How often do methamphetamine-induced psychotic symptoms persist long after methamphetamine is discontinued, as appeared to be the case in our patient? The available literature on this topic, much of which is in Japanese, suggests that persistent methamphetamine psychosis is not uncommon. In Japan, methamphetamine has been by far the most widely abused illicit drug for more than 50 years; until recently, Japanese substance abusers rarely consumed drugs other than methamphetamine, thus allowing investigators to assess the effects of methamphetamine without the confounding effects of other substances (29). One early Japanese study (13) described 74 patients with methamphetamine psychosis observed prior to the era of neuroleptics. About two-thirds remitted within 20 days after stopping methamphetamine, but about 10% displayed psychosis lasting more than 6 months and in some cases even a few years. In another early study, Teraoka (28) reported "schizophrenia-like symptoms" in 32 (28%) of 114 former methamphetamine users followed up after 8–12 years. A more recent study (19) described 132 consecutive patients with methamphetamine psychosis admitted to a Tokyo hospital from 1978 to 1987; about 28% required more than 61 days of hospitalization. A subsequent report from the same group (15) described 104 additional patients with methamphetamine psychosis admitted to the same hospital from 1988 to 1991; despite abstinence from methamphetamine and administration of antipsychotic drugs, 16 (15%) required more than 3 months of hospitalization. A more recent Japanese study at another center found that 28% of inpatients with methamphetamine psychosis had symptoms that persisted for longer than 6 months of abstinence (29). Similarly, Akiyama (14) described 32 female prisoners treated with standard antipsychotic medications for methamphetamine psychosis; none of these women was reported to have displayed psychosis or a diagnosis of schizophrenia prior to methamphetamine use. As prisoners, the women had no access to further methamphetamine. Although the exact numbers of those who did and did not respond to treatment cannot be calculated from the article, it appears that a majority of patients, especially those with more severe symptoms, were still symptomatic even after many months of antipsychotic treatment.

An additional literature, much of it also in Japanese (23, 30, 38–42), has noted that methamphetamine users may display a rapid recurrence of psychotic symptoms on reexposure to the drug—as appeared to be the case with our patient. This phenomenon of long-lasting "sensitization" or "reverse tolerance" to methamphetamine and other dopamine agonists has been demonstrated in animals (21, 22, 43) and is believed to reflect noradrenergic hyperactivity and increased dopamine release (44).

Japanese investigators generally concur that methamphetamine can produce prolonged psychotic syndromes even in individuals who had no premorbid psychiatric symptoms or evidence of a psychotic diathesis (17, 20). By contrast, Western observers seem to have been more hesitant to adopt this view; for example, Connell's classic 1958 monograph (12) implies that prolonged cases of amphetamine psychosis must reflect some "latent paranoia." Similarly, as recently as 1996, a U.S. review noted that "it is widely taught that if psychotic symptoms persist beyond 6 weeks of sobriety, such symptoms can no longer be linked to drug abuse, no matter how severe the abuse or how long the drugs were used" (45, p. 263). Although DSM-IV-TR does not place a specific time limit on "substance-induced psychotic disorder," it implies that persistence of psychotic symptoms for "a substantial period of time (i.e., a month or more)" after stopping the drug would tend to suggest a primary psychotic illness (p. 339). However, the patient described here showed no evidence of a primary psychotic illness or predisposition to a psychotic disorder in either his personal history or that of his immediate family, yet he developed apparent methamphetamine-associated psychotic symptoms that persisted for months after stopping the drug—an observation consistent with the Japanese consensus that methamphetamine alone can cause such persistent syndromes. If the Japanese view is correct, it would follow that the prevalence of methamphetamine psychosis may currently be underestimated in the United States, because patients like Mr. A might be misclassified as having primary psychotic disorders.

Even in individuals with no obvious premorbid disposition, there may nevertheless be specific risk factors for methamphetamine-induced psychotic or mood disorders, such as a history of head injury (46), personality factors (47), familial loading for schizophrenia (48), or a history of attention deficit hyperactivity disorder (31). However, it may well be that with a sufficient cumulative lifetime dose of methamphetamine, even fully intact individuals may develop methamphetamine-induced psychosis as a result of damage to dopaminergic, serotonergic, and noradrenergic circuits. For example, methamphetamine-induced accumulation of intracellular dopamine is thought to engender the creation of free radicals that damage dopa­minergic neurons (49). Also, unlike many other stimulants, methamphetamine affects serotonergic neurons as well. The mechanism of this serotonergic neurotoxicity is less well understood but again may be attributable to free radical formation (49).

Antipsychotic medications may have limited efficacy in methamphetamine psychosis, as seemed to be the case in our patient. The paucity of research in this area is highlighted by a 2008 Cochrane Review (50) that found only one randomized controlled trial of treatment of amphetamine psychosis in all of the published literature. That study (51) compared olanzapine and haloperidol in 58 patients with amphetamine psychosis (presumably most or all methamphetamine) in Thailand; 27 (93%) of 29 patients on olanzapine and 23 (79%) of 29 patients on haloperidol showed at least 40% improvement on the Brief Psychiatric Rating Scale after 4 weeks, but it is not clear how many patients still exhibited psychotic symptoms at endpoint. Also, because the study lacked a placebo arm, it is difficult to judge whether the improvement observed was significantly superior to the natural course of amphetamine psychosis alone. Two recent case reports found risperidone (52) and olanzapine (53) effective for methamphetamine psychosis, but each described only a single patient. By contrast, as noted above, Japanese studies have frequently reported discouraging results with standard antipsychotic drugs, with many patients remaining clinically psychotic even after many months of treatment (14, 24).

Given the limited evidence for the efficacy of antipsychotic drugs, the apparent response of our patient to ECT is encouraging. The mechanism whereby ECT might benefit methamphetamine psychosis remains speculative, however. Notably, striatal dopamine is reduced in rhesus monkeys (54) and rodents (55, 56) exposed to methamphetamine and is also reduced in postmortem tissue from persons with methamphetamine addiction (57). Conversely, chronic electroconvulsive shock (ECS) increases striatal dopamine in healthy rats (58, 59). Neuroimaging findings in chronic methamphetamine users show a decrease in dopamine transporters that recovers only gradually after prolonged abstinence, suggesting dopamine terminal damage that is very slow to repair (60). Recent animal data suggest that chronic methamphetamine exposure leads to decreased immediate early gene (e.g., c-fos) expression (61). By contrast, ECS is associated with increased brain-derived neurotrophic factor, nerve growth factor, and immediate early gene (e.g., c-fos) expression, and therefore ECT may confer neuroprotection and neuroplasticity (59). Thus, one might speculate that ECT counteracts the effects of methamphetamine at least partially through normalization of the neural environment or by stimulating the proliferation of nerve terminals. However, one must be very cautious in extrapolating from animal studies, given that such studies may use larger amphetamine doses than used by humans and may not mimic the gradual escalation of dosage typical in human abusers, a pattern that may attenuate amphetamine-associated neurotoxic effects (56).

To our knowledge, there are no other published reports of ECT in methamphetamine-induced mood or psychotic disorders. Given the extensive Japanese experience with methamphetamine psychosis, one might at first expect to find such a report from Japan, but because ECT was not widely used in Japanese psychiatry until recently (62), it is not surprising to find that the Japanese literature lacks trials of ECT in methamphetamine psychosis. We are aware of one case from Germany somewhat analogous to ours, describing an individual with extensive use of Ecstasy who displayed depression refractory to pharmacological treatment but was responsive to bilateral ECT (63). The authors hypothesized that Ecstasy use was associated with a disruption of serotonergic neurons, which rendered ineffective the antidepressants that the patient had tried.

Like other case reports, ours describes observations of a single individual. Thus, several limitations of our report should be considered. First, although the nature and timing of Mr. A's symptoms appear to be typical of those described in the literature on methamphetamine psychosis, we cannot exclude the possibility that his symptoms were at least partially attributable to the use of other drugs, such as cannabis and Ecstasy. Unfortunately, toxicological screening was not performed during the patient's admissions, and thus the history is based on his self-report. However, the patient's self-report remained consistent with several different observers during two hospital admissions and was corroborated by his outpatient therapist.

Second, we must consider the possibility that some of the patient's symptoms might have been attributable to an underlying primary axis I disorder. However, the patient showed good academic and occupational functioning prior to regular methamphetamine smoking. The latency from his first methamphetamine smoking to the onset of psychosis was in the same range as that reported in previous studies of methamphetamine psychosis, as noted earlier (18). After the patient was discharged from his first hospitalization, he exhibited no psychotic symptoms or major mood disorder during the time that he remained abstinent from methamphetamine. However, when he resumed regular methamphetamine smoking, he rapidly developed a recurrence of psychotic symptoms similar to those of the previous episode, precipitating his second admission. Given this chronology, illicit methamphetamine smoking appears to be the most parsimonious explanation for the etiology of his symptoms.

Third, we lack formal assessments of the patient's cognitive status. Cognitive difficulties, such as deficits in verbal memory, are reported in methamphetamine-dependent individuals (64, 65), and indeed neurocognitive testing was ordered during the patient's second admission. However, the testing was not performed because the patient started ECT, which could confound the test results. The patient's cognition appeared to improve markedly after ECT on both occasions. However, when considering the possibility of ECT in other methamphetamine-dependent patients, some element of caution might need to be exercised in light of the fact that such patients may have existing cognitive deficits that might be compounded, at least temporarily, by ECT. Cognitive testing would likely be of value in such cases.

Fourth, the patient's improvement following ECT is confounded with time, and in the absence of a placebo condition, it cannot be stated with certainty that the improvement was attributable to ECT. However, given the chronicity of symptoms prior to initiation of ECT and the rapid remission of symptoms on two separate occasions following the initiation of ECT, it seems likely that ECT was responsible for the patient's improvement.

Further experience with other patients will be required to support our impressions from this case. Given the public health problem posed by illicit methamphetamine use, it would seem warranted to pursue further investigation of patients with apparent methamphetamine-induced syndromes.

The authors thank Drs. Dost Öngür and Elizabeth Liebson for their comments on a draft of the manuscript.