Adverse Drug Experience Review
Medical Toxicologyand Adverse Drug Experience 4: 127-143 (1989) 0113-5244/89/0003-0127 /$08 .50/0 © ADIS Press Limited
All rights reserved.
Drug-Induced Mania - Causative Agents, Clinical Characteristics and Management
A Retrospective Analysis of the Literature
David L. Sultzer and Jeffrey L. Cummings Neurobehavior Unit. West Los Angeles VAMC (Brentwood Division) and the Departments of Neurology and Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles. California. USA
Contents
Summary
Summary I. Method of Analysis of Case Reports 1.1 Diagnost ic Criteria 1.2 Review Process 2. Results of Literature Analysis 2.1 Drugs That Induce Mania 2.2 Patient Profile 2.3 Latency to Onset 2.4 Specific Signs and Symptoms of Mania 2.5 Treatment of Patients with Drug-Induced Mania 2.6 Duration of Manic Episode 2.7 Recurrence of Manic Episodes and Lithium Prophylaxis of Drug-Induced Mania 2.8 Mania Induced by Drugs Used in the Treatment of Mood Disorders 3. Discussion 3.1 Diagnostic Criteria 3.2 Role of the Causative Agents 3.3 Patient Characteristics 3.4 Characteristics of the Manic Episode 3.5 Treatment Considerations 3.6 Rechallenge with the Causative Agent 3.7 Physiology of Mood Regulation
127 128 128 128 129 129 129 132 132 133 133 133 134 134 134 135
136 136 137 138 138
J28 case reports of drug-induced mania were reviewed. Steroids. levodopa and other dopaminergic agents, iproniazid. sympathomimetic amines. triazolobenzodiazepines and hallucinogens were the agents that most commonly induced manic syndromes. The most common characteristics of drug-induced manic episodes were increased activity, rapid speech. elevated mood, and insomnia. Patient s who developed mania often had a prior history, family history, or current symptoms ofmood disturbance. The episodes were m ost commonly treated by discontinuing or reducing the dose ofcausative agent. Discontinuation of the inciting drug and treatment with neuroleptic agents were equally efficacious; lithium treatment was less effective. The majority of agents that induce mania have an effect on monoaminergic systems.
Drug-Induced Mania
Mania is most commonly associated with bipolar mood disorder. However, manic episodes can be produced by medical illnesses or by drugs. Focal brain lesions (neoplasms , cerebrovascular lesions), other neurological conditions (multiple sclerosis, epilepsy), infection, metabolic disturbances, medications, and illegal drugs have occasionally induced manic episodes (Cummings 1986; Extein & Gold 1986; Hollister 1986; Krauthammer & Klerman 1978; Stasiek & Zetin 1985). When there is a known cause of the mania, the phenomenon is referred to as 'secondary mania' (Krauthammer & Klerman 1978) or organic mood disorder of the manic type (American Psychiatric Association 1987). This review focusses on the phenomenon of drug-induced mania . The following areas are presented: (a) agents reported to induce mania ; (b) characteristics of patients who develop drug-induced manic episodes , including their prior psychiatric histories; (c) the profile of manic signs exhibited by patients with drug-induced mania ; (d) time-course of the manic episode; (e) approaches to treatment of drug-induced mania ; (f) effectiveness of treatments; and (g) the theoretical implications regarding the aetiology of mania .
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1. Method of Analysis of Case Reports 1.1 Diagnostic Criteria Modified diagnostic criteria from the third edition of the Diagnostic and Statist ical Manual of Mental Disorders (DSM III) [American Psychiatric Association 1980) for Organic Affective Syndrome were utilised for case identification. The criteria were as follows: I. The predominant disturbance was a disturbance in mood, and there were at least 2 of 7 associated symptoms (increase in activity, more talkative than usual, flight of ideas or racing thoughts, inflated self-esteem, decreased need for sleep, distractibility , and risk-taking behaviours, e.g. buying sprees, sexual indiscretions, foolish business investments, reckless driving). 2. There was no clouding of consciousness, as in delirium; no significant loss of intellectual abilities, as in dementia; no predominant delusions or hallucinations, as in organic delusional syndrome or organic hallucinosis. 3. There was evidence from the history, physical examination or laboratory tests of a specific agent that was judged to be aetiologically related to the disturbance. Although DSM III criteria require that the symptoms be present for at least I week, we required no specific time limit; in many cases the manic episode was treated and/or resolved within I week. DSM IIIR (American Psychiatric Association 1987) criteria were not used because they are less specific and would have necessitated the inclusion of many cases beyond those traditionally considered as examples of secondary mania . We included case reports where the patient had a prior psychiatric history, including mania , if the reporting clinician attributed the mania to a drug. The psychiatric history was carefully noted with each case.
5
1.2 Review Process Age (years)
Fig. 1. Age distr ibution of patients with drug-induced mania.
A careful search of the literature revealed 246 journal articles or book chapters related to the topic of drug-induced mania. There were 124 articles
Drug-Induced Mania
There were several reports that contained case series or noted the number of cases of mania that resulted when a large number of patients were treated with a particular drug. From this data, an estimate of the prevalence of secondary mania associated with those specific compounds can be made. Results from these studies are summarised in table II. These reports indicate that drug-induced mania can occur in a considerable proportion of patients treated with prednisone (0.9%), adrenocorticotrophic hormone or cortisone (1.5 to 9%), levodopa (0.8 to 12%), bromocriptine (20%), iproniazid (15%), and baclofen (1.8%).
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2.2 Patient Profile
Fig. 2. Latency to onset of manic symptoms after initiation of drug .
containing 169 individual case descriptions. 128 of the case reports described a manic episode induced by a drug not used in the treatment of mood disorders. 41 case reports involved drugs that are usually used to treat mood disorders (tricyclic antidepressants, monoamine oxidase inhibitors or lithium) . Data from each case report were tabulated, including: (a) patient's age, sex, prior psychiatric history, and family psychiatric history; (b) drug dose and time latency to onset of mania ; (c) specific symptoms and signs of mania; and (d) time course of manic episode, treatment modalities used, and their reported effectiveness. In addition, there were approximately 30 articles that reported case series or prevalence information concerning druginduced mania associated with a particular agent.
2. Results
129
0/ Literature Analysis
2.1 Drugs That Induce Mania The drugs that were reported to induce mania are listed in table I. This table includes only those agents that are not customarily used in the treatment of primary mood disorders , and is based on information from 128 case reports.
Case reports included 69 males and 58 females. The distribution of patient age is shown in figure 1.The number of cases of secondary mania is higher in the young. Medical illnesses are more common in older age groups and drug exposure is likely greater in patients of more advanced age. Thus, drug-induced mania may be disproportionately frequent among younger individuals. Prior psychiatric histories and family psychiatric histories of patients who developed mania are shown in table III. This table also summarises the psychiatric symptoms present at the time of treatment with the agent that induced mania. 41 (32%) of the 128 patients had a prior history of a mood disturbance. 16 (39%) of these 41 patients had had at least 1 previous manic episode. In addition, 20 (16%) of the patients who developed mania had a family history of mood disorder. The most frequent disorder was unipolar depression (11 of 20 cases, or 55%). Family history of bipolar disorder was noted in 8 of the 20 cases (40%). Finally, 23 (18%)of the patients had mood disturbances at the time of treatment with the agent that induced mania. 22 of these patients were depressed; 1 patient was mildly euphoric. In a large proportion of the case reports, no information was given regarding prior psychiatric history, family psychiatric history, or presence of psychiatric symptoms at the time of treatment (table III). Thus, mood disturbance may be even more prevalent in patients who
11
1 1 10
2 4 1 1 1 2 1 3 3 3 1 1 1
Alprazolam
Adinazolam Triazolam
Levodopa
Levodopa + carbidopa Bromocriptine
Lisuride Piribedil
Thyro id hormone Triiodothyronine
Isoniaz id Iproniazid
Ephedrine
Phenylpropano lamine Isoetharine Pseudoephedrine Phenylephrine
Thyroid supplement
Antituberculosis medications
Sympathomimetics
d-Amphetam ine Methylphenidate Pemoline Amphetam ine withdrawal
Phencyclidine LSD
CNS stimulants
Hallucinogens
Dopaminergic agents
4 1
2 1 1 1
3 1 1 1
Cort isone ACTH Hydrocortisone Dexamethasone
Rosen (1979); Slavney et al. (1977) Lake et al. (1981)
Gerner et al. (1976); Van Kammen & Murphy (1975) Koehler-Troy et al. (1986) Sternbach (1981) Liebowitz et al. (1980)
Hoaken (1987) Waters & Lapierre (1981)
Lake et al. (1983); Roxanas & Spalding (1977); Waters & Lapierre (1981) Achor & Extein (1981); Norvenius et at, (1979) Goldman & Tiller (1987)
Jackson (1957) Bloch et al. (1954); Crane (1956)
Earle (1970) Evans et al. (1986)
Caine et al. (1969); Celesia & Barr (1970); Muenter (1970); O'Brien et al. (1971); Pearlman (1971); Ryback & Schwab (1971); Van Woert et at, (1971) Harsch et al. (1985); Lin & Ziegler (1976) Brook & Cookson (1978); Johnson (1981); Turner (1984); Vlissides et at, (1978) Turner (1984) Gerner et al. (1976)
Arana et al. (1985); France & Krishnan (1984); Goodman & Charney (1987); Mayerhoff et al. (1986); Pecknold & Fleury (1986); Remick (1985); Strahan et al. (1985) Papart et al. (1986) Weilburg et al. (1987)
Garner & Falk (1967); Goggans et al. (1983); Hall et al. (1979); Lewis & Smith (1983); Pies (1981) Glaser (1953); Goolker & Schein (1953) Glaser (1953) Hall et al. (1979) Lewis & Smith (1983)
12
Prednisone
Steroids
Triazolobenzodiazepines
References
Number of case reports
Agent
Class
Table I. Drugs that have been reported to induce mania
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Mepacrine (quinacrine) Tryptophan Cyclobenzaprine Cimet idine Carbamazepine Cyproheptadine Digitalis Clonidine Clonid ine withdrawal Aspartame Cyclosporin A Diltiazem Diethyl-M -toluamide Metoclopramide Propranolol Propranolol withdrawal I-Glutamine Flutamide Reserpine withdrawal Calcium Oxandrolone Oxymetholone Propafenone Procyclidine Bromide Hydrostatic pressure Yohimbine Captopril Zidovudine (azidothymidine AZT)
Indomethacin Procarbazine Baclofen Baclofen withdrawal Metrizamide Procainamide Disulfiram
2
1
3
1 1 1 1 1 1 1 1 1
2
1 1 1 1 1 1 1 1 1
2
1 1
3
2
3
1
2 2 4
1 1
2 2 Bishop et al. (1987); Ryan (1985) Carney et al. (1982); Mann & Hutchinson (1967) Wo lf et at. (1982) Arnold et al. (1980) Israel & Prather (1984); Kwentus et at, (1984) McCrum & GUidry (1978); Rice et al. (1988) Bakish & Lapierre (1986); Lacoursiere & Swatek (1983); Martensen-Larsen (1951); Winsh ip (1957) Evans et al. (1984) Goff (1985); Thomas & Rubin (1984) Beeber & Manring (1983) ; Harsch (1984) Hubain et al. (1982); Titus (1983) Reiss & O'Donnell (1984) Gold et al. (1980) Moench (1929) Ahsanuddin (1982) Tollefson (1981) Walton (1986) Wamboldt et al. (1984) Palat et al. (1984) Snyder et at. (1986) Ritchie & Preskorn (1984) Patterson (1984) Jouvent et al. (1986) Mebane (1984) Lajeunesse et at, (1986) Kent & Wilber (1982) Groat & Mackenzie (1980) Freinhar & Alvarez (1985) Freinhar & Alvarez (1985) Jack (1985) Coid & Strang (1982) Sayed (1976) Stoudemire et al. (1984) Price et al. (1984b) McMahon (1985) Maxwell et al. (1988)
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Drug-Induced Mania
develop mania, and in their families, than our data indicate. 2.3 Latency to Onset The interval between initiation of drug treatment and the onset of manic symptoms is shown in figure 2. Nearly half of the manic reactions (45%) occurred within the first week of treatment. A smaller proportion (34%) occurred between 1 and
7 weeks of treatment. 12% of the manic reactions occurred after 7 weeks or more of treatment. 2.4 Specific Signs and Symptoms of Mania The spectrum of specific manic symptoms in patients with drug-induced mania is shown in figure 3. The most common symptoms were increased activity (74%), rapid speech (66%), elevated mood (59%)and insomnia (51%). Delusions or hallucinations occurred in 45 (35%)of the cases.
Table II. Case series and prevalence reports of drugs reported to induce mania
Agent
Findings
Prednisone
8/676 patients developed inappropriate euphoria; another 6 developed mania with psychosis 2/80 patients with medical illnesses treated with ACTH or cortisone developed malignant euphoria 3 of approximately 200 patients developed mania 2/44 patients treated for > 100 days developed 'pathological excitement' 4/44 patients developed mania 5% of patients experienced severe psychiatric reactions ; 30% of these (1.5% of total) developed mania 4/45 patients with Parkinsonism developed mania 1/20 patients with Parkinson 's disease developed mania 1/20 patients with postencephalitic Parkinsonism developed hypomania 4/32 Parkinson 's disease patients treated for more than 1 year developed mania or hypomania 1/126 patients with Parkinsonism treated for 1-3 years developed hypomania 6/7 depressed patients with a history of bipolar disorder and 1 of 11 patients with a history of unipolar depression developed hypomania during levodopa therapy 1/18 patients with Parkinson 's disease developed hypomania when treated with levodopa for 3 weeks 2/10 patients with depression and Parkinsonism developed hypomania 13 hypothyroid patients developed mania when treated with thyroid replacement. Nearly all of these patients showed significant psychopathology (organic mood disorder or psychosis) at the time of initial treatment with thyroid replacement 5/34 patients developed manic psychosis 11 patients developed overactivity, excitement . feeling of well-being 24 subjects developed symptoms similar to mania 6/20 psychotic patients with high urine cannabinoid concentrations were manic 2/113 patients experienced euphoria
Cortisone or ACTH
Cortisone ACTH Steroids Levodopa
Bromocriptine I-Thyroxine
Iproniazid d-Amphetamine Cannabis Baclofen
Boston (1972) Goolker & Schein (1953) Glaser (1953) Freyberg et ai. (1951) Falk et al. (1979) Lewis & Smith (1983) Celesia & Barr (1970) O'Brien et al. (1971) Caine et al. (1969) Muenter (1970) Presthus & Holmsen (1974) Murphy et al. (1971)
Godwin-Austen et at, (1969) Jouvent et al. (1983) Josephson & Mackenzie (1980)
Block et al. (1954) Crane (1956) Jacobs & Silverstone (1986) Rottanburg et al. (1982) Jones & Lance (1976)
Drug-Induced Mania
133
Table III. Prior psychiatric history. family psychiatric history. and presence of psychiatric symptoms in patients who developed drug-induced mania Psychiatric history
Number of patients (%)
Prior psych iatric history Bipolar disorder Unipolar depression Manic episode Other mood disorder Other mental disorder None Not specified
15 9 1 16 23 50 19
(12%) ( 7%) ( 1%) (13%) (18%) (39%) (15%)
Family psychiatric history Bipolar disorder Unipolar depression Other mood disorder Other mental disorder None Not specified
8 11 1 6 34 69
( 6%) ( 9%) ( 1%) ( 5%) (27%) (54%)
Psychiatric symptoms at time of treatment Depression Other mood disorder Other mental disorder None Not specified
22 1 21 50 36
(17%) ( 1%) (16%) (39%) (28%)
Risk-taking behaviours, distractibility and expansive mood were reported least frequently (11%). The spectrum of manic symptoms was compared among the classes of causative drugs. Delusions and hallucinations were more common in manic states induced by steroids and hallucinogens than by other drugs. Insomnia was more common in triazolobenzodiazepine-induced man ia. Irritable mood was more commonly noted in ephedrine/ phenylpropanolamine-induced mania . 2.5 Treatment of Patients with Drug-Induced Mania Each case report was examined for methods used to treat the drug-induced mania . It was also noted whether the author judged the treatment modality to be at least partially effective. The results are shown in table IV. Dose reduction or discontinua-
tion of causative agent were the most commonly used treatment approaches (67%of cases). This was judged at least partially effective in 77%of the cases in which it was used. Administration of neuroleptic agents was used in 49 cases and found effective in 35 of these cases (71%). Lithium was used to treat drug-induced mania in 22 of the 128 cases, and judged at least partially effective in 10 (45%). 2.6 Duration of Manic Episode The duration of the manic episode was recorded for each case of drug-induced mania. The summarised results are shown in figure 4. Many (41%) of the manic episodes resolved within I week; a smaller proportion (32%) of the episodes resolved after I to 7 weeks. The manic episode lasted longer than 7 weeks in 12 cases (9%). 2.7 Recurrence of Manic Episodes and Lithium Prophylaxis of Drug-Induced Mania Metoclopromide (Ritchie & Preskorn 1984), propranolol (Patterson 1984), cimetidine (Hubain et at. 1982), procarbazine (Carney et at. 1982), alprazolam (Mayerhoff et at. 1986), zidovudine (AZT) [Maxwell et al. 1988] and levodopa (Van Woert et at. 1971) were all reported to induce manic episodes that resolved with discontinuation of causative agent, but then recurred when the patient was rechallenged with the drug. In addition, cotreatTable IV. Treatment of drug-induced mania Treatment modality
Number of cases
Number (%) of cases in which modality was at least partially effective
Reduce dose of agent Discontinue agent Neuroleptic Lithium Benzodiazepine Other No treatment Not specified
10 79 49 22
7 (70%) 60 (76%) 35 (71%) 10 (45%) 2 (67%) 6 (55%) 2 ( 7%)
3 11 30 12
134
Drug-Induced Mania
several patients with no prior history of manic episodes. Similarly, isocarboxazid withdrawal precipitated mania in a patient with history of depression who was euthymic at the time of withdrawal.
Risk behaviours Distract ibility Expansive mood Hallucinations
3. Discussion
Hypersexuality F==-., Grandiosity Delusions Racing thoughts Irritable mood Insomnia Elevated mood
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Rapid speech Increased activity ~
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10 20 3040 50 60 70 80 90100
Number of patients
Fig. 3. Spec if ic symptoms and signs of drug-induced mania .
ment with lithium was shown to delay or prevent the recurrence of manic episodes in several patients treated with levodopa (Van Woert et al. 1971), zidovudine (AZT) [Maxwell et al. 1988] or prednisone (Goggans et al. 1983). In another report , adrenocorticotrophic hormone (ACTH) treatment alone was shown to induce mania in a considerable number of patients , but cotreatment with lithium and ACTH did not induce any cases of mania (Falk et al. 1979).
3.1 Diagnostic Observations Terminological confusion complicates a retrospective review of the type undertaken here. Authors used a wide variety of diagnostic criteria to identify drug-induced mania. Some used Research Diagnostic Criteria (Spitzer et al. 1978), DSM IIIR (American Psychiatric Association 1987) characteristics, or changes on clinical rating instruments. Others did not record what symptoms or signs indicted a diagnosis of mania. 'Toxic psychosis' was used variably to describe an organic mood disorder, organic delusional syndrome, or delirium. Retrospective reviews are also impeded by the likely biases of case reporting: manic episodes that result from a newly developed drug are more likely to be reported, and dramatic behavioural syndromes are more likely to be reported than subtle disorders. Despite these reservations, the large number of cases reviewed and the utilisat ion of specific criteria in the review process allow tentative conclusions to be drawn regarding drug-induced mania.
2.8 Mania Induced by Drugs Used in the Treatment of Mood Disorders 50
There were 41 case reports of mania induced by tricyclic antidepressants, monoamine oxidase inhibitors or lithium (table V). These reports were not included in the preceding results. There were reports of mania induced by tricyclic antidepressants and monoamine oxidase inhibitors in patients both with and without a prior history of manic episodes. In addition, lithium induced mania in 4 depressed patients who had a history of either unipolar depression or bipolar disorder. Tricyclic antidepressant withdrawal precipitated mania in
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. l <0Ld. -"?:~8·~'1:.a ,1"~'~'3<:'''''~" Duration of manic episode (days)
Fig. 4. Durat ion of drug- induced man ic episodes.
Drug-Induced Mania
135
Table V. Drugs used in the treatment of mood disorders that have been reported to induce mania Class
Agent
Number of case reports
References
Tricyclic antidepressants (TCA)
Trazodone
7
Fluoxetine
4
Arana & Kaplan (1985); Knobler et al. (1986); Warren & Sick (1984) Chouinard & Steiner (1986); Lebegue (1987); Settle & Settle (1984); Turner et al. (1985) Van Scheyen & Van Kammen (1979) Haggerty & Jackson (1985) Arana & Kaplan (1985) Steinberg & Chouinard (1985) Laporta et al. (1987) Van Scheyen &Van Kammen (1979) Theilman & Christenbury (1986) Liebowitz et al. (1980) Nelson et al. (1983) Gupta & Narang (1986); Jones et al. (1984) DUbovsky et al. (1985); Mattsson & Seltzer (1981) Folks & Arnold (1983) Cohen et al. (1980) Rothschild (1985) Delisle (1986); Louie & Meltzer (1984); Price et al. (1984a)
TCA withdrawal
MAO inhibitors
MAOI withdrawal Lithium
Clomipram ine Imipramine Desipramine Tomoxetine Sertraline Amitripty line Trazodone Amitripty line Desipramine Imipramine Phenelzine Pargyline Clorgyline Isocarboxazid Lithium
6
2 2 1
2 1 1 1 2
2 2 1 1 2 4
The most important diagnostic observation emerging from this review is that there is no discrete set of symptoms that constitute drug-induced mania. Many patients demonstrated at least minimal evidence of delirium, psychosis, depression, or personality disorder in addition to the manic symptoms . The continuum of behavioural symptoms observed in response to a drug can be represented by a 3-dimensional model with intersecting axes for mood, psychosis, and delirium (fig. 5). A behavioural syndrome induced by a drug can potentially lie anywhere in this 3-dimensional space. A case of 'pure ' mania would have symptoms lying along the mood axis only. However, many of the cases have additional elements of psychosis or delirium. Those cases considered drug-induced mania are those with symptoms closest to the mood axis; however, the occurrence of manic-like symptoms in patients with prominent delirium makes the distinction between these syndromes arbitrary. This problem can be minimised by the use of specific diagnostic criteria and exclusion of patients with marked signs of an acute confusional state.
3.2 Role of the Causative Agents The term 'drug-induced mania' indicates that the manic symptoms can be attributed to an ingested agent. Drugs, however, are usually prescribed to treat medical illnesses, and medically ill patients are also at risk for developing mania from the effects of the illness on cerebral function (e.g. systemic lupus erythematosis, tumour metastases, etc.). Also, illness-related alterations in metabolism or clearance of drug increase the patient's vulnerability to drug toxicity. In addition, medically ill patients are often treated with several medications concurrently , raising the potential for toxicity through adverse drug interactions. Some of the patients who developed drug-induced mania were taking more than one medication when the manic episode occurred. Finally, patients with medical illnesses experience considerable stress, and psychological stressors may contribute to the development of manic episodes (Pies 1981). The close temporal relationship of manic symptoms to drug initiation, the resolution of mania with drug dis-
136
Drug-Induced Mania
Mood
_
---
....Psychosis
;-'
Delirium
Fig . 5. Three-dimensional model that represents the cont inuum of potent ial drug -induced symptoms.
continuation, the ability to reproduce mania when the patient is retreated with the original agent, and the observation that mania is more likely to be indued by specific classes of drugs all suggest that in the cases reviewed here, the drug played an essential role in producing or precipitating the manic behaviour. 3.3 Patient Characteristics Demographic features of patients with drug-induced mania and those with idiopathic bipolar mood disorders are similar. In both cases there is approximately equal involvement of men and women. Likewise, the age offirst occurrence of both is similar. Onset of most cases of idiopathic bipolar disorder has been reported to occur between ages 15 and 55, with a median age of onset of 24 years (Goodwin & Jamison 1984). There is a tendency for fewer cases in later years. This age distribution is very similar to that for drug-induced mania shown in figure I. Of the 128 cases of drug-induced mania , half of the patients had a prior psychiatric history; approximately two-thirds of the prior diagnoses were mood disorders. In addition, nearly 20% of the
patients had a mood disorder at the time of treatment with the drug that induced mania. Finally, there was a family history of mood disorder in 16% of patients who developed manic behaviour. Thus, patients who developed drug-induced mania frequently had a personal history of mood disorder or current symptoms of mood disturbance. They had a lower prevalence of family history of mood disorder than patients who spontaneously develop bipolar disorder, but a higher prevalence than found in the general population (Gershon et al. 1982). Clinicians should be particularly alert for manic symptoms in patients with prior histories or current symptoms of mood disorders when treating with drugs likely to induce mania (i.e. prednisone or dopaminergic agents). 3.4 Characteristics of the Manic Episode There is marked variability in the latency from initiation of drug treatment to the onset of druginduced mania. Most of the cases (60%) appeared within 2 weeks, although some were deferred for more than 7 weeks after drug initiation. late-appearing cases bring into question the hypothesis that the drug caused the mania , since a close temporal relationship between drug exposure and behavioural change is felt to be an important factor in the designation 'secondary mania' (Krauthammer & Klerman 1978). However, many of the 'deferredonset' cases resolved after discontinuation of the drug, implying a causative role for the agent. In some cases, the dose of causative agent was increasing during the period from initial treatment to onset of mania , possibly indicating a threshold dose for development of mania . It is also possible that development of mania requires long exposure of the central nervous system to the drug in some patients or with specific agents. This hypothesis is consistent with the observation that changes in neurotransmitter receptor sensitivity and mood may require prolonged exposure to antidepressants in depressed patients. There was also marked variability in the duration of the manic episode. Half of the manic episodes had resolved or were considerably improved
Drug-Induced Mania
within 2 weeks. In 12 cases, the manic episode lasted longer than 7 weeks. In 10 of these 12 cases, the causative agent had been present for a considerable period. It is also noteworthy that all of the 4 cases of mania induced by antituberculosis medications (isoniazid, I case; iproniazid, 3 cases) lasted longer than 7 weeks. In the patients with iproniazid-induced mania, the drug was continued for a prolonged period despite manic symptoms. In addition, iproniazid inhibits monoamine oxidase, an action that may induce more longstanding neurotransmitter changes. The characteristics of drug-induced mania are similar to those of other secondary manias. In a study of 17 patients who developed secondary mania after brain injury, Robinson et al. (1988) found that the most common manic symptoms were elation, hyperactivity, pressured speech and insomnia. These same symptoms were found to be most common in drug-induced mania (fig. 3). This indicates that the prevalence of specific symptoms is similar in manic episodes resulting from different neurological disorders. In addition, Robinson and colleagues found that patients with mania secondary to brain injury had a higher frequency of positive family histories of mood disorders than neurologically ill patients without mood disorders; they suggested that genetic loading may be present in at least a subgroup of patients with secondary mania. We found that patients with drug-induced mania have a higher frequency of family histories of mood disorders than those in the general population, an observation that supports the hypothesis that genetic factors play a role in development of secondary mania, regardless of specific aetiology. 3.5 Treatment Considerations Treatment of drug-induced mania was approached in several different ways. In a few cases where the manic episode was not known to be related to a drug, the causative drug was j udged medically essential, and where the patient did not present for treatment, there was no intervention for a prolonged period. Eventually, there was a therapeutic intervention
137
in nearly all cases. The most common treatment was reduction of drug dosage or discontinuation of the agent (67%of cases). Many patients were treated with more than one modality ; the most common combination was discontinuation of the causative drug and treatment with a neuroleptic agent. Lithium was used less frequently. Dose reduction , drug discontinuation and neuroleptic treatment were judged by the authors to be about equally effective, but lithium was less effective (table IV). This may indicate that drug-induced mania is biologically 'different' from a manic episode in a patient with idiopathic bipolar mood disorder and the neurophysiological response to lithium may be less predictable. In addition, several weeks may be required for a clinical response to lithium. We found that many patients were often effectively treated in shorter periods by discontinuing the causative drug or using neuroleptic agents. It is possible that lithium treatment is effective, but requires longer periods of treatment. These observations suggest a treatment strategy shown in the Clinical Management Guide (p. 139). When a manic episode is identified, an organic aetiology should be considered. If there is a potential causative agent (i.e. a drug that has been previously shown to induce mania and/or a close temporal relationship between drug initiation and onset of mania), the degree of medical necessity for the agent should be determined. If the agent is not necessary, it should be discontinued or the dose reduced, if clinical circumstances allow. Additional treatment depends on the clinical situation and severity of symptoms. If mania persists or symptoms are disabling, a neuroleptic drug can be added. A low dose of a high potency neuroleptic (e.g. haloperidol 0.5 to 2.0mg, fluphenazine 0.5 to 2.0mg, or trifluoperazine 2.0 to 5.0mg) is recommended as an initial choice; dosage adjustment should be made based on clinical response and development of side effects (extrapyramidal signs, sedation, hypotension). If there continues to be no improvement, additional agents such as lithium , carbamazepine, or a benzodiazepine may be useful, although there is less convincing evidence for their efficacy. The initiallithium carbonate dose should be 300mg three
Drug-Induced Mania
times daily with subsequent dose changes based on plasma concentration (therapeutic range: 0.8 to 1.4 mEqfL) and side effects. Clonazepam, a benzodiazepine that has been shown to be effective in the treatment of idiopathic manic episodes (Chouinard 1987, would be a logical choice except, perhaps, in cases of triazolobenzodiazepine-induced mania. However, the efficacy of clonazepam in drug-induced mania is unknown. 3.6 Rechallenge with the Causative Agent In several case reports a patient who had previously developed a drug-induced manic episode had a recurrence of manic symptoms when rechallenged with the causative agent. This observation supports the hypothesis that the agent caused the mania. In addition, cotreatment with lithium was shown to delay or prevent the recurrence of drug-induced mania in some cases. This indicates that lithium may have an important prophylactic role in patients requiring treatment with agents that previously induced a manic episode. 3.7 Physiology of Mood Regulation Review of the agents responsible for secondary mania may contribute to understanding the physiology of bipolar mood disorders and of normal mood regulation. Steroids, levodopa, other dopaminergic agents, iproniazid, sympathomimetic amines, triazolo benzodiazepines and hallucinogens are the agerits that most commonly induced mania (tables I and II). These medications and those in table I more rarely associated with mania represent a wide variety of classes of pharmacologicalagents. Most of the drugs are known to cross the blood-brain barrier and many are known to interact with neurotransmitters or postsynaptic receptors (Gilman et at. 1985). Levodopa and other dopaminergic agents have effects on dopamine metabolism or act directly as dopamine agonists. Mania was observed in patients receiving levodopa monotherapy and in those receiving levodopa combined with carbidopa. Thyroid hormone increases activation of the sympathetic nervous sys-
138
tern. Triazolobenzodiazepines can potentiate neuronal inhibition mediated by ,,-aminobutyric acid, which in turn regulates the firing of monoaminergic neurons. Unlike classic benzodiazepines, but similar to tricyclic antidepressants, triazolobenzodiazepines inhibit reserpine-induced up-regulation of ,8-adrenergic receptors (Papart et at. 1986). Amphetamines and methylphenidate are sympathomimetic amines. Ephedrine and phenylpropanolamine are also sympathomimetic amines but with less prominent actions as central nervous system stimulants. Phencyclidine can inhibit reuptake of dopamine, serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (norepinephrine) by synaptosomes. Procarbazine and iproniazid inhibit monoamine oxidase. Carbamazepine and cyclobenzaprine share pharmacological properties with tricyclic antidepressants. Metoclopramide antagonises dopamine in the CNS. Yohimbine can enhance neural release of noradrenaline. Corticosteroids are known to affect lipid and glucose metabolism and regulate sodium/potassium balance. Thus, the majority of these agents have in common an effect on monoaminergic systems and these agents may have a shared mechanism of action in producing manic symptoms. There remains considerable controversy in the literature regarding the role of tricyclic antidepressants and monoamine oxidase inhibitors in the induction of mania. Several authors (Bunney 1978; Jann et at. 1982; Nasrallah et al. 1982; Quitkin et al. 1981 ; Van Scheyen & Van Kammen 1979; Wehr & Goodwin 1979) have reported that a significant proportion of patients with either unipolar depression or bipolar mood disorder develop mania when treated with either class of drug. This has been reported to be more common in patients with bipolar mood disorders than in those with unipolar depressive syndromes (Prien et al. 1973). In a recent review, Wehr and Goodwin (1987) interpreted the evidence as suggestingthat antidepressants can precipitate mania in bipolar patients and can induce reversible rapid cycling between mania and depression in some patients. Antidepressant agents are known to have effects on noradrenaline and serotonin reuptake, as well as effects on histamine,
Drug-Induced M ania
139
Medical Toxicology
A
Medical ToxIcology and Adverse Drug Experience 4: 139. 1989
d"
Management of Drug-Induced Mania
Clinical Management Guide"
Manic episode diagnosed
1 Causative drug identified
If drug is medically necessary. reduce dosage, if possible
No causative agent identifiable
If drug is not medically necessary, discont inue
Add neuroleptic drug, if necessary
If no improvement, consider lithium or alternative agent
• Guide prepared by Drs Sultzer and Cummings
Exclude organic aetiology • stroke • metabolic change
Consider diagnosis of idiopathic bipolar disorder and treat accordingly
Drug-Induced Mania
cholinergic, and a-adrenergic receptors (Snyder & Peroutka 1984). It seems likely that their effect on monoaminergic systems mediates the development of mania. Noradrenaline and dopamine have been hypothesised to have a major role in idiopathic bipolar disorder and the switch to a manic episode. Several authors (Bunney et al. 1977; Pickar et al. 1984) have proposed that mania can result from changes in neurotransmitter availability relative to postsynaptic receptor sensitivity. Others (Dilsaver & Greden 1984, 1986) have proposed that a manic episode can result from dysfunction of mechanisms that maintain balance between opposing neurotransmitter systems. It is possible that the drugs that induce mania (tables I and V) may similarly create an imbalance between neurotransmitter availability and receptor sensitivity or an imbalance between different neurotransmitter systems. Most patients treated with the agents in tables I and V do not develop mania . There is possibly an underlying predisposition in some patients who have diminished neurophysiological control over neurotransmitter or receptor sensitivity regulation and a consequent vulnerability to mood instability. This is supported by the high proportion of patients who have a prior history, family history, or symptoms of mood disturbance at the time of treatment with the mania-inducing agent.
Acknowledgements This project was supported by the Veterans Administration. Norene Hiekel helped prepare the manuscript.
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Autho rs' addres s: Dr J.L. Cummings. Neurobehaviour Unit 69 1/ Bi ll. West Los Angeles VA Center. 11301 Wilsh ire Boulevard . Los Angeles. CA 90073 (U SA).
Third International Symposium on
Drug Analysis
Date: 16-19 May 1989 Venue: Antwerp, Belgium For further information. please contact: Dr G. Laekeman Congress Secretary Department of Pharmaceutical Sciences University of Antwerp Universiteitsplein I B-2610 Wilrijk BELGIUM
