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Adverse Reactions to Antidepressants in Consultation-Liaison Psychiatry Inpatients

Received August 15, 2001; revised January 15, 2002; accepted January 30, 2002. From the Consultation-Liaison Psychiatry Research Unit, Monash University Department of Psychological Medicine and Southern Health, Melbourne, Australia. Address for correspondence and reprints: Professor G. C. Smith, Monash University Department of Psychological Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail; graeme.smith{at}med.monash.edu.au

ABSTRACT

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In a practice-based, prospective study of 1,551 inpatients referred to a consultation-liaison psychiatry service and prescribed an antidepressant, an adverse drug reaction judged sufficient to warrant discontinuation of the drug was noted in 158 (10.2%). The factors associated were older age (P < 0.05); ICD-9 genitourinary disorder (mainly renal failure) (P < 0.01); DSM-IV "delirium, dementia, etc." (P < 0.05); length of stay (P < 0.001); number of visits (P < 0.001); and time spent on case (P < 0.05). Neither psychological functioning (GAF) nor physical functioning (Karnofsky ratings) were associated with a reaction, nor was multiple psychotropic drug prescription. Tricyclics were more likely than selective serotonin reuptake inhibitors/norepinephrine reuptake inhibitors to be associated with a reaction (P < 0.05). Consultation-liaison psychiatrists need to be well informed about pharmacodynamics and drug interactions in patients with physical/psychiatric comorbidity.

Key Words: Consultation-Liaison • Antidepressants

INTRODUCTION

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Adverse drug reactions (ADRs) pose a major challenge for modern medicine.^1–3 Lazarou et al., ⁴ in a systematic review of the literature, concluded that ADRs appear to be between the fourth and sixth leading cause of death in the United States and that they lead to an additional $4 billion in direct hospital costs per year. Serious ADRs, defined as those that require hospitalization, permanently disable, or result in death, had an incidence of 6.7% in their review of hospitalized patients. Bates¹ points out that this figure is much higher than is generally recognized, possibly because most hospitals have relied on a system of spontaneous reporting. In one study, spontaneous reporting was found to identify only 1 in 20 ADRs. ⁵ Bates¹ draws attention to the paucity of research that might lead to identification of risk factors for ADRs and to the development of preventive measures.

Trindade et al. ⁶ reviewed ADRs in major depression in psychiatric patients. They concluded that there was no difference between the classes of antidepressants in rates of drop-out due to ADR. However, they were able to establish significantly different profiles of ADRs between classes. Grohman et al. ⁷ reported on ADRs in 48,564 psychiatric inpatients using a multisite, prospective monitoring database. They found an incidence of 1.84% for severe ADR, with no significant difference between tricyclics and selective serotonin reuptake inhibitors (SSRIs). Their definition of severe was "fatal, life-threatening, disabling, requires hospitalization, or leads to prolongation of inpatient treatment." Barbui et al. ⁸ reviewed drug adherence in patients with depression and reported that there was a slightly lower dropout rate for SSRIs (27%) versus tricyclics/heterocyclics (30%). The main factor was side effects rather than inefficacy. These authors noted methodological problems and were cautious about their conclusions.

There are some data available about antidepressants and ADRs in the medically ill. Popkin et al. ⁹ reviewed 50 cases of major depression in hospitalized medically ill patients treated with tricyclic antidepressants. In 32%, the antidepressant was discontinued because of side effects judged to be unacceptable by the physicians or psychiatrists. Delirium accounted for half of such side effects. Subsequent randomized, controlled trials of antidepressants in physically ill patients have been subjected to systematic review by Gill and Hatcher. ¹⁰ They have included other classes of antidepressants as well. The reviewers used the dropout rate from trials as a proxy for ADR and concluded that there was no difference in the dropout rate between antidepressants (30%) and placebo (27%) or between tricyclics (32%) and SSRIs (33%). However, like other authors, Gill and Hatcher noted methodological problems and the small number of patients studied and warned that their conclusions were tentative. They were also cautious about generalizing results from trials to real practice situations.

Thus there is a need for further data from practice-based research. ¹¹ Reliable documentation of the interventions and observations made by experienced consultation-liaison (C-L) psychiatrists when they use antidepressants is an important part of the process of developing guidelines. ^12,13 Such research aims to establish meaningful questions for subsequent controlled trials in the process of refining treatment guidelines. It requires the use of a well-defined and supervised prospective clinical database. ¹⁴ Using such methodology, we have shown that, for depressed, physically ill inpatients, C-L psychiatrists prescribed antidepressants liberally, ranging from a rate of 69% for a confirmed diagnosis of major depression to 17% for a differential diagnosis of adjustment disorder. ¹⁵

The objective of the study reported here was to describe the prevalence and correlates of ADRs to antidepressants in inpatients referred to a C-L psychiatry service. We hypothesized that the prevalence of ADRs would be lower for SSRIs/selective norepinephrine reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs)/reversible inhibitors of monoamine oxidase (RIMAs) than for tricyclics and tetracyclics. We also hypothesized that demographic, diagnostic, treatment, and hospital process variables would be associated differentially with an ADR.

METHODS

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Data were collected prospectively over a 7-year period between 1990 and 1997 on 5,665 consecutive inpatients referred to the integrated adult C-L psychiatry services of two metropolitan general teaching hospitals affiliated with Monash University: Monash Medical Centre and Dandenong Hospital. Ten experienced C-L psychiatrists (including the first three authors) and their third- and fourth-year psychiatry trainees doing their 6-month C-L psychiatry rotation, working in a mixture of liaison and consultation mode, saw referrals from medical, surgical, and specialty units, including obstetrics and gynecology. The MICRO-CARES clinical database system was being used routinely in clinical work. ^14,16 Data from it were used for auditing and for research purposes. Supervisors were responsible for seeing that the data entered reflected accurately the clinical process, particularly the diagnoses; the results thus reflect the practice of experienced C-L psychiatrists. Training and quality assurance practices were used to ensure reliability and were supervised by one of the authors (G.C.S.). This involved the use of glossary definitions for all items including interventions and regular checks of adherence to protocol. ¹⁴

The data collected relevant to this study were 1) demographic data; 2) reasons for referral and relevant problems as stated by the consultee (referring doctor) and by the consultant (psychiatrist)—up to five reasons/problems per patient; 3) psychiatric diagnostic data—confirmed (meet criteria) DSM-IV Axis I and II terminal diagnoses for the admission episode (up to six diagnoses per patient), Axis V ratings (highest level for past 12 months), global psychiatric impairment (scored 1–4), and life events; 4) physical diagnostic data—ICD-9CM diagnoses for the admission episode (up to three diagnoses) and Karnofsky rating of physical functioning in past month and at termination; 5) interventions—drug and nondrug; and 6) hospital process—site, referring unit, length of stay in general hospital unit excluding any stay in a psychiatric unit, lag time between admission and referral, urgency of referral, time spent, number of visits, administrative action, and discharge location. DSM-III-R diagnoses were recoded to DSM-IV diagnoses where necessary by use of the guidelines provided in DSM-IV. ¹⁷

From the referred patients, we created a cohort of those prescribed an antidepressant (n = 1,551, 27% of referred patients), using the MICRO-CARES items for new and continued prescription. This cohort was divided into four mutually exclusive groups by use of the MICRO-CARES drug codes: SSRI/SNRI (fluoxetine, paroxetine, sertraline, and venlafaxine), 21%; tricyclic (amitriptyline, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, dothiepin, and clomipramine), 56%; tetracyclic (mianserin), 15%; MAOI/RIMA (isocarboxazid, phenelzine, tranylcypramine, and moclobemide), 8%.

An ADR was defined as a physical or psychological reaction sufficient to warrant discontinuation of the drug, consistent with the World Health Organization¹⁸ definition; "any noxious, unintended, and undesired effect of a drug which occurs at doses used in human prophylaxis, diagnosis, or therapy." The definition excludes therapeutic failure, intentional and accidental poisoning, drug abuse, errors in drug administration, and noncompliance. The MICRO-CARES items for somatic and psychological reactions were used for assignation to groups. Training and auditing procedures were used to help ensure that these items were scored only if the reaction was judged sufficient to warrant discontinuation of the suspected drug. ¹⁴

Statistical Analyses
Comparison between groups was performed by use of analysis of variance and the t-test for continuous variables¹⁹ and ^{2 19} and test of proportions²⁰ for categorical variables. Odds ratios for the comparison of drug groups were corrected for age, sex, psychiatric diagnoses, Axis V score, Initial Global Psychiatric Impairment score, physical diagnosis, and initial Karnofsky score, as defined above.

RESULTS

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A total of 1,511 (27%) were prescribed an antidepressant drug. Mean age was 59 SD 19 years, 64% were female, 22% lived alone, and they were almost exclusively white (95%), which reflects the populations served by the hospitals. Seventy-eight percent had had a serious physical illness in the 12 months prior to the current episode, and 36% had had a psychiatric illness. Referral for depression was the most common reason given (67%), and 10% were referred for anxiety. Of relevance to the ADRs, 17% were referred for resolution of a diagnostic problem, 16% for psychotropic medication assessment, and 8% for organic brain syndrome. The prevalences of the main confirmed DSM-IV Axis I diagnoses were mood disorder, 33%; delirium, etc., 10%; adjustment disorder, 8%; substance-related disorder, 6%; and anxiety disorder, 5%. Mood disorder was considered as a rule-out diagnosis in a further 52%, and the other diagnoses had similar high rule-out prevalences. The mean Axis V Global Assessment of Functioning (GAF) rating (highest in the past 12 months) was 65 SD 14. The mean initial and terminal Global Psychiatric Impairment scores were 2.20 SD 0.67 and 2.04 SD 0.70, respectively. On Axis III, cardiovascular disorders (which include stroke) (26%), neoplasms (18%), and nervous system disorders (13%) were the most frequent diagnoses. The mean initial Karnofsky score (highest level of function in the past month prior to hospitalization) was 59 SD 20, and the mean terminal Karnofsky score was 57 SD 22. The psychiatric staff spent a mean of 3.7 hours, over a mean of 4.0 visits, for a mean length of stay of 20.0 days.

One hundred and fifty-eight (10.2%) of those patients prescribed an antidepressant were noted to have had an ADR. Variables which distinguish the "adverse reaction" and "no adverse reaction" groups are shown in Table 1. Significant differences were observed for only one of the demographic variables, age; those with ADRs were older. Those with ADRs were more likely to have been referred for organic brain syndrome, psychotropic medication assessment or agitation, or transfer to psychiatry. Axis III diagnoses of genitourinary disorder (mainly end-stage renal failure) were more likely, and of neoplasm less likely, in those with an ADR. Initial and terminal Karnofsky scores were not significantly different. Those with ADRs were more likely to have an Axis I diagnosis of delirium, dementia and other cognitive disorders and less likely to have a diagnosis of adjustment disorder. Axis V and initial and terminal Global Psychiatric Impairment scores were not significantly different. There were no significant differences in life events. For those patients with an ADR, the psychiatrists were more likely to recommend more laboratory investigations, more behavioral control, and a delay in discharge date. ADRs were associated with increased number of visits and time spent by C-L psychiatrists and longer length of stay but were not differentiated on any of the other hospital process variables. There were no differences in concomitant psychotropic drug prescription.

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TABLE 1.

Comparison of Drug Groups
The prevalence/odds ratios of ADRs within drug groups were SSRI/SNRIs 7.3%/4.8, tricyclics 11.7%/7.7, tetracyclics 8.9%/6.1, and MAOIs/RIMAs 9.4%/7.1. Tricyclics were significantly more likely to be associated with an ADR than the other groups (test of proportions; P < 0.014, Z = 2.19). After correcting for demographic and diagnostic variables, odds ratios were SSRI/SNRIs, 3.6; tricyclics, 5.5; tetracyclics, 4.7; and MAOIs/RIMAs, 4.2.

DISCUSSION

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The definition of ADR used in this study complied with that of the World Health Organization (1966) in excluding cases of deliberate or accidental drug overdose. As well as physical reactions, it includes psychological reactions such as delirium, anxiety, depression, and hallucinations, as is customary for reports on psychotropic drugs. ^7,21 The threshold of seriousness used was the judgment by the physician or psychiatrist that the ADR warranted discontinuation. This required and received weekly auditing. ¹⁴ One of the problems in interpreting the literature on ADRs is the lack of consistency in definition, and often the lack of clarity. Any plans for prospective monitoring will need to deal with this problem.

Prevalence
The incidence of ADRs to antidepressants in this population of adult medical, surgical, and obstetric/gynecological patients referred to C-L psychiatry was 10.2%. This compares with the figure of 32% found by Popkin et al. ⁹ for tricyclics in a similar population. In the current study, some 11.7% of those prescribed tricyclics had an ADR. This was significantly greater than for SSRIs/SNRIs; however, the incidence for the other antidepressants groups was high, ranging from 7.3% to 9.4%. Correction for demographic, diagnostic, and severity variables lowered the odds ratios; however, tricyclics still had the highest likelihood of ADR and SSRIs/SNRIs the lowest. This differential finding is in contrast with Gill and Hatcher's¹⁰ systematic review of dropout rate in physically ill patients but is consistent with the systematic review of Barbui et al. ⁸ for patients in general with depression. Both of these reviews used dropout rates from trials as their measure. It is not surprising that the rates reported, which were 30% for both Barbui et al. ⁸ and Gill and Hatcher, ¹⁰ were much higher than those reported here, because those rates would include dropouts for reasons other than ADRs. The incidence in the present study is much higher than the figure of 1.84% reported for psychiatric patients in general. ⁷ It is higher than that for ADRs for all drugs in all hospitalized medical patients (6.7%). ⁴

Characteristics of the Adverse Reaction Cohort
The adverse reaction cohort was older than the no adverse reaction one. This is consistent with opinions expressed in the literature that ADRs are more frequent in the elderly. However, there are few data to support that view. In Lazarou et al.'s⁴ review of ADRs in inpatients in general, age accounted for only a small percentage of the variance. Mittman et al. ²² performed a systematic review of 16 randomized trials of antidepressants in patients age 60 years. They reported dropout rates of 11%–27% for the classes of antidepressants in the current study. This is similar to the rates reported by Gill and Hatcher¹⁰ for the medically ill of all ages. The ADR incidence found by Mittmann et al. ²² was much higher than the dropout rate, but they did not define ADR, citing as a reason the fact that the majority of studies included had no severity of ADR measure.

The adverse reaction cohort did not differ from the no adverse reaction cohort on any of the measures of illness severity (serious physical illness during past 12 months, Karnofsky score for past month, and terminal Karnofsky score). Lazarou et al. ⁴ were not able to measure illness severity or even the type of medical illness in their meta-analysis of ADRs in general; this is an indication of how difficult it would be to explore further these factors in the depressed physically ill.

Patients with genitourinary disorders (mainly those with renal failure) were more likely to have had an ADR. Such patients often have multiple medical problems—many have diabetes mellitus and its complications—and are on multiple medications. It is often difficult to distinguish depression from "exhaustion" and "demoralization." ²³ A trial of antidepressants in such cases may exacerbate a covert delirium or induce a serotonergic or other type of acute brain syndrome. It is not clear why having a neoplasm made it less likely that an ADR would occur. We noted that the patients in the adverse reaction cohort were referred more often for suspected "organic brain syndrome" and more often diagnosed by the psychiatrists as having delirium, dementia or other cognitive disorders. However, it was not possible to tell whether this diagnosis preceded or followed the introduction of antidepressants. That will be explored in a subsequent study.

There were no differences in concomitant psychotropic drug prescription. Although there is much clinical evidence of ADRs occurring because of the interaction of such drugs, ²⁴ the systematic reviews have not addressed this. A great deal of attention is paid to the possibility of psychotropic and other drug interactions, particularly those involving the cytochrome P450 system, in the American Psychiatric Association guideline²⁴ and other literature. ²⁵ Trindade et al. ⁶ and Spigset, ²¹ using data from a systematic review and a prospective database respectively, give useful information about the types of ADRs found in relation to different antidepressants in patients in general.

Referral for agitation, psychotropic medication assessment, and transfer to psychiatry were more frequent in the adverse reaction cohort. This conveys a good sense of what it is that determines whether patients with an ADR are referred to psychiatry. It seems that physicians tend to refer patients whose behavior is most disturbing and that they seem to want these patients taken off their hands.

The drug reaction cohort had more visits and more time spent on the consultation. This serves to emphasize the importance of ADRs in C-L psychiatry practice in terms of skills, training and service organization. The adverse reaction cohort also had a longer length of stay, in keeping with the recommendation that discharge be delayed. Because there was no evidence that they were more seriously ill before or after their admission, it is reasonable to conclude that the ADR was associated with a need for more intensive care for a period of time, which resulted in a prolonged stay. Increased length of stay is a frequently reported correlate of ADR. ^4,26 However, this is confounded by the fact that it is accompanied by increased exposure to drugs; the extent to which ADRs account for prolonged stay is therefore difficult to assess.

Limitations of the Study
This was a practice-based study. It did not use structured interviews but rather attempted to capture the normal clinical diagnostic and management practice of a group of experienced C-L psychiatrists. The validity of this approach is well supported¹¹ and complements data from other methods, the validity of which has a different quality. The reliability of the data was enhanced by the use of a standardized data collection strategy, the use of a manual, the training procedures, and random checks of the patient records. Further prospective studies will be required to ascertain the temporal, and therefore causal, relationship between events: ADR, delirium, and length of stay. Caution should be used in generalizing the findings to nonreferred populations because of the referral bias and because this was an almost exclusively white population, albeit one that reflects the population of the State of Victoria. Future studies should collect data on the type and severity of ADRs, the probability of the antidepressant causing the ADR, the dosage and titration of antidepressants, and on concomitant use of nonpsychotropic drugs.

CONCLUSION

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There is a need for the development of a uniform, prospective, well-defined monitoring program to enhance awareness and promote research into the costly and dangerous phenomenon of ADRs in depressed medically ill inpatients and for drugs and patients in general. This practice-based research study has shown the high rate of ADRs likely to be found in such populations and some correlates of an ADR. C-L psychiatrists need to be well informed about pharmacodynamics and drug interactions in patients with physical/psychiatric comorbidity. Further studies are needed to help identify risk factors and facilitate the development of protocols to minimize such reactions.

ACKNOWLEDGMENTS

 
We are grateful to the psychiatry trainees and their consultant supervisors who faithfully contributed to the database and participated in the quality control training and auditing, and to Dean McKenzie for statistical advice. The work was supported by Glaxo Smith Kline Pty Ltd. and the Buckland Foundation.

REFERENCES

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