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* Antidepressants
Psychosomatics 43:221-227, June 2002
© 2002 The Academy of Psychosomatic Medicine

Consultation-Liaison Psychiatrists' Use of Antidepressants in the Physically Ill

Graeme C. Smith, M.B.B.S., M.D., F.R.A.N.Z.C.P., M.P.M., F.A.P.M., David M. Clarke, M.B.B.S., Ph.D., F.R.A.N.Z.C.P., F.R.A.C.G.P., Dennis Handrinos, M.B.B.S., M.P.M., F.R.A.N.Z.C.P., and Dean P. McKenzie, B.A. (Hons.), F.S.S.

Received July 25, 2001; revised January 26, 2002; accepted February 13, 2002. From the Consultation-Liaison Psychiatry Research Unit, Department of Psychological Medicine, Monash University and Southern Health, Melbourne, Australia. Address for correspondence and reprints: Professor G. C. Smith, Monash University Department of Psychological Medicine, 246 Clayton Rd, Clayton VIC 3168, Australia. E-mail; graeme.smith{at}med.monash.edu.au


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
In a practice-based, prospective study of 917 inpatients referred to a consultation-liaison psychiatry service and diagnosed as depressed, 41% were prescribed an antidepressant: 40% tricyclics, 35% selective serotonin reuptake inhibitors (SSRIs), 15% monoamine oxidase inhibitors (MAOIs)/reversible inhibitors of monoamine (RIMAs) (mainly moclobemide), and 11% tetracyclics (mianserin). Factors associated with choice of antidepressant type included age, referral for pain, length and seriousness of physical illness, type of physical illness, and concurrent antipsychotics (P < 0.01). Tetracyclics and MAOI/RIMAs were used significantly more often than tricyclics in the more severely physically ill and the elderly. The percentage of patients prescribed an antidepressant increased significantly over time, which is accounted for by the greater use of SSRIs across all age groups and degrees of seriousness of illness. There is a paucity of randomized controlled trials on which to base practice guidelines. Practice-based research such as this helps inform those guidelines.

Key Words: Antidepressants • Consultation-Liaison

  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Decisions about the use of antidepressants in the management of depression in patients with physical illness poses a considerable challenge for consultation-liaison (C-L) psychiatrists. This form of physical/psychiatric comorbidity is common1–9 and carries increased mortality and morbidity, even for subsyndromal depressive and anxiety symptoms.5–7,10–15 The paucity of treatment trials for this condition is reflected in the fact that the American Psychiatric Association (APA)16 and the Agency for Health Care Policy and Research17 guidelines for the treatment of depression deal only in a limited way with physical/psychiatric comorbidity.

The difficulties of defining and measuring depression and anxiety in the presence of physical illness,4,18–20 and of conducting trials of psychotropic medication in this population21 all contribute to the lack of data. Most controlled trials of the treatment of depression have been performed on patients with major depression, without physical comorbidity, and in psychiatric settings.13 Although there have been a number of reported clinical trials of antidepressants in the medically ill which have helped shape a consensus view,21–25 Gill and Hatcher26 were able to identify only 18 randomized controlled trials, involving only 838 patients, that met criteria for a Cochrane Collaboration systematic review. These included studies on cancer,27 diabetes,28 HIV/AIDS,29–30 cardiovascular disease,31 pulmonary disease,32 renal disease,33 and stroke.34 Gill and Hatcher noted methodological problems in many of the trials that they included in the review, so their conclusions must be regarded as tentative. There were insufficient data for them to be able to reach conclusions about the efficacy and acceptability of different types of antidepressants in the physically ill and about the indications for specific types of antidepressants in specific physical illnesses. The exception to that was the finding that nortriptyline destabilizes hypoglycemic control.

Guidelines for the management of depression and anxiety in the physically ill thus depend to a large extent on consensus opinion.35–38 Practice-based research that uses a well-defined and supervised prospective clinical database is indicated to establish meaningful questions for subsequent controlled trials in the process of refining treatment guidelines.12,39–40 Using such methodology,41 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.42

In the current study, we explore this further, using a cohort of patients from the earlier study. The aims were to determine 1) the demographic, referral, diagnostic, and cotreatment correlates of the C-L psychiatrists' choice of antidepressant type in patients with confirmed DSM-IV mood disorder, anxiety disorder, or adjustment disorder with a mood component and 2) the change in proportion of patients treated with antidepressants over the time period studied.


  METHODS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Data were collected prospectively over a 4-year period between 1993 and 1997 on 3,307 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.41,43 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.41

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, 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 in referral, urgency of referral, time spent and number of visits, administrative action, and discharge location. DSM-III-R diagnoses were recoded to DSM-IV diagnoses by use of the guidelines provided in DSM-IV Appendix D.44

The cohort studied was the 373 (41%) of 917 referred patients given confirmed DSM-IV diagnoses of mood disorder (including bipolar disorder), anxiety disorder, or adjustment disorder with depressed mood, anxiety, or mixed depression and anxiety. This cohort was further subdivided on the basis of the type of antidepressant prescribed: 1) tricyclic; 2) selective serotonin reuptake inhibitor (SSRI)—fluoxetine, paroxetine, and sertraline; 3) monoamine oxidase uptake inhibitor (MAOI) or reversible inhibitor of monoamine oxidase (RIMA), 86% of which were the RIMA moclobemide; or 4) tetracyclic, all of which were mianserin.

Statistical Analyses
Comparison between groups was performed by use of ANOVA and t-tests for continuous variables and {chi}2 for categorical variables, by use of the SPSS/PC+ package.45 The magnitude of effects was assessed by use of the {eta}246 and {phi}2 or V247 coefficients for continuous and categorical variables respectively. The larger the value of {eta}2 and {phi}2 or V2, the greater the amount of variance in the dependent variable is accounted for by a particular independent variable. In the advent of a significant (P < 0.01) ANOVA or {chi}2 test, KnowledgeSEEKER48 was used to form homogenous clusters and for exploratory decision tree analysis.49 Thus, in Table 4 below, the significance figures refer to the difference between clusters of the four subgroups, adjusted for the number of comparisons performed.


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TABLE 4.




  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Demographic data for the cohort of 373 patients prescribed an antidepressant were as follows: mean age 57.6 SD 19.8, 65% female, 52% married, 95% white, 15% employed, 14% professionals, and 22% living alone. For those not receiving an antidepressant, data were mean age 47.9 SD 20.0, 63% female, 49% married, 91% white, 20% employed, 16% professionals, and 19% living alone. There were significant differences in age (t = 7.40, P < 0.001) and employment status ({chi}2 = 7.08, P < 0.01). Forty percent were prescribed a tricyclic, 35% an SSRI, 15% a MAOI/RIMA, and 11% a tetracyclic (mianserin) (Table 1). There was a significant difference ({chi}2 = 161.14, P < 0.001) between diagnostic groups in the likelihood of being prescribed an antidepressant, mood disorders 61%, anxiety disorders 37%, and adjustment disorders 17% (Table 2). However, there was no significant difference in drug versus diagnostic group.


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TABLE 1.




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TABLE 2.



The changing pattern of choice of antidepressant over time is shown in Table 3. There was a significant increase over time in the proportion of patients recommended an antidepressant ({chi}2 = 11.22, P < 0.01). This was not related to age or seriousness of illness; neither mean age nor percentage of those age >65 years prescribed antidepressants changed, nor did their initial Karnofsky score. The increase in recommendations for use of an antidepressant was accounted for by an increase in those for SSRIs across all age groups and degrees of seriousness of illness ({chi}2 = 66.04, P < 0.001). There was a decrease in the recommendations for use of a tricyclic.


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TABLE 3.



Correlates of the choice of antidepressants are shown in Table 4. Antidepressant groups were differentiated on 1 of 9 demographic variables, 2 of 35 referral variables, type of referring unit, 2 of 8 life events variables, and 3 of the physical diagnosis groups. Measures of severity of physical and psychiatric illness were also differentiating factors. No investigative recommendations, nondrug interventions, or hospital process variables differentiated the groups. No combination of variables examined by use of KnowledgeSEEKER decision-tree analysis gave a classification accuracy that was >5% greater than that of a single variable.


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The C-L psychiatrists prescribed antidepressants for 41% of patients with confirmed DSM-IV mood disorder, anxiety disorder, or adjustment disorder with depressed or anxious mood. For mood disorder, the rate of prescription was 60%, similar to that in our previous study,42 where the factors determining whether or not a physically ill patient diagnosed as having major depression was prescribed an antidepressant were explored. As in that study, we found that older age was a correlate of prescription. Despite the problems involved and without adequate practice guidelines, in both the current and previous studies, the psychiatrists were using antidepressants in physically ill inpatients at a rate similar to that used in the wider population of patients with mood and anxiety disorders.50,51 This is consistent with the limited amount of evidence now available; the systematic review of all placebo-controlled randomized controlled trials of antidepressants for depression in the physically ill performed by Gill and Hatcher,26 using Cochrane Collaboration methodology, concluded that there was evidence that use of antidepressants, significantly more frequently than either placebo or no treatment, is associated with improvement in symptoms of depression in patients with a wide range of physical diseases. They also concluded that antidepressants seemed reasonably acceptable to such patients, as judged by the low drop-out rate from trials.

In this study, the percentage of patients treated with an antidepressant increased significantly over time. Our finding that this was accounted for by the greater use of SSRIs across all age groups and degree of seriousness of illness is in keeping with the findings in a wider spectrum of patients with depression.50,51

These C-L psychiatrists exercised a choice of type of antidepressant in relation to a number of seemingly relevant factors. These included age; seriousness of psychiatric illness; length, seriousness, and type of physical illness; referral for pain; pregnancy; and concurrent prescription of antipsychotics. Psychiatric comorbidity was not correlated with choice of antidepressant.

Patients prescribed tricyclics were likely to be younger than those prescribed SSRIs and MAOI/RIMAs, and these in turn were younger than those prescribed tetracyclics. Data relevant to age as a determinant of choice of antidepressants were reviewed by Mittman et al.52 in a meta-analysis of studies on the efficacy, safety, and tolerability of antidepressants in late-life depression; they found no significant differences between the four classes of antidepressant. The APA guideline16 states that the considerations that go into choosing among psychotherapy, pharmacotherapy, and electroconvulsive therapy for the elderly are essentially the same as for younger patients. The guideline states that fluoxetine, sertraline, doxepin, and the tricyclics desipramine and nortriptyline are frequently chosen rather than dothiepin and the tricyclics amitriptyline and imipramine. Moclobemide has been shown to be safe, well-tolerated and effective in the treatment of depression in the elderly.53

For those patients with higher scores for seriousness of physical illness, tetracyclics were preferred over SSRIs and MAOI/RIMAs, and these in turn were preferred over tricyclics. However, Gill and Hatcher,26 in their systematic review of drug trials in the physically ill, found no difference between tricyclics and SSRIs in efficacy or dropout rate. This reflects the findings of a systematic review of the relative efficacy of those classes of antidepressants in depression in general.54 However, Barbui et al.55 concluded that there was a slightly lower dropout rate for SSRIs versus tricyclics/heterocyclics in a similar study. The main factor was side effects rather than inefficacy. Trindade et al.56 reached a similar conclusion but established significantly different profiles of adverse effects that might help explain the choice of antidepressant type.

In the current study, MAOI/RIMAs and tetracyclics were preferred over SSRIs and tricyclics in turn in circulatory and respiratory disorders. The APA guideline and other reviews35–38 have urged that tricyclics should be used with care in patients with some forms of ischemic heart disease, but this is based on case reports and theoretical considerations. The case for care in the use of tricyclics and irreversible MAOI/RIMAs in patients on antihypertensive agents seems stronger. The APA guideline warns of the danger of interactions of irreversible MAOI/RIMAs and sympathomimetic bronchodilators; other antidepressants do not appear to pose such a problem.

Tricyclics were the preferred antidepressant during pregnancy. The APA guideline reviews the risks associated with the use of antidepressants in pregnancy and recommends that if an antidepressant is required, it should be either a tricyclic or an SSRI that has been studied in pregnant women. The data on which such recommendations are made are case-based.

Tricyclics were preferred in patients referred for pain, in keeping with guidelines.57–59 Tricyclics were preferred in those receiving antipsychotic drugs concurrently. This may reflect the perception that tricyclics are more effective in severe depression.16 Other particular physical disorders addressed in the APA guideline are glaucoma, epilepsy, and Parkinson's disease. Only for glaucoma is there a differential recommendation. The only physical illness-specific finding reported by Gill and Hatcher26 in their systematic review was that nortriptyline worsened hypoglycemic control. However, in this study, endocrine disorder was not a significant variable.

Limitations of the Study
The limitations of this study include the fact that, although considerable effort was put into the training and ongoing surveillance of staff in the use of the database and glossary of definitions, it remains a study of clinical practice. Application of DSM criteria was checked, but reliability and validity ultimately depend on the clinician's practice. We have argued elsewhere for the proposition that data collected in the course of clinical work have a different type of validity that complements that produced by use of structured interviews.41 Although compliance with recommendations was not measured in the current study, it was determined to be 86% in a study conducted in the same setting just prior to this study.60 The changing use of antidepressants over the time period studied limits the significance of the other findings. The severity measures used were not specific for mood and anxiety disorders.

The extent to which the results have been influenced by the referral patterns of the hospitals involved can only be assessed by repeating the study in other centers and controlling for this variable. We established that there were no significant differences between sites. A larger study would be needed to control for the linking of psychiatrist with referring service. Measurement of outcome would require a longer timeframe than that which applies to a study of inpatients in a general hospital.


  CONCLUSIONS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Tetracyclics (mianserin) and MAOI/RIMAs (mainly moclobemide) were used significantly more often than tricyclics in the more severely physically ill and the elderly. Increasing use of SSRIs was associated with a significant increase in the percentage of patients with disorders of mood and anxiety who were being treated with an antidepressant. SSRIs became the preferred antidepressant overall, including for the elderly and those with more serious and chronic physical illness. Evidence-based guidelines for the management of patients with physical/psychiatric comorbidity and somatization are required and are in early stages of development. Practice-based research that documents what C-L psychiatrists do when they make various diagnoses is helping to direct such research but does not replace it.


  ACKNOWLEDGMENTS

 
We are grateful to the psychiatry trainees and consultants who faithfully contributed to the database, and to Tom Trauer for statistical advice. The work was supported by Glaxo Smith Kline Australia and the Buckland Foundation.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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