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Lithium augmentation in geriatric depression
Journal Elsevier
of Affective Disorders, 20 (1990) 217-223
217
JAD 00760
Lithium augmentation
in geriatric depression
H.W.J. van Marwijk ‘, F.M. Bekker ‘3*, W.A. Nolen 2, P.A.F. Jansen I, J.F. van Nieuwkerk 1 and W.C.J. Hop 3 ’ Geriatric Training Department and ’ Psychiatric Training Department, Bloemendaal Psychiatnc Hospital, The Hague and’ Department
of Epidemiologv
and Biostatistics,
Erasmus
University, Rotterdam,
The Netherlands
(Received 21 May 1990) (Revision received 11 July 1990) (Accepted 6 August 1990)
Summary In the geriatric department of a Dutch psychiatric hospital the charts of 51 patients treated with lithium in addition to cyclic antidepressants were reviewed. A response was seen in 33 patients (65%). For patients with recurrent depressive episodes, a statistical trend was found towards more responders with more complete responses, compared to patients with first depressive episodes. During lithium augmentation, 10 patients suffered from severe adverse effects 12 times. In spite of adverse effects, with expert monitoring lithium augmentation can, in our opinion, be of value in the treatment of older depressed patients.
Key words: Elderly;
Depression;
Lithium
augmentation
Introduction In the elderly, clinical depression is a frequently encountered problem (Jefferson, 1983; Plotkin et al., 1987). For major depression in elderly persons living in the community, international studies show prevalence rates of l-13%, depending on definitions of disease, measurement instruments and populations under study (Kay et
Address for correspondence: H.W.J. Department of General Practice, Leiden 2088, 2301 CB Leiden, The Netherlands.
van Marwijk, M.D., University, P.O. Box
* Present address: De Wellen Psychiatric Hospital, 9028, 7300 EL Apeldoorn, The Netherlands. 0165-0327/90/$03.50
P.O. Box
0 1990 Elsevier Science Publishers
al., 1985; Copeland et al., 1987a,b; Blazer, 1989). Although there is no agreement on the exact prevalence of major depression in the elderly in the general population, depression is considered to be the most frequently occurring mental disorder in persons between 65 and 80 years old (Health Council of The Netherlands, 1988). Cyclic antidepressants, including both tricyclic antidepressants and non-tricyclic compounds (mono-, bi- and tetracyclics), are of great importance in the treatment of geriatric depression (Plotkin et al., 1987; Baldwin, 1988). Two factors, however, restrict the use of these drugs in this age group: firstly the occurrence of severe side-effects that counteract an often fragile physical balance and secondly a primary refractoriness to adequate
B.V. (Biomedical
Division)
218
treatment with cyclic antidepressants (Murphy, 1983; Baldwin and Jolley, 1986). For those patients who do not respond to treatment with antidepressants, because of side-effects or because of non-responsiveness, there is a need for an alternative. In a number of countries electroconvulsive therapy (ECT) is considered to be such an alternative (Cowen, 1988; Blazer. 1989). In The Netherlands, discussion about the place of ECT in treatment schedules for elderly depressives has been opened only recently (Van Marwijk et al., 1988). As yet there is no general acceptance of ECT in Dutch public opinion and only a few patients are treated with it each year. (In 1986 a total number of 71 patients, 35 of whom were 60 years and older. Chief Inspectorate on Mental Health, personal communication. 1987.) Because of potential (postural) hypotensive side-effects of monoamine oxidase (MAO) inhibitors in the elderly, their therapeutic usefulness is also restricted. The need for an alternative to cyclic antidepressants remains. The addition of lithium to antidepressants. i.e.. ‘lithium addition’ or ‘lithium augmentation’. is advocated in younger depressed adults not responding to cyclic antidepressants therapy. Studies on lithium augmentation have been discussed in a recent review by Katona (1988). A number of hypotheses have been formulated to elucidate neurotransmitter mechanisms responsible for the efficacy of lithium as an antidepressant in lithium augmentation. There is some evidence that lithium-induced enhancement of serotonergic neuis involved rotransmission (Rasmussen and Keitner, 1987; Katona, 1988). Surveying the literature on the use of lithium augmentation of previous cyclic antidepressants in geriatric patients. only a few reports were found, each describing only a small number of patients. adding up to 16 cases. Different diagnostic criteria were used in each study (Kushnir. 1986; De Hooge, 1988; Finch and Katona, 1989). As so little is known about the treatment of geriatric patients with lithium augmentation, we performed a retrospective study on the effects of the use of lithium in addition to prior (cyclic) antidepressant therapy in a group of elderly patients.
Patients and methods All patients studied had been admitted to the geriatric department of Bloemendaal Psychiatric Hospital. Together with three other psychiatric hospitals in The Hague, this hospital serves a catchment area of about 900,000 people. 180,000 of whom are elderly (20%). There are 300-350 admissions to the geriatric department each year. in approximately 40% of the cases for depression. Because most patients are severely depressed, biological therapies form the mainstay of treatment. The hospital serves as a regional center for ECT. Non-pharmacological treatment is based on a number of psycho-. socio- and physiotherapeutic lines designed to activate patients as much as possible. Musical. creative and other activity therapies are offered, as well as a resocialization program. psychomotor therapy and swimming facilities. Although psychotherapy is not applied in a systematic way, supportive psychotherapy is offered to all patients and in many cases also to their relatives. All patients who had not responded to a previous regimen of cyclic antidepressants and who had started with lithium augmentation between March 1985 and July 1987 were included in the study. As a rule. lithium augmentation of previous cyclic antidepressant therapy was the primary choice for secondary treatment. Patients were reviewed who had been treated clinically with lithium augmentation for depression. Fifty-one inpatients were selected. Patients were identified by checking laboratory lists of serum lithium levels, which were assessed routinely in all patients receiving lithium at least once every 2 weeks. Medical and nursing charts of these patients were reviewed independently by two authors (F.M.B. and H.W.J.v.M.). Based on these data a retrospective DSM-Ill (axis I) diagnosis was made by consensus.
The sample consisted of 51 inpatients (46 women, five men), aged 64&X8 years (mean age 77 years). According to DSM-III criteria a major depression was diagnosed in 41 patients. A bipolar disorder. depressed, was diagnosed in nine patients and an atypical depression in one patient. For 16 patients it was the first depressive episode. for eight patients the second episode. Twenty-
219
seven patients had experienced more than one previous depressive episode. Melancholia was present in 46 patients, psychotic features in 29 patients. Adequacy and efficacy of previous antidepressant treatment were assessed. In line with recent recommendations in the literature (Peabody et al., 1986; Blazer, 1989) we defined previous treatment with cyclic antidepressants as adequate when at least 75 mg of imipramine or an equivalent dosage of another antidepressant was used during a period of at least 4 weeks. According to this definition, 47 patients had previously received adequate cyclic antidepressant therapy. Lithium carbonate was added to the following antidepressants: amitriptyline in 39 cases, maprotiline in five cases, mianserin in three cases, imipramine in two cases and dothiepin and clomipramine each in one case (51 patients). The mean daily dose of cyclic antidepressants was 80 mg (range: 30-150). Usually patients starting lithium therapy were given 200 mg (half a tablet) of lithium carbonate sustained release (Priadel@) nocte. After 2 or 3 days, serum lithium levels were assessed 12 h after the last intake of lithium medication and the dosages were adjusted. Laboratory monitoring of serum lithium levels took place at least once a week in the first 2-3 weeks and after that at least once every 2 weeks. Final dosages ranged from 100 to 1000 mg once a day (mean dose 400 mg). Steady-state lithium plasma levels were kept between 0.40 and 0.80 mmol/l, in accord with Hardy et al. (1987). Steady-state plasma concentrations of lithium were plotted versus time in weeks, to evaluate a possible relationship between serum lithium levels and side-effects. Improvement was measured by comparing global clinical impressions, differentiating a complete response to treatment from a partial response or no response, following clinical practice. Patients were classified as having a complete response when pretreatment (DSM-III) symptoms of major depression had completely vanished. Treatment response was considered partial if symptoms had not completely disappeared. Variables with a possible predictive value towards outcome of lithium augmentation therapy were evaluated: psychotic features and melancho-
lia. Only a limited number of sociodemographic parameters were studied as all patients were treated on an inpatient basis. An inventory was made of severe side-effects of lithium augmentation. As patients with a history of possible organic brain damage seem more susceptible to toxic effects of lithium (Tyrer and Shopsin, 19X0), all records of the patients in the sample were reviewed retrospectively for past symptoms and signs of cerebrovascular disturbance: transient ischemic attacks or stroke. Non-psychotropic medication was not evaluated. Co-medication is the rule rather than the exception in elderly patients (Jefferson, 1983). Drugs that possibly interact with lithium are mainly diuretics and non-steroid anti-inflammatory drugs. These drugs are frequently used in this age group (Johnston et al., 1987). Because of frequent serum lithium level monitoring, interactions of non-psychotropic medication influencing serum lithium levels were registered early. With respect to cyclic antidepressants clinically important interactions of this kind were not to be expected (Johnston et al., 1987).
Results Thirty-three patients (65%) treated with lithium augmentation responded completely or partially to therapy: in 18 patients (35%) a complete response was found and 15 patients (30%) showed a partial response (Table 1). Of patients with a unipolar depression, 26 of 42 (62%) responded to therapy versus seven out of nine patients (78%) with a bipolar depression. A statistical trend (two-tailed P = 0.07) was apparent for patients with previous episodes of depressive disorder and response, using Mann-Whitney’s test. Compared to patients with a first depressive episode, more patients with a recurrent depressive episode showed more complete responses. Statistical analysis showed no other significant difference between groups. In Table 2 data on the number of patients receiving predominantly noradrenaline (NA), predominantly serotonin (5HT) or mixed reuptake inhibiting antidepressants are presented versus response (Green and Nutt, 1983).
220 TABLE
1
EFFECTS
OF LITHIUM
AUGMENTATION
ESM-III diagnosis
ACCORDING
No response
Major depressive disorder. first episode recurrent Bipolar disorder, depressed Atypical depression Total
8 (50%) 8 (32%) 2 (22%)
5 (31%) 8 (32%) 2 (22%)
18 (35%)
15 (29%)
2
EFFECTS ING TO NUMBER
OF LITHIUM DIFFERENT OF PATlENTS
AUGMENTATION ACC’ORDCYCLIC ANTIDEPRESSANTS,
_
Amitryptiline A Maprotiline h Mianserin ‘ Imipramine “ Clomipramine ’ Dothiepin’ Total
No response
Partial response
Complete response
Total
13
12 3
2
14 2 1
1
1
39 5 3 2 1
1 1 18
1 15
18
DIAGNOSIS.
Partial response
For diagnostic category (including the unipolar/ bipolar distinction), age, sex, psychotic features, melancholia and cerebrovascular disturbance no statistically significant relationships with response were discerned. Due to the retrospective nature of this study, the latency of response, in other studies between 1 and 28 days (Katona, 1988), could not be ascertained. During lithium augmentation severe adverse effects were noted 12 times in 10 patients (Table 2). Six patients (11%) presented symptoms and signs of lithium neurotoxicity, according to criteria formulated by Tyrer and Shopsin (1980). In four patients lithium neurotoxicity was diagnosed because of lowered consciousness, disturbances of memory and/or confusion. Two patients showed symptoms and signs of ataxia and/or parkinsonism. In the group of seven patients with cerebro-
TABLE
TO DSM-III
51 -
Modes of action: * mixed NA and 5HT reuptake inhibition; ’ predominance of NA reuptake inhibition: ‘ no reuptake inhibition, but binding to serotonin (5HTz) and histamine (H,) receptors; ’ predominance of 5HT reuptake inhibition.
NUMBER
OF PATIENTS
Complete response
Total
3 (19%) 9 (36%) 5 (55%) 1 (100%) 18 (35%)
16 (31%) 25 (49%) 9 (18%) 1(2%) 51
vascular disturbance, two patients suffered from lithium neurotoxicity. After stopping lithium, a complete recovery was seen in all cases. In comparing longitudinally assembled data on lithium plasma levels with the occurrence of lithium neurotoxicity, no relation between the two was apparent. Additionally. four patients developed hypothyroidism during lithium augmentation, one patient suffered from heart failure and one patient became manic. None of these complications were considered serious enough to stop lithium treatment. Discussion
Our analysis shows a response percentage of 65, similar to percentages found in other studies on younger adults (Katona, 1988). This indicates that lithium addition can also be effective in older patients. The efficacy of the addition of lithium to a previously started regimen of cyclic antidepressants drugs has been established only for younger patients. Six reports indicate that in the treatment of refractory depression in younger adults lithium augmentation of cyclic antidepressants can be of value (De Montigny et al., 1981, 1983, 1985; Heninger et al., 1983; Louie and Meltzer, 1984; Price et al., 1986). To our knowledge, there is no larger study on this subject in an elderly population. An increased response rate among patients with a recurrent episode was found, although in our study this finding was of marginal statistical significance. Similar observations have been made elsewhere (Blazer, 1989). No other variables correlated significantly with outcome of therapy.
221
The present study analyzed two clinical (DSMIII) signs of major depressive disorder as variables with a possible predictive value towards outcome of therapy: psychotic features and melancholia. Their absence or presence was considered as an indicator of the severity of the depression. As melancholia was present in 46 patients and psychotic features in 29 patients, the studied patients were severely depressed. In a study by De Montigny et al. (1983) the most dramatic responses were seen in the most severely depressed patients. Pai et al. (1986) observed successful treatment with lithium augmentation in patients suffering from delusional tricyclic-refractory depression. Price et al. (1983) described dramatic responses to lithium augmentation treatment of delusional depression in three out of six cases. In another study the highest rates of marked response to lithium augmentation in combined antidepressant-neuroleptic treatment were found among melancholic patients (Price et al., 1986). Intervals between initiating lithium therapy and the onset of response could not reliably be evaluated. Large differences in these intervals were found in other studies (Katona, 1988). Our minimum time criterion for adequacy of initial antidepressant treatment of 4 weeks might have been too short in some cases. Some of the lithium responses might have been delayed responses to the original antidepressant. This possibility cannot be excluded for some patients, although most patients were treated for more than 4 weeks. No conclusive data on the minimum time criterion are available in the literature. Periods between 3 and 6 weeks are mentioned (Quitkin et al., 1984; Peabody et al., 1986). De Montigny and Cournoyer (1987) advise a treatment period of at least 3 weeks prior to lithium augmentation. In populations older than 60 years Rockwell et al. (1988) compared 16 controlled studies of cyclic antidepressant drugs. A total of 1281 patients treated with 12 different drugs were involved. In 10 of these studies the duration of antidepressant treatment was 4 weeks. Physical morbidity was not assessed in this study. The multiplicity of somatic diseases of patients in this very old age group (Murphy, 1983; Baldwin and Jolley, 1986) and the retrospective character of the study made it difficult to analyze
physical health parameters in relation to outcome. Objective criteria for ‘disease’, such as electrocardiographic abnormalities, are frequently encountered in elderly persons. These criteria do not necessarily accompany somatic complaints or imply actual ‘disease’. Furthermore, depressed patients, especially patients with delusions, often complain excessively about physical health (Murphy, 1983). The number of side-effects probably caused by lithium addition was high. In spite of careful monitoring of serum lithium levels, kept relatively low in accordance with recommendations in the literature, 11% of patients suffered from lithium neurotoxicity. Lithium has a narrow therapeutic index. Lithium neurotoxicity appears at therapeutic levels as well as at toxic levels. Some authors claim this susceptibility to neurotoxic effects of lithium to be present in geriatric patients in general (Smith and Helms, 1982). The high number of patients with signs of neurotoxicity found in this study (six, 11%) supports this hypothesis. Out of seven patients with circulatory disturbances of the brain, two patients developed signs of lithium neurotoxicity. Because of the small size of this group, no conclusions can be drawn as to whether these patients are more susceptible to the development of lithium neurotoxicity, as has been suggested in the literature. Four of these seven patients nevertheless responded to lithium augmentation without signs of neurotoxicity. When other therapies fail, lithium can, in our experience, also be used for patients with cerebrovascular disturbances. Two patients developed lithium neurotoxicity during febrile illnesses; infectious disease is described elsewhere as a predisposing factor (Tyrer and Shopsin, 1980). EEGs can be of great value in making a diagnosis of lithium neurotoxicity, especially when they can be compared to pretreatment EEGs (Foster and Rosenthal, 1980). Four patients developed hypothyroidism during lithium treatment. Lithium seems to exert an inhibitory effect on the thyroid. This complication was rapidly disco.vered because of routine serum thyroid function tests (thyroid stimulating hormone, TSH and L-thyroxine, T4, at least once every 6 months), as is generally recommended
222
(Schou, 1986). The incidence of hypothyroidism in persons receiving lithium is higher than the spontaneous incidence of hypothyroidism (Mannisto, 1980) while the incidence depends on the criteria used for defining hypothyroidism. Replacement therapy for hypothyroidism is instituted with T4, while continuing lithium treatment. One patient became manic. In previous studies in younger adults, this was described in only five patients (Louie and Meltzer, 1984; Price, 1987). At least every 3 months patients were monitored routinely for renal damage by examination of serum urea, creatinine, sodium and potassium. When lithium therapy was started, these tests were done more frequently (Jefferson et al., 1987). No indication of renal damage caused by institution of lithium therapy was found in this study. In our opinion, older depressed patients may benefit from treatment with lithium augmentation when cyclic antidepressant drugs are ineffective. Careful monitoring of patients and serum lithium levels is warranted and serious side-effects of lithium treatment have to be taken into account. It would be worthwhile to investigate whether lower serum lithium levels than those usually advocated for younger adults are equally effective. Our experience supports recent guidelines on treatment strategies for elderly depressives (Blazer, 1989). The first step in these strategies is to achieve and maintain an adequate dosage of a cyclic antidepressant drug during at least 4 weeks, defined in this study as at least 75 mg of imipramine or an equivalent dosage of another antidepressant. If this is not effective, our second step is usually to try another cyclic antidepressant. Response to therapy and the occurrence of side-effects largely dictate dosage schedules. Blood pressure measurements with the patient standing up and lying down are essential to recognize one of the major side effects: postural hypotension. After these first step(s), in many countries ECT is considered one of the early treatment modalities. However, the use of ECT in the treatment of elderly depressives in The Netherlands is limited. When there is no response to treatment with either a second antidepressant or ECT, or if the patient refuses ECT (Pai et al., 1986) lithium augmentation can be of value. The classical non-selective MAO inhibitors are to be considered in the last
resort, in view of their hypotensive side-effects, potentially causing falls and injury in frail elderly people. We conclude that in the treatment of older depressed patients, lithium augmentation can be of value.
References American Psychiatric Association (1980) Diagnostic and Statistical Manual of Mental Disorders, 3rd edn. American Psychiatric Association, Washington. DC. Baldwin, B. (1988) Late life depression: undertreated? Br. Med. J. 296. 519. Baldwin, R.C. and Jolley, D.J. (1986) The prognosis of depression in old age. Br. J. Psychiatry 149. 5744583. Ben-Arie, O., Swartz, L. and Dickman, B.J. (1987) Depression in the elderly living in the community. Br. J. Psychiatry 150, 169-174. Blazer, D. (1989) Current concepts. Depression in the elderly. N. Engl. J. Med. 320. 1644166. Copeland. J.R.M., Dewey, M.E., Wood, N., Searle. R., Davidson, LA. and McWilliam. C. (1987a) Range of mental illness among the elderly in the community. Prevalence in Liverpool using the GMS-AGECAT package. Br. J. Psychiatry 150, 815-823. Copeland, J.R.M., Gurland, B.J.. Dewey, M.E.. Kelleher. M.J.. Smith, A.M.R. and Davidson, I.A. (1987b) Is there more dementia, depression and neurosis in New York? A comparative study of the elderly in New York and London using the computer diagnosis AGECAT. Br. J. Psychiatry 151, 466-473. Cowen, P.J. (1988) Depression resistant to tricyclic antidepressants. Adding lithium will often work. Br. Med. J. 297. 435-436. De Hooge. J.K. (1988) Lithium in combination with cyclic antidepressant drugs as treatment for therapy resistant geriatric depressions. Tijdschr. Psychiatric 30. 356-375. De Montigny, C. and Cournoyer, G. (1987) Lithium addition in treatment resistant major depression. In: I. Zohar and R.H. Belmaher (Eds.). Treating Resistant Depression. PMA Publishing Corporation, New York. NY. pp. 147-162. De Montigny, C.. Grunberg. F.. Mayer, A. and Deschenes, J.P. (1981) Lithium induces rapid relief in tricyclic antidepressant drug non-responders. Br. J. Psychiatry 138. 2522 256. De Montigny. C., Cournoyer, G.. Morisette, R., Langlois, R. and Caille, G. (1983) Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Arch. Gen. Psychiatry 40, 132771334. De Montigny, C.. Elie, R. and Caille, G. (1985) Rapid response to the addition of lithium in iprindole-resistant unipolar depression: a pilot study. Am. J. Psychiatry 142, 220-223. Finch, E.J.L. and Katona. C.L.E. (1989) Lithium augmentation in the treatment of refractory depression in old age. Int. J. Geriatr. Psychiatry 4, 41-46. Foster, J.R. and Rosenthal, J.S. (1980) Lithium treatment in
223 the elderly. In: F.N. Johnston (Ed.), Handbook of Lithium Therapy. MTP Press, Lancaster, pp. 414-420. Green, A.R. and Nutt, D.J. (1983) Antidepressants. In: D.G. Grahame-Smith and P.J. Cowen (Ed.), Psychopharmacology, Part 1: Preclinical Psychopharmacology. Excerpta Medica. Amsterdam/Oxford/Princeton, pp. l-37. Hardy, B.G., Shulman. K.J., Mackenzie, SE.. Kutcher. S.P. and Silverberg, J.D. (1987) Pharmacokinetics of lithium in the elderly. J. Clin. Pharmacol. 7, 153-158. Health Council of The Netherlands (1988) Advice on Psychogeriatric Clinical Syndromes. The Hague. Heninger, G.R., Charney. D.S. and Sternberg, D.E. (1983) Lithium carbonate augmentation of antidepressant treatment. Arch. Gen. Psychiatry 40, 133551342. Jefferson, J.W. (1983) Lithium and affective disorder in the elderly. Compr. Psychiatry 24, 166-178. Jefferson, J.W., Greist. J.H., Ackerman, D.L. and Caroll, J.A. (1987) Lithium Encyclopedia for Clinical Practice. 2nd edn. American Psychiatric Press. Washington, DC. Johnston, H.F. (1987) Principles and range of combination treatments involving lithium. In: F.N. Johnston (Ed.). Lithium Combination Treatment. Karger. Basel, pp. 179214. Katona, C.L. (1988) Lithium augmentation in refractory depression. Psychiatr. Dev. 6. 153-171. Kay. D.W.K., Henderson, A.S., Scott, R., Wilson. J., Rickwood, D. and Grayson, D.A. (1985) Dementia and depression among the elderly living in the Hobart community: the effect of the diagnostic criteria on the prevalence rates. Psychol. Med. 15, 771-788. Kushnir. S.L. (1986) Lithium-antidepressant combinations in the treatment of depressed, physically ill geriatric patients. Am. J. Psychiatry 143, 378-379. Louie. A.K. and Meltzer, H.Y. (1984) Lithium potentiation of antidepressant treatment. J. Clin. Pharmacol. 4, 316-321. Mannisto, P.T. (1980) Endocrine side effects of lithium. In: F.N. Johnston (Ed.). Handbook of Lithium Therapy. MTP Press, Lancaster, pp. 310-322. Murphy, E. (1983) The prognosis of depression in old age. Br. J. Psychiatry 142. 11-19.
Pai, M., White, A.C. and Deane, A.G. (1986) Lithium augmentation in the treatment of delusional depression. Br. J. Psychiatry 148, 736-738. Peabody, C.A., Whiteford, H.A. and Hollister, L.E. (1986) Antidepressants and the elderly. J. Am. Geriatr. Sot. 34. 8699874. Plotkin, D.A., Gerson, SC. and Jarvik, L.F. (1987) Antidepressant drug treatment in the elderly. In: H.Y. Meltzer (Ed.), Psychopharmacology: The Third Generation of Progress Raven Press, New York, NY, pp. 1149-1158. Price, L.H. (1987) Mania induced by lithium augmentation. Am. J. Psychiatry 144, 389. Price, L.H.. Conwell. Y. and Nelson. J.C. (1983) Lithium augmentation of combined neuroleptic-tricyclic treatment in delusional depression. Am. J. Psychiatry 140. 318-322. Price. L.H., Charney, D.S. and Heninger, G.R. (1986) Variability of response to lithium augmentation in refractory depression. Am. J. Psychiatry 143. 1387-1392. Quitkin. F.M.. Rabkin, J.G.. Ross. D. and McGrath, P.J. (1984) Duration of antidepressant drug treatment. What is an adequate trial. Arch. Gen. Psychiatry 41. 238-245. Rasmussen. S.A. and Keitner, G.I. (1987) Tricyclic antidepressants. In: F.N. Johnston (Ed.), Lithium Combination Treatment. Karger, Basel. pp. 179-214. Rockwell, E., Lam. R.W. and Zisook, S. (1988) Antidepressant drug studies in the elderly. Psychiatr. Clin. North Am. 11, 215-233. Schou. M. (1986) Lithium treatment: a refresher course. Br. J. Psychiatry 149, 541-547. Smith. R.E. and Helms. P.M. (1982) Adverse effects of lithium therapy in the acutely ill elderly patient. J. Clin. Psychiatry 43, 94-99. Tyrer. S. and Shopsin. B. (1980) Neural and neuromuscular side-effects of lithium. In: F.N. Johnston (Ed.), Handbook of Lithium Therapy. MTP Press. Lancaster, pp. 289-309. Van Marwijk. H.W.J.. Bekker. F.M., Hop. W.C.J., Jansen. P.A.F. and Van Nieuwkerk. J.F. (1988) Electroconvulsive therapy of aged depressed patients: a retrospective study of efficacy and safety. Ned. Tijdschr. Geneesk. 132. 13961399.
of Affective Disorders, 20 (1990) 217-223
217
JAD 00760
Lithium augmentation
in geriatric depression
H.W.J. van Marwijk ‘, F.M. Bekker ‘3*, W.A. Nolen 2, P.A.F. Jansen I, J.F. van Nieuwkerk 1 and W.C.J. Hop 3 ’ Geriatric Training Department and ’ Psychiatric Training Department, Bloemendaal Psychiatnc Hospital, The Hague and’ Department
of Epidemiologv
and Biostatistics,
Erasmus
University, Rotterdam,
The Netherlands
(Received 21 May 1990) (Revision received 11 July 1990) (Accepted 6 August 1990)
Summary In the geriatric department of a Dutch psychiatric hospital the charts of 51 patients treated with lithium in addition to cyclic antidepressants were reviewed. A response was seen in 33 patients (65%). For patients with recurrent depressive episodes, a statistical trend was found towards more responders with more complete responses, compared to patients with first depressive episodes. During lithium augmentation, 10 patients suffered from severe adverse effects 12 times. In spite of adverse effects, with expert monitoring lithium augmentation can, in our opinion, be of value in the treatment of older depressed patients.
Key words: Elderly;
Depression;
Lithium
augmentation
Introduction In the elderly, clinical depression is a frequently encountered problem (Jefferson, 1983; Plotkin et al., 1987). For major depression in elderly persons living in the community, international studies show prevalence rates of l-13%, depending on definitions of disease, measurement instruments and populations under study (Kay et
Address for correspondence: H.W.J. Department of General Practice, Leiden 2088, 2301 CB Leiden, The Netherlands.
van Marwijk, M.D., University, P.O. Box
* Present address: De Wellen Psychiatric Hospital, 9028, 7300 EL Apeldoorn, The Netherlands. 0165-0327/90/$03.50
P.O. Box
0 1990 Elsevier Science Publishers
al., 1985; Copeland et al., 1987a,b; Blazer, 1989). Although there is no agreement on the exact prevalence of major depression in the elderly in the general population, depression is considered to be the most frequently occurring mental disorder in persons between 65 and 80 years old (Health Council of The Netherlands, 1988). Cyclic antidepressants, including both tricyclic antidepressants and non-tricyclic compounds (mono-, bi- and tetracyclics), are of great importance in the treatment of geriatric depression (Plotkin et al., 1987; Baldwin, 1988). Two factors, however, restrict the use of these drugs in this age group: firstly the occurrence of severe side-effects that counteract an often fragile physical balance and secondly a primary refractoriness to adequate
B.V. (Biomedical
Division)
218
treatment with cyclic antidepressants (Murphy, 1983; Baldwin and Jolley, 1986). For those patients who do not respond to treatment with antidepressants, because of side-effects or because of non-responsiveness, there is a need for an alternative. In a number of countries electroconvulsive therapy (ECT) is considered to be such an alternative (Cowen, 1988; Blazer. 1989). In The Netherlands, discussion about the place of ECT in treatment schedules for elderly depressives has been opened only recently (Van Marwijk et al., 1988). As yet there is no general acceptance of ECT in Dutch public opinion and only a few patients are treated with it each year. (In 1986 a total number of 71 patients, 35 of whom were 60 years and older. Chief Inspectorate on Mental Health, personal communication. 1987.) Because of potential (postural) hypotensive side-effects of monoamine oxidase (MAO) inhibitors in the elderly, their therapeutic usefulness is also restricted. The need for an alternative to cyclic antidepressants remains. The addition of lithium to antidepressants. i.e.. ‘lithium addition’ or ‘lithium augmentation’. is advocated in younger depressed adults not responding to cyclic antidepressants therapy. Studies on lithium augmentation have been discussed in a recent review by Katona (1988). A number of hypotheses have been formulated to elucidate neurotransmitter mechanisms responsible for the efficacy of lithium as an antidepressant in lithium augmentation. There is some evidence that lithium-induced enhancement of serotonergic neuis involved rotransmission (Rasmussen and Keitner, 1987; Katona, 1988). Surveying the literature on the use of lithium augmentation of previous cyclic antidepressants in geriatric patients. only a few reports were found, each describing only a small number of patients. adding up to 16 cases. Different diagnostic criteria were used in each study (Kushnir. 1986; De Hooge, 1988; Finch and Katona, 1989). As so little is known about the treatment of geriatric patients with lithium augmentation, we performed a retrospective study on the effects of the use of lithium in addition to prior (cyclic) antidepressant therapy in a group of elderly patients.
Patients and methods All patients studied had been admitted to the geriatric department of Bloemendaal Psychiatric Hospital. Together with three other psychiatric hospitals in The Hague, this hospital serves a catchment area of about 900,000 people. 180,000 of whom are elderly (20%). There are 300-350 admissions to the geriatric department each year. in approximately 40% of the cases for depression. Because most patients are severely depressed, biological therapies form the mainstay of treatment. The hospital serves as a regional center for ECT. Non-pharmacological treatment is based on a number of psycho-. socio- and physiotherapeutic lines designed to activate patients as much as possible. Musical. creative and other activity therapies are offered, as well as a resocialization program. psychomotor therapy and swimming facilities. Although psychotherapy is not applied in a systematic way, supportive psychotherapy is offered to all patients and in many cases also to their relatives. All patients who had not responded to a previous regimen of cyclic antidepressants and who had started with lithium augmentation between March 1985 and July 1987 were included in the study. As a rule. lithium augmentation of previous cyclic antidepressant therapy was the primary choice for secondary treatment. Patients were reviewed who had been treated clinically with lithium augmentation for depression. Fifty-one inpatients were selected. Patients were identified by checking laboratory lists of serum lithium levels, which were assessed routinely in all patients receiving lithium at least once every 2 weeks. Medical and nursing charts of these patients were reviewed independently by two authors (F.M.B. and H.W.J.v.M.). Based on these data a retrospective DSM-Ill (axis I) diagnosis was made by consensus.
The sample consisted of 51 inpatients (46 women, five men), aged 64&X8 years (mean age 77 years). According to DSM-III criteria a major depression was diagnosed in 41 patients. A bipolar disorder. depressed, was diagnosed in nine patients and an atypical depression in one patient. For 16 patients it was the first depressive episode. for eight patients the second episode. Twenty-
219
seven patients had experienced more than one previous depressive episode. Melancholia was present in 46 patients, psychotic features in 29 patients. Adequacy and efficacy of previous antidepressant treatment were assessed. In line with recent recommendations in the literature (Peabody et al., 1986; Blazer, 1989) we defined previous treatment with cyclic antidepressants as adequate when at least 75 mg of imipramine or an equivalent dosage of another antidepressant was used during a period of at least 4 weeks. According to this definition, 47 patients had previously received adequate cyclic antidepressant therapy. Lithium carbonate was added to the following antidepressants: amitriptyline in 39 cases, maprotiline in five cases, mianserin in three cases, imipramine in two cases and dothiepin and clomipramine each in one case (51 patients). The mean daily dose of cyclic antidepressants was 80 mg (range: 30-150). Usually patients starting lithium therapy were given 200 mg (half a tablet) of lithium carbonate sustained release (Priadel@) nocte. After 2 or 3 days, serum lithium levels were assessed 12 h after the last intake of lithium medication and the dosages were adjusted. Laboratory monitoring of serum lithium levels took place at least once a week in the first 2-3 weeks and after that at least once every 2 weeks. Final dosages ranged from 100 to 1000 mg once a day (mean dose 400 mg). Steady-state lithium plasma levels were kept between 0.40 and 0.80 mmol/l, in accord with Hardy et al. (1987). Steady-state plasma concentrations of lithium were plotted versus time in weeks, to evaluate a possible relationship between serum lithium levels and side-effects. Improvement was measured by comparing global clinical impressions, differentiating a complete response to treatment from a partial response or no response, following clinical practice. Patients were classified as having a complete response when pretreatment (DSM-III) symptoms of major depression had completely vanished. Treatment response was considered partial if symptoms had not completely disappeared. Variables with a possible predictive value towards outcome of lithium augmentation therapy were evaluated: psychotic features and melancho-
lia. Only a limited number of sociodemographic parameters were studied as all patients were treated on an inpatient basis. An inventory was made of severe side-effects of lithium augmentation. As patients with a history of possible organic brain damage seem more susceptible to toxic effects of lithium (Tyrer and Shopsin, 19X0), all records of the patients in the sample were reviewed retrospectively for past symptoms and signs of cerebrovascular disturbance: transient ischemic attacks or stroke. Non-psychotropic medication was not evaluated. Co-medication is the rule rather than the exception in elderly patients (Jefferson, 1983). Drugs that possibly interact with lithium are mainly diuretics and non-steroid anti-inflammatory drugs. These drugs are frequently used in this age group (Johnston et al., 1987). Because of frequent serum lithium level monitoring, interactions of non-psychotropic medication influencing serum lithium levels were registered early. With respect to cyclic antidepressants clinically important interactions of this kind were not to be expected (Johnston et al., 1987).
Results Thirty-three patients (65%) treated with lithium augmentation responded completely or partially to therapy: in 18 patients (35%) a complete response was found and 15 patients (30%) showed a partial response (Table 1). Of patients with a unipolar depression, 26 of 42 (62%) responded to therapy versus seven out of nine patients (78%) with a bipolar depression. A statistical trend (two-tailed P = 0.07) was apparent for patients with previous episodes of depressive disorder and response, using Mann-Whitney’s test. Compared to patients with a first depressive episode, more patients with a recurrent depressive episode showed more complete responses. Statistical analysis showed no other significant difference between groups. In Table 2 data on the number of patients receiving predominantly noradrenaline (NA), predominantly serotonin (5HT) or mixed reuptake inhibiting antidepressants are presented versus response (Green and Nutt, 1983).
220 TABLE
1
EFFECTS
OF LITHIUM
AUGMENTATION
ESM-III diagnosis
ACCORDING
No response
Major depressive disorder. first episode recurrent Bipolar disorder, depressed Atypical depression Total
8 (50%) 8 (32%) 2 (22%)
5 (31%) 8 (32%) 2 (22%)
18 (35%)
15 (29%)
2
EFFECTS ING TO NUMBER
OF LITHIUM DIFFERENT OF PATlENTS
AUGMENTATION ACC’ORDCYCLIC ANTIDEPRESSANTS,
_
Amitryptiline A Maprotiline h Mianserin ‘ Imipramine “ Clomipramine ’ Dothiepin’ Total
No response
Partial response
Complete response
Total
13
12 3
2
14 2 1
1
1
39 5 3 2 1
1 1 18
1 15
18
DIAGNOSIS.
Partial response
For diagnostic category (including the unipolar/ bipolar distinction), age, sex, psychotic features, melancholia and cerebrovascular disturbance no statistically significant relationships with response were discerned. Due to the retrospective nature of this study, the latency of response, in other studies between 1 and 28 days (Katona, 1988), could not be ascertained. During lithium augmentation severe adverse effects were noted 12 times in 10 patients (Table 2). Six patients (11%) presented symptoms and signs of lithium neurotoxicity, according to criteria formulated by Tyrer and Shopsin (1980). In four patients lithium neurotoxicity was diagnosed because of lowered consciousness, disturbances of memory and/or confusion. Two patients showed symptoms and signs of ataxia and/or parkinsonism. In the group of seven patients with cerebro-
TABLE
TO DSM-III
51 -
Modes of action: * mixed NA and 5HT reuptake inhibition; ’ predominance of NA reuptake inhibition: ‘ no reuptake inhibition, but binding to serotonin (5HTz) and histamine (H,) receptors; ’ predominance of 5HT reuptake inhibition.
NUMBER
OF PATIENTS
Complete response
Total
3 (19%) 9 (36%) 5 (55%) 1 (100%) 18 (35%)
16 (31%) 25 (49%) 9 (18%) 1(2%) 51
vascular disturbance, two patients suffered from lithium neurotoxicity. After stopping lithium, a complete recovery was seen in all cases. In comparing longitudinally assembled data on lithium plasma levels with the occurrence of lithium neurotoxicity, no relation between the two was apparent. Additionally. four patients developed hypothyroidism during lithium augmentation, one patient suffered from heart failure and one patient became manic. None of these complications were considered serious enough to stop lithium treatment. Discussion
Our analysis shows a response percentage of 65, similar to percentages found in other studies on younger adults (Katona, 1988). This indicates that lithium addition can also be effective in older patients. The efficacy of the addition of lithium to a previously started regimen of cyclic antidepressants drugs has been established only for younger patients. Six reports indicate that in the treatment of refractory depression in younger adults lithium augmentation of cyclic antidepressants can be of value (De Montigny et al., 1981, 1983, 1985; Heninger et al., 1983; Louie and Meltzer, 1984; Price et al., 1986). To our knowledge, there is no larger study on this subject in an elderly population. An increased response rate among patients with a recurrent episode was found, although in our study this finding was of marginal statistical significance. Similar observations have been made elsewhere (Blazer, 1989). No other variables correlated significantly with outcome of therapy.
221
The present study analyzed two clinical (DSMIII) signs of major depressive disorder as variables with a possible predictive value towards outcome of therapy: psychotic features and melancholia. Their absence or presence was considered as an indicator of the severity of the depression. As melancholia was present in 46 patients and psychotic features in 29 patients, the studied patients were severely depressed. In a study by De Montigny et al. (1983) the most dramatic responses were seen in the most severely depressed patients. Pai et al. (1986) observed successful treatment with lithium augmentation in patients suffering from delusional tricyclic-refractory depression. Price et al. (1983) described dramatic responses to lithium augmentation treatment of delusional depression in three out of six cases. In another study the highest rates of marked response to lithium augmentation in combined antidepressant-neuroleptic treatment were found among melancholic patients (Price et al., 1986). Intervals between initiating lithium therapy and the onset of response could not reliably be evaluated. Large differences in these intervals were found in other studies (Katona, 1988). Our minimum time criterion for adequacy of initial antidepressant treatment of 4 weeks might have been too short in some cases. Some of the lithium responses might have been delayed responses to the original antidepressant. This possibility cannot be excluded for some patients, although most patients were treated for more than 4 weeks. No conclusive data on the minimum time criterion are available in the literature. Periods between 3 and 6 weeks are mentioned (Quitkin et al., 1984; Peabody et al., 1986). De Montigny and Cournoyer (1987) advise a treatment period of at least 3 weeks prior to lithium augmentation. In populations older than 60 years Rockwell et al. (1988) compared 16 controlled studies of cyclic antidepressant drugs. A total of 1281 patients treated with 12 different drugs were involved. In 10 of these studies the duration of antidepressant treatment was 4 weeks. Physical morbidity was not assessed in this study. The multiplicity of somatic diseases of patients in this very old age group (Murphy, 1983; Baldwin and Jolley, 1986) and the retrospective character of the study made it difficult to analyze
physical health parameters in relation to outcome. Objective criteria for ‘disease’, such as electrocardiographic abnormalities, are frequently encountered in elderly persons. These criteria do not necessarily accompany somatic complaints or imply actual ‘disease’. Furthermore, depressed patients, especially patients with delusions, often complain excessively about physical health (Murphy, 1983). The number of side-effects probably caused by lithium addition was high. In spite of careful monitoring of serum lithium levels, kept relatively low in accordance with recommendations in the literature, 11% of patients suffered from lithium neurotoxicity. Lithium has a narrow therapeutic index. Lithium neurotoxicity appears at therapeutic levels as well as at toxic levels. Some authors claim this susceptibility to neurotoxic effects of lithium to be present in geriatric patients in general (Smith and Helms, 1982). The high number of patients with signs of neurotoxicity found in this study (six, 11%) supports this hypothesis. Out of seven patients with circulatory disturbances of the brain, two patients developed signs of lithium neurotoxicity. Because of the small size of this group, no conclusions can be drawn as to whether these patients are more susceptible to the development of lithium neurotoxicity, as has been suggested in the literature. Four of these seven patients nevertheless responded to lithium augmentation without signs of neurotoxicity. When other therapies fail, lithium can, in our experience, also be used for patients with cerebrovascular disturbances. Two patients developed lithium neurotoxicity during febrile illnesses; infectious disease is described elsewhere as a predisposing factor (Tyrer and Shopsin, 1980). EEGs can be of great value in making a diagnosis of lithium neurotoxicity, especially when they can be compared to pretreatment EEGs (Foster and Rosenthal, 1980). Four patients developed hypothyroidism during lithium treatment. Lithium seems to exert an inhibitory effect on the thyroid. This complication was rapidly disco.vered because of routine serum thyroid function tests (thyroid stimulating hormone, TSH and L-thyroxine, T4, at least once every 6 months), as is generally recommended
222
(Schou, 1986). The incidence of hypothyroidism in persons receiving lithium is higher than the spontaneous incidence of hypothyroidism (Mannisto, 1980) while the incidence depends on the criteria used for defining hypothyroidism. Replacement therapy for hypothyroidism is instituted with T4, while continuing lithium treatment. One patient became manic. In previous studies in younger adults, this was described in only five patients (Louie and Meltzer, 1984; Price, 1987). At least every 3 months patients were monitored routinely for renal damage by examination of serum urea, creatinine, sodium and potassium. When lithium therapy was started, these tests were done more frequently (Jefferson et al., 1987). No indication of renal damage caused by institution of lithium therapy was found in this study. In our opinion, older depressed patients may benefit from treatment with lithium augmentation when cyclic antidepressant drugs are ineffective. Careful monitoring of patients and serum lithium levels is warranted and serious side-effects of lithium treatment have to be taken into account. It would be worthwhile to investigate whether lower serum lithium levels than those usually advocated for younger adults are equally effective. Our experience supports recent guidelines on treatment strategies for elderly depressives (Blazer, 1989). The first step in these strategies is to achieve and maintain an adequate dosage of a cyclic antidepressant drug during at least 4 weeks, defined in this study as at least 75 mg of imipramine or an equivalent dosage of another antidepressant. If this is not effective, our second step is usually to try another cyclic antidepressant. Response to therapy and the occurrence of side-effects largely dictate dosage schedules. Blood pressure measurements with the patient standing up and lying down are essential to recognize one of the major side effects: postural hypotension. After these first step(s), in many countries ECT is considered one of the early treatment modalities. However, the use of ECT in the treatment of elderly depressives in The Netherlands is limited. When there is no response to treatment with either a second antidepressant or ECT, or if the patient refuses ECT (Pai et al., 1986) lithium augmentation can be of value. The classical non-selective MAO inhibitors are to be considered in the last
resort, in view of their hypotensive side-effects, potentially causing falls and injury in frail elderly people. We conclude that in the treatment of older depressed patients, lithium augmentation can be of value.
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