- Email: [email protected]
L-11 Clinical Efficacy of Antidepressants in Unipolar Depression
Lectures
gated in long term treatment. These long treatment studies have added considerably to our knowledge of the need for a period of continuation treatment to consolidate response. The studies of citalopram in long term treatment specifically examined the continuation treatment period in responders to treatment with citalopram who were then randomized to continue with the same dose of citalopram or placebo (Montgomery, Rasmussen and Tanghoj, 1993; Robert and Montgomery, 1995). A significant advantage of citalopram in reducing the risk of relapse was seen in both studies. Other SSRls have been investigated in one year studies and their efficacy in relapse prevention assessed by analyzing the first four months of the study period (Montgomery and Dunbar, 1993; Doogan and Caillard, 1992). Both sertraline and paroxetine were shown to be effective in these analyses with efficacy demonstrated for both the continuation and prophylactic phases of treatment. It is important
to note that patients who had responded to placebo prior to entry to the study of Montgomery et al (1993) were continued on placebo to preserve blindness in the study. These patients relapsed at a very similar rate to those who had responded to citalopram who were then discontinued to placebo. In other words, response to placebo was temporary and patients remained vulnerable to relapse. The reappearance of depressive symptoms in the months immediately following apparent response of an acute episode of depression if antidepressants are discontinued is a consistent finding in the early and later studies. It is now generally accepted that a period of continuation treatment is necessary and it is recommended in different consensus guidelines that all courses of antidepressant treatment continue for at least six months (Montgomery, Bebbington, Cowen et al., 1993; Montgomery, Racagni. Coppen et al., 1993; WHO Mental Health Collaborating Centers, 1995). Cost effectiveness in /ong term treatment: Anton et al. (1994) reported that nefazadone and imipramine were both effective in maintaining response over a one year period compared to placebo. In this study, there were, as expected, significantly more dropouts because of side effects in patients treated with the TCA, with the result that overall there was little difference between imipramine and placebo whilst nefazadone showed a significant overall advantage. The cost calculations showed that, when the consequences of discontinuing treatment prematurely because of side effects was taken into account, it was much cheaper to use the more expensive antidepressant. Preventing new episodes of depression: Most depression is recurrent and early optimistic estimates of the number which occurred as single episodes have had to be revised as longer follow up studies have been carried out. Attention has increasingly focused on the appropriateness of long term prophylactic treatment with antidepressants to prevent new episodes. Patients with recurrent depression need to continue treatment to consolidate response and then to persist with treatment to reduce the risk of new episodes. To be sure that an antidepressant is effective in preventing new episodes it must be tested in patients who have definitively recovered from an episode of depression and for this reason a period of continuation treatment is included in studies of prophylaxis during which patients must remain well to be eligible for inclusion. The efficacy of antidepressants in reducing the risk of new episodes has been established for both older antidepressants, for example imipramine (Kupfer, Frank, Perel et al., 1992) and the newer SSRls (Montgomery, Dufour, Brion et al., 1988). It is consistently found that although actual rates of recurrence may vary between studies the rate may be halved by prophylactic treatment with antidepressants. It appears from the studies that efficacy is not lost over time and patients continue to be protected by prophylactic treatment. The clearest demonstration of the need to continue prophylactic treatment was reported in a study of imipramine which showed that the risk of recurrence persists even after many years of successful treatment. Patients who had remained well for three years in the placebo controlled study were randomized to continue treatment with imipramine or discontinue double blind to placebo. The patients randomized to placebo suffered a recurrence of their depression in spite of the intervening long period they had remained well at a similar rate to those in the three year study. The
implication
of this
finding
is that
patients
with
recurrent
need to continue treatment for as long as they want to reduce new episodes. Patients may be unwilling to embark an indefinite and if this is the case they need to be informed of the risks followed up in order that treatment can be instituted early depression recurs.
depression
the risk of treatment and to be when the
References Montgomery, fluoxetine
S.A., Dufour, H., Brian, S. et al. (1966) The prophylactic efficacy in unipolar depression, Brit J Psychiatry 153 (Suppl 3), 69-76.
01
Doogan, D.P. and Caillard. V. (1992) Sertraline in the prevention of depression, Brit J Psychiatry 160, 217-222. Kupfer, D.J., Frank, E., Perel, J.M. (1992) Five-year outcome for maintenance therapies in recurrent depression, Arch Gen Psychiatry 49, 769-773. Montgomery. S.A., Rasmussen, J.G.C. and Tanghoj, P. (1993) A 24 week study of 20 m g citelopram, 40 m q citalopram and placebo in the prevention of relapse of major d&es&n Int Clin Piychopharmacol a, 181-168. Montgomery, S.A. and Dunbar, G.C. (1993) Paroxetine is better that placebo in relapse prevention and the prophylaxis of recurrent depression, Int Clin Psychopharmacol 6, 189-195. Montgomery, S.A., Bebbington. P.E.. Cowen, P. et al. (1993) Guidelines for treating depressive illness with antidepressants, J Psychopharmacol 7, 19-23. Montgomery, S.A., Racagni. G.. Coppen, A., et al. (1993) Impact of neuropharmacology in the 1990s - Strategies for the therapy of depressive illness, Eur Neuropsychopharmacol 3, 153-l 56. Anton, SF., Robinson, D.S., Roberts, D.L., Ken&r, T.T., English, P.A. and Archibald, D.G. (1994) Long term treatment of depression with nefezodone, Psychopharmacol Bull 30. 165169. Robert, P.&d Montgomery, S.A. (1995) Citalopram in doses of 20 mgs to 60 mgs are effective in relapse prevention: a placebo controlled 6 month study, Int Clin Psychopharmacol lO(Sa). 29-35. WHO Mental Health Collaborating Centers (1995) Pharmacotherapy of depressive disorders, A consensus statement, J Affect Disord 17, 197-196.
IL-l
1 Clinical Efficacy of Antidepressants Depression
E.S. Paykel. Addenbrooke‘s Keywords:
University Hospital, Depression,
The introduction marked a major time
span
tricyclic
of Cambridge Cambridge
Department CB2 2QQ,
their
Over
of Psychiatry, UK.
antidepressants
of antidepressants revolution in the antidepressants
to psychiatty at the end of the 1950s treatment of depression. Within a short became
established
ments for most depressive disorders. The occupied a similar place until the recognition limited
in Unipolar
as first
line
treat-
monoamine oxidase inhibitors of interactions with tyramine
use.
the next twenty
years
many
more
drugs
became
available
with a few exceptions, they were confined to the already known logical classes. A major advance came about with demonstration of lithium the widespread use and its introduction into widespread
although pharmacoof efficacy use, first
as acute treatment in mania, then in maintenance treatment of bipolar disorder, subsequently as maintenance treatment and potentiator of antidepressants in unipolar depression. The 1980s and 1990s have seen further considerable advances with the introduction of the serotonin reuptake inhibitors, other uptake inhibitors with greater receptor specificity, with fewer side effects and greater safety, RIMAs, and atypical antidepressants with
other
modes
of action.
This paper reviews efficacy of antidepressants and their indications in acute treatment of depression. A large number of studies have established efficacy of the tricyclic antidepressants over placebo. Contrary to earlier beliefs, these do not appear to be selective for endogenous depression but are broad spectrum drugs with effects across a wide range of depressive features. These drugs are also useful in somewhat milder depressions such as those treated in general practice, with clear evidence of a threshold for severity which excludes the very mildly ill, at which they become superior to placebo (Paykel et al, 1988). Older MAOls have been used less but there have been many controlled trials. Although there is some superiorii to tricyclics in atypical depression, the effects again extend more widely, in keeping with the usual role of these drugs as second choice treatments after uptake inhibitors, in many depressives. The RIMA moclobemide is considerably safer and has clearly been shown to produce benefit in more severe and typical depressions. There are now at least five selective serotonin inhibitors in clinical use, and these drugs, being comparatively recent developments, were well evaluated in placebo controlled trials before introduction. Efficacy is comparable to that of the tricyclics, with fewer side effects and greater safety. Contrary to hypotheses of a specific serotonin-deficient type of depression, which originally gave impetus to development of this class of drugs, there do not appear to be specifically responsive depressive subtypes. Where selectivity does appear is in obsessive compulsive disorder, where serotoninergic drugs are clearly superior to the more noradreneraic QntideDreSSantS. There may also be some superiority in anxiety disorders. Recent new developments among antidepressants include the selective noradrenaline and serotonin reuptake inhibitor venlafagine, and the atypical antidepressants nefazodone and mirtazepine. It is noteworthy that modes
Lectures
SI-8 of action of all available antidepressants still appear likely to involve potentiation of noradrenergic and/or serotoninergic neurotransmission. There is now a wide range of antidepressants available, and better drugs for such difficult treatment situations as suicidal risk, susceptibility to side effects, elderly patients and medically ill. However, antidepressants are still often not used well in practice, particularly by non-psychiatrists. Efforts have now widened in many countries, to include educational programmes for general practitioners and other doctors and for the general public.
References Hollyman, E.S., Freeling, J.A., Freeling, P. 8 Sedgwick, P. (1986) Predictors of therapeutic benefit from amitriptyline in mild depression: a general practice placebocontrolled trial. J. Affect. Disord. 14. 63-95.
IL-131
New strategies depression
T.G. Dinan. Department Hospita/, London ECIA Keywords:
Refractory
in the management
of Psychological 76E, UK
depression;
Lithium;
Medicine,
of refractory St Bartholomew’s
T3; Dexamethasone.
There have been significant strides in the management of depression since the original tricyclic antidepressants were developed in the late 50s and 60s. The major advances have clearly been made in terms of tolerability and safety. The problem of treatment non-response is shared by newer and older antidepressants alike. Approximately 30% of patients with major depression fail to respond to an adequate dosage and duration of treatment. Whilst there is still some debate as to what constitutes an adequate dosage of antidepressant, there is general agreement that treatment should be for at least six weeks before a patient is defined as a non-responder. The use of lithium augmentation has, in recent years, been popularised by DeMontigny and his colleagues (1981). They showed that lithium augmented clomipramine in patients who were refractory to the antidepressant. We have compared the efficacy of this strategy with electroconvulsive therapy in patients with severe depression (Dinan and Barry 1989). Patients were randomly allocated to treatment either with lithium or with electroconvulsive therapy. In both cases, the antidepressant was con-
tinued. Outcome in both groups over a four week period was equal, but those patients treated with lithium showed a more rapid response. At the end of week 1, patients treated with lithium in combination with an antidepressant had a lower Hamilton score than those patients treated with electroconvulsive therapy. A number of research groups have focused on the hypothalamic-pituitary-adrenal axis as a target for antidepressant action. A short course of high-dose dexamethasone is reported to have antidepressant action. In patients previously resistant to sertraline or fluoxetine, we added dexamethasone 4 mg daily for three days. The dexamethasone was then discontinued and the patient remained on the antidepressant alone. Such an approach resulted in a significant drop in Hamilton depression scores. Ketoconazole, the antifungal agent, is a potent inhibitor of cortisol synthesis, We have examined its effectiveness in patients with melancholic depression who had elevated cortisol levels (Thakore & Dinan 1995). In all patients, ketoccinazole treatment produced a marked reduction in cortisol. At the same time, in each subject it enhanced serotonergic neurotransmission as indexed by the d-fenfluramine\prolactin stimulation test. In all cases, subjects showed greater prolactin release in response to d-fenfluramine challenge following ketoconazole treatment than they had at baseline. Overall, ketoconazole treatment produced a significant reduction in Hamilton depression scores. This strategy offers a second means of targeting the hypothalamic-pituitary-adrenal axis in patients who have refractory depression. Grade II hypothyroidism, characterised by elevated TSH levels and normal T4 and T3 levels, can pose significant problems when associated with depression. Studies to date indicate that such patients can be relatively treatment refractory. Whether or not they respond better to hi-iodothyronine or i-thyroxine has yet to be demonstrated in placebo controlled studies. Nonetheless, it is clear from placebo controlled studies of patients who are antidepressant resistant, that T, is a useful strategy in many patients.
References De Montigny, C., Grunberg, F.. Mayer, A. & Deschenes, J.P. (1961) Lithium induces rapid relief of depression in tricyclic drug non-responders. British Journal of Psychiatry 136, 252-256. Dinan T.G. & Barry S. (1989) A comparison of electroconvulsive therapy with a combined lithium and tricyclic combination in depressed tricyclic non-responders. Acta Psychiatrica Scandinavica 80, 97-100.
r 1
5
21
t
DAY
5
2,
DAY
1 5 21 DAY
Figure 1. Treatment illustrated.
resistant
patients
in whom dexamethasone
(4 mg) for 3 days was added to an SSRI. Hamilton
depression
scores (HAMD)
and baseline
cortisol
values
are
gated in long term treatment. These long treatment studies have added considerably to our knowledge of the need for a period of continuation treatment to consolidate response. The studies of citalopram in long term treatment specifically examined the continuation treatment period in responders to treatment with citalopram who were then randomized to continue with the same dose of citalopram or placebo (Montgomery, Rasmussen and Tanghoj, 1993; Robert and Montgomery, 1995). A significant advantage of citalopram in reducing the risk of relapse was seen in both studies. Other SSRls have been investigated in one year studies and their efficacy in relapse prevention assessed by analyzing the first four months of the study period (Montgomery and Dunbar, 1993; Doogan and Caillard, 1992). Both sertraline and paroxetine were shown to be effective in these analyses with efficacy demonstrated for both the continuation and prophylactic phases of treatment. It is important
to note that patients who had responded to placebo prior to entry to the study of Montgomery et al (1993) were continued on placebo to preserve blindness in the study. These patients relapsed at a very similar rate to those who had responded to citalopram who were then discontinued to placebo. In other words, response to placebo was temporary and patients remained vulnerable to relapse. The reappearance of depressive symptoms in the months immediately following apparent response of an acute episode of depression if antidepressants are discontinued is a consistent finding in the early and later studies. It is now generally accepted that a period of continuation treatment is necessary and it is recommended in different consensus guidelines that all courses of antidepressant treatment continue for at least six months (Montgomery, Bebbington, Cowen et al., 1993; Montgomery, Racagni. Coppen et al., 1993; WHO Mental Health Collaborating Centers, 1995). Cost effectiveness in /ong term treatment: Anton et al. (1994) reported that nefazadone and imipramine were both effective in maintaining response over a one year period compared to placebo. In this study, there were, as expected, significantly more dropouts because of side effects in patients treated with the TCA, with the result that overall there was little difference between imipramine and placebo whilst nefazadone showed a significant overall advantage. The cost calculations showed that, when the consequences of discontinuing treatment prematurely because of side effects was taken into account, it was much cheaper to use the more expensive antidepressant. Preventing new episodes of depression: Most depression is recurrent and early optimistic estimates of the number which occurred as single episodes have had to be revised as longer follow up studies have been carried out. Attention has increasingly focused on the appropriateness of long term prophylactic treatment with antidepressants to prevent new episodes. Patients with recurrent depression need to continue treatment to consolidate response and then to persist with treatment to reduce the risk of new episodes. To be sure that an antidepressant is effective in preventing new episodes it must be tested in patients who have definitively recovered from an episode of depression and for this reason a period of continuation treatment is included in studies of prophylaxis during which patients must remain well to be eligible for inclusion. The efficacy of antidepressants in reducing the risk of new episodes has been established for both older antidepressants, for example imipramine (Kupfer, Frank, Perel et al., 1992) and the newer SSRls (Montgomery, Dufour, Brion et al., 1988). It is consistently found that although actual rates of recurrence may vary between studies the rate may be halved by prophylactic treatment with antidepressants. It appears from the studies that efficacy is not lost over time and patients continue to be protected by prophylactic treatment. The clearest demonstration of the need to continue prophylactic treatment was reported in a study of imipramine which showed that the risk of recurrence persists even after many years of successful treatment. Patients who had remained well for three years in the placebo controlled study were randomized to continue treatment with imipramine or discontinue double blind to placebo. The patients randomized to placebo suffered a recurrence of their depression in spite of the intervening long period they had remained well at a similar rate to those in the three year study. The
implication
of this
finding
is that
patients
with
recurrent
need to continue treatment for as long as they want to reduce new episodes. Patients may be unwilling to embark an indefinite and if this is the case they need to be informed of the risks followed up in order that treatment can be instituted early depression recurs.
depression
the risk of treatment and to be when the
References Montgomery, fluoxetine
S.A., Dufour, H., Brian, S. et al. (1966) The prophylactic efficacy in unipolar depression, Brit J Psychiatry 153 (Suppl 3), 69-76.
01
Doogan, D.P. and Caillard. V. (1992) Sertraline in the prevention of depression, Brit J Psychiatry 160, 217-222. Kupfer, D.J., Frank, E., Perel, J.M. (1992) Five-year outcome for maintenance therapies in recurrent depression, Arch Gen Psychiatry 49, 769-773. Montgomery. S.A., Rasmussen, J.G.C. and Tanghoj, P. (1993) A 24 week study of 20 m g citelopram, 40 m q citalopram and placebo in the prevention of relapse of major d&es&n Int Clin Piychopharmacol a, 181-168. Montgomery, S.A. and Dunbar, G.C. (1993) Paroxetine is better that placebo in relapse prevention and the prophylaxis of recurrent depression, Int Clin Psychopharmacol 6, 189-195. Montgomery, S.A., Bebbington. P.E.. Cowen, P. et al. (1993) Guidelines for treating depressive illness with antidepressants, J Psychopharmacol 7, 19-23. Montgomery, S.A., Racagni. G.. Coppen, A., et al. (1993) Impact of neuropharmacology in the 1990s - Strategies for the therapy of depressive illness, Eur Neuropsychopharmacol 3, 153-l 56. Anton, SF., Robinson, D.S., Roberts, D.L., Ken&r, T.T., English, P.A. and Archibald, D.G. (1994) Long term treatment of depression with nefezodone, Psychopharmacol Bull 30. 165169. Robert, P.&d Montgomery, S.A. (1995) Citalopram in doses of 20 mgs to 60 mgs are effective in relapse prevention: a placebo controlled 6 month study, Int Clin Psychopharmacol lO(Sa). 29-35. WHO Mental Health Collaborating Centers (1995) Pharmacotherapy of depressive disorders, A consensus statement, J Affect Disord 17, 197-196.
IL-l
1 Clinical Efficacy of Antidepressants Depression
E.S. Paykel. Addenbrooke‘s Keywords:
University Hospital, Depression,
The introduction marked a major time
span
tricyclic
of Cambridge Cambridge
Department CB2 2QQ,
their
Over
of Psychiatry, UK.
antidepressants
of antidepressants revolution in the antidepressants
to psychiatty at the end of the 1950s treatment of depression. Within a short became
established
ments for most depressive disorders. The occupied a similar place until the recognition limited
in Unipolar
as first
line
treat-
monoamine oxidase inhibitors of interactions with tyramine
use.
the next twenty
years
many
more
drugs
became
available
with a few exceptions, they were confined to the already known logical classes. A major advance came about with demonstration of lithium the widespread use and its introduction into widespread
although pharmacoof efficacy use, first
as acute treatment in mania, then in maintenance treatment of bipolar disorder, subsequently as maintenance treatment and potentiator of antidepressants in unipolar depression. The 1980s and 1990s have seen further considerable advances with the introduction of the serotonin reuptake inhibitors, other uptake inhibitors with greater receptor specificity, with fewer side effects and greater safety, RIMAs, and atypical antidepressants with
other
modes
of action.
This paper reviews efficacy of antidepressants and their indications in acute treatment of depression. A large number of studies have established efficacy of the tricyclic antidepressants over placebo. Contrary to earlier beliefs, these do not appear to be selective for endogenous depression but are broad spectrum drugs with effects across a wide range of depressive features. These drugs are also useful in somewhat milder depressions such as those treated in general practice, with clear evidence of a threshold for severity which excludes the very mildly ill, at which they become superior to placebo (Paykel et al, 1988). Older MAOls have been used less but there have been many controlled trials. Although there is some superiorii to tricyclics in atypical depression, the effects again extend more widely, in keeping with the usual role of these drugs as second choice treatments after uptake inhibitors, in many depressives. The RIMA moclobemide is considerably safer and has clearly been shown to produce benefit in more severe and typical depressions. There are now at least five selective serotonin inhibitors in clinical use, and these drugs, being comparatively recent developments, were well evaluated in placebo controlled trials before introduction. Efficacy is comparable to that of the tricyclics, with fewer side effects and greater safety. Contrary to hypotheses of a specific serotonin-deficient type of depression, which originally gave impetus to development of this class of drugs, there do not appear to be specifically responsive depressive subtypes. Where selectivity does appear is in obsessive compulsive disorder, where serotoninergic drugs are clearly superior to the more noradreneraic QntideDreSSantS. There may also be some superiority in anxiety disorders. Recent new developments among antidepressants include the selective noradrenaline and serotonin reuptake inhibitor venlafagine, and the atypical antidepressants nefazodone and mirtazepine. It is noteworthy that modes
Lectures
SI-8 of action of all available antidepressants still appear likely to involve potentiation of noradrenergic and/or serotoninergic neurotransmission. There is now a wide range of antidepressants available, and better drugs for such difficult treatment situations as suicidal risk, susceptibility to side effects, elderly patients and medically ill. However, antidepressants are still often not used well in practice, particularly by non-psychiatrists. Efforts have now widened in many countries, to include educational programmes for general practitioners and other doctors and for the general public.
References Hollyman, E.S., Freeling, J.A., Freeling, P. 8 Sedgwick, P. (1986) Predictors of therapeutic benefit from amitriptyline in mild depression: a general practice placebocontrolled trial. J. Affect. Disord. 14. 63-95.
IL-131
New strategies depression
T.G. Dinan. Department Hospita/, London ECIA Keywords:
Refractory
in the management
of Psychological 76E, UK
depression;
Lithium;
Medicine,
of refractory St Bartholomew’s
T3; Dexamethasone.
There have been significant strides in the management of depression since the original tricyclic antidepressants were developed in the late 50s and 60s. The major advances have clearly been made in terms of tolerability and safety. The problem of treatment non-response is shared by newer and older antidepressants alike. Approximately 30% of patients with major depression fail to respond to an adequate dosage and duration of treatment. Whilst there is still some debate as to what constitutes an adequate dosage of antidepressant, there is general agreement that treatment should be for at least six weeks before a patient is defined as a non-responder. The use of lithium augmentation has, in recent years, been popularised by DeMontigny and his colleagues (1981). They showed that lithium augmented clomipramine in patients who were refractory to the antidepressant. We have compared the efficacy of this strategy with electroconvulsive therapy in patients with severe depression (Dinan and Barry 1989). Patients were randomly allocated to treatment either with lithium or with electroconvulsive therapy. In both cases, the antidepressant was con-
tinued. Outcome in both groups over a four week period was equal, but those patients treated with lithium showed a more rapid response. At the end of week 1, patients treated with lithium in combination with an antidepressant had a lower Hamilton score than those patients treated with electroconvulsive therapy. A number of research groups have focused on the hypothalamic-pituitary-adrenal axis as a target for antidepressant action. A short course of high-dose dexamethasone is reported to have antidepressant action. In patients previously resistant to sertraline or fluoxetine, we added dexamethasone 4 mg daily for three days. The dexamethasone was then discontinued and the patient remained on the antidepressant alone. Such an approach resulted in a significant drop in Hamilton depression scores. Ketoconazole, the antifungal agent, is a potent inhibitor of cortisol synthesis, We have examined its effectiveness in patients with melancholic depression who had elevated cortisol levels (Thakore & Dinan 1995). In all patients, ketoccinazole treatment produced a marked reduction in cortisol. At the same time, in each subject it enhanced serotonergic neurotransmission as indexed by the d-fenfluramine\prolactin stimulation test. In all cases, subjects showed greater prolactin release in response to d-fenfluramine challenge following ketoconazole treatment than they had at baseline. Overall, ketoconazole treatment produced a significant reduction in Hamilton depression scores. This strategy offers a second means of targeting the hypothalamic-pituitary-adrenal axis in patients who have refractory depression. Grade II hypothyroidism, characterised by elevated TSH levels and normal T4 and T3 levels, can pose significant problems when associated with depression. Studies to date indicate that such patients can be relatively treatment refractory. Whether or not they respond better to hi-iodothyronine or i-thyroxine has yet to be demonstrated in placebo controlled studies. Nonetheless, it is clear from placebo controlled studies of patients who are antidepressant resistant, that T, is a useful strategy in many patients.
References De Montigny, C., Grunberg, F.. Mayer, A. & Deschenes, J.P. (1961) Lithium induces rapid relief of depression in tricyclic drug non-responders. British Journal of Psychiatry 136, 252-256. Dinan T.G. & Barry S. (1989) A comparison of electroconvulsive therapy with a combined lithium and tricyclic combination in depressed tricyclic non-responders. Acta Psychiatrica Scandinavica 80, 97-100.
r 1
5
21
t
DAY
5
2,
DAY
1 5 21 DAY
Figure 1. Treatment illustrated.
resistant
patients
in whom dexamethasone
(4 mg) for 3 days was added to an SSRI. Hamilton
depression
scores (HAMD)
and baseline
cortisol
values
are