The treatment of mood disorders
- Medication and physical treatments
- Acute treatments for depression
- Acute treatments for mania
- Longer-term treatment for mania
- Psychological treatments
- Acute treatment of depression
- Longer-term treatment
- Bipolar disorder
- General aspects
- Medication and physical treatments
- Acute treatment of unipolar disorder
- Longer-term treatment
- Bipolar disorder
- Psychological treatments
- Acute treatment of unipolar disorder
- Acute treatment of mania
- Longer-term treatment
This article will review evidence on efficacy of treatment and deal with practical management of affective disorders, both unipolar and bipolar.
Medication and physical treatments
Acute treatments for depression
Antidepressants: general issues
The first modern antidepressants, tricyclics and monoamine oxidase inhibitors, became available in the late 1950s, coinciding with the introduction of randomized controlled trials in psychiatry, which were therefore widely used for these drugs. A progressive tightening of requirements by drug licensing authorities since has ensured that efficacy evidence is good for most antidepressants in use. Overall efficacy of most antidepressants appears to be similar as does speed of response at effective dose, although newer drugs with lower side-effects may permit more rapid build-up of dose.
The evidence also indicates limitations in the magnitude of efficacy. Differences in proportions of subjects responding well on antidepressant and on placebo are of the order of 30 per cent. Few reviews have used the concept of effect size, but they suggest effect sizes of 0.4 to 0.8. (1) This is partly due to the good response often seen in placebo groups in controlled trials. This group controls for all effects except that of the active medication, including those of spontaneous improvement, and non-specific treatment effects such as those of seeing a helping figure, supportive and specific psychotherapies, and, for inpatients, admission to hospital. For milder depressives, spontaneous remission is common and non-specific effects may be powerful. There is little to suggest that the effects of the inert pill itself contributes a large amount to remission. One meta-analysis of trials of tricyclics against active placebo, predominantly atropine, (1) pointed to smaller effects in these and suggested partial unblinding with inert placebos. This is a possibility in most trials, but the studies reviewed tended to be of only 3 to 4 weeks' duration, too short for full therapeutic effects. Outcome in placebo groups may also vary; it tends to be worse among severely ill inpatients, but here also antidepressants may be less effective, compared with electroconvulsive therapy (ECT). Placebo-controlled trials are still mandated by regulatory authorities for new antidepressants, since comparisons between active drugs have a high risk of type 2 error.
There have been many reviews of tricyclics, and further studies have accumulated as tricyclics have been used as active comparators in placebo-controlled trials of new antidepressants. An early comprehensive review (2) of the limited selection of tricyclics then available in the United States found 93 placebo-controlled trials, of which 61 found the drug to be better than placebo. The negative studies may partly be due to poor trial methodology, but also reflect the limited therapeutic benefit overall.
Regarding predictor studies of who responds best, (3,4) earlier views that tricyclics were more effective in endogenous and psychotic depressives have not been well supported. There is evidence of effects across a broad spectrum of depressives, including some dysthymics and extending more widely into anxiety disorders, panic disorder, and obsessive–compulsive disorder. A severity threshold exists at which superiority over placebo develops a little below major depression but excluding mild illness. (5,6)
Selective serotonin reuptake inhibitors
Meta-analyses of selective serotonin reuptake inhibitors (SSRIs) (7,8,9 and 10) show efficacy comparable with that of tricyclics. Conclusions differ as to rates at which patients discontinue the drugs because of side-effects. These are probably lower than for older tricyclics, but comparable withother newer antidepressants. (10)
There do not appear to be any major differences in responsive patients within depression, although there is debate, with conflicting evidence, as to whether SSRIs may be less effective than tricyclics and other combined noradrenaline (norepinephrine) and serotonin reuptake inhibitors in severe depression. There is good evidence that SSRIs and clomipramine, the most serotoninergic tricyclic, are more effective than noradrenergic tricyclics in obsessive–compulsive disorder. (11,12)
Monoamine oxidase inhibitors
There are few monoamine oxidase inhibitors available, reflecting their use mainly as second-line treatments by psychiatrists. Following recognition of the cheese reaction, they were withdrawn in some countries, but generally use remained at a lower level.
Controlled trials of the older monoamine oxidase inhibitors (13,14) show superiority to placebo in depression, and in anxiety disorders. Absence of efficacy in some large early studies appears in retrospect to be due to too low doses or short treatment periods; high doses are necessary. The reversible monoamine oxidase-A selective drug moclobemide has been reviewed more recently. (15) Again, dosage is the key. Doses below 450 mg daily are not superior to placebo, and evidence is best for 600 mg. The older hydrazine monoamine oxidase inhibitors, phenelzine and isocarboxazid, are acetylated in metabolism, and slow acetylators show better clinical response. (16)
From the late 1950s, following the views of Sargant, there have been suggestions that monoamine oxidase inhibitors are preferentially effective in atypical depression, variously regarded as non-endogenous depression, anxiety disorder with depression, or a pattern of reversed vegetative symptoms with increased appetite, increased sleep, evening worsening, reactivity, and other features. (17) The last of these meanings is currently predominant in the United States.
The evidence for selective efficacy is not very strong, but comparative trials of phenelzine and tricyclics point to better effects than tricyclics with anxiety disorders and reversed vegetative symptoms. (14) The latter has emerged in studies from the New York group. (18) On the other hand monoamine oxidase inhibitorss have been used commonly as second-line drugs where other antidepressants have failed, irrespective of clinical picture, and a meta-analysis of trials of moclobemide against tricyclics and other antidepressants showed no selective differential response. (19)
Space does not permit full review of efficacy of many other antidepressants of smaller classes. Readers are referred to textbooks (20,21) and review articles. (22)
Among older drugs, mianserin and trazodone are sedative in side-effects. Mianserin carries a definite although low risk of agranulocytosis which has had limited use since its recognition. Trazodone carries a risk of priapism in males. Bupropion is relatively stimulant and is used primarily in the United States. It has epileptogenic potential.
Among newer drugs, nefazodone (23 )is claimed to be relatively free of sexual side-effects. Venlafaxine (24) inhibits reuptake both of serotonin and noradrenaline and is an effective and useful drug in severe depression. Mirtazepine shares some actions of mianserin with additional effects on serotonin receptors; clinically it is sedative. Reboxetine is a specific noradrenaline reuptake inhibitor, similar to desipramine and maprotiline but without tricyclic effectson other receptors. Only limited evidence is available on amineptine, which has effects predominantly on dopamine reuptake, (25) and tianeptine, an atypical drug which enhances serotonin reuptake. (26)
ECT, the earliest of modern treatments, is still the most effective in severe depression. The best efficacy evidence comes from six double-blind trials against simulated ECT carried out in the United Kingdom in the late 1970s and early 1980s (reviewed by Paykel (27) ). All were carried out in severely ill inpatients. Earlier, in the 1960s there were a number of non-blind randomized controlled trials of ECT against antidepressants, mainly in hospitalized samples, which overall showed ECT superior to tricyclic antidepressants and markedly superior to monoamine oxidase inhibitors. (27,28)
Early predictor literature on ECT suggesting best effects in psychotic depression has been confirmed. Two of the trials against simulated ECT found best effects in depressives with psychomotor retardation and delusions. (29) There is also some evidence, which is not conclusive, that ECT may benefit mania. (30)
More recent studies of ECT have focused on qualities of the convulsive stimulus. Bilateral ECT is more effective overall than unilateral although it produces more memory disturbance. (31,32and 33) Low-dose electrical stimulus produces weaker response.
A recent experimental approach is transcranial magnetic stimulation—the application of repeated short-lived magnetic stimulation. Preliminary studies suggest some benefit, (34) but samples have been small.
Acute treatments for mania
The treatment of acute mania may include neuroleptics, atypical antipsychotics, and ECT as well as mood stabilizers. A review of 18 uncontrolled and three controlled studies of the use of lithium in acute mania suggested that 60 to 70 per cent of patients respond within 7 to 10 days, compared to 40 per cent of patients receiving placebo. (35) McElroy et al. (36) reviewed trials of valproate in acute mania. Overall, valproate was at least moderately effective in 60 per cent of patients, many of whom had previously failed to respond to lithium. West et al. (37) reviewed five placebo-controlled and two lithium-controlled studies of the treatment of acute mania and found valproate significantly more effective than placebo and as effective as lithium. However, few of the studies met stringent criteria. In a multicentre double-blind randomized controlled study of 179 manic patients, Bowden et al. (38) reported a response rate of 49 per cent on lithium, 48 per cent on valproate but only 25 per cent on placebo.
Controlled studies of carbamazepine in acute mania have been reviewed by Ketter et al. (39) Although many of the studies have methodological weaknesses, the evidence suggests that about two-thirds of acutely manic patients respond to carbamazepine within 7 to 10 days.
Longer-term treatment for mania
In recent years, it has become apparent from follow-up studies that the long-term outcome of depression is still often problematic. It is customary to distinguish between relapse, or early symptom return, assumed to be a return of the original episode, and later recurrence of a new episode. (40) In parallel, drug treatment after the acute episode has been divided into earlier continuation treatment, to prevent relapse, and longer-term maintenance treatment to prevent recurrence.
There have been many controlled trials of continuation treatment, in which responders to acute treatment are randomized either to withdraw double blind on to placebo or to continue on active drug for 6 to 8 months. All studies show substantial benefit from continuation. (41) A recent controlled trial of fluoxetine with staged withdrawal showed benefit of continuation for 24 and 38 weeks, but not 62 weeks. (42)
Longer-term maintenance studies of antidepressants including tricyclics, monoamine oxidase inhibitors and SSRIs have mostly employed withdrawal designs but a small number have commenced the maintenance drug after other acute treatment. The withdrawal design may exaggerate therapeutic benefit if withdrawal is abrupt with rebound symptom return, and also because it selects responders to the particular acute treatment, often from samples chosen as highly recurrent beforehand.
The trials show clear benefit from antidepressants in maintenance treatment of unipolar depression. (41) However, benefits are weaker than in continuation treatment and recurrence rates in drug-treated patients have often remained moderately high.
There may be withdrawal reactions if antidepressants are stopped abruptly. There has long been recognition of a transient withdrawal syndrome after abrupt stopping of tricyclics, often in high dose for long periods, with malaise, coryza-like symptoms, vomiting, and diarrhoea. It has been attributed to withdrawal of atropinic effects, but somewhat similar symptoms have been reported recently on withdrawal of SSRIs and other antidepressants. (43)
A number of trials of lithium in maintenance treatment of severe recurrent unipolar depressives also show benefit over placebo. (44) The relative benefits of lithium and antidepressants are not clear, with direct comparisons somewhat evenly balanced. In practice, response to an antidepressant followed by its maintenance is a much more common clinical practice.
Maintenance treatment of bipolar disorder
Maintenance treatment of bipolar disorder has been reviewed extensively. (45,46 and 47) Controlled trials of lithium against placebo have been criticized because of the possibility of withdrawal effects, (48) but there is little doubt of therapeutic effects. (49) Lithium is also superior to tricyclic antidepressant alone, particularly because of high rates of mania with the latter. (44) Lithium has not been well evaluated as an active antidepressant, but effects appear to be weak. (50)
It has become clear that there are high rates of early recurrence, particularly of mania, when lithium is discontinued after long-term use. (51,52) This rebound, which may have exaggerated therapeutic benefit in trials, mandates slow withdrawal in practice. One study (53) has indicated greater benefit on residual symptoms for doses producing blood levels 0.8 to 1.0 mmol/l than for 0.4 to 0.6 mmol/l.
There have been fewer long-term studies of anticonvulsants. (50,54) Valproate is approved in the United States for treatment of mania. Controlled trial evidence of efficacy in prophylaxis is sparse although it is commonly used in this circumstance. Carbamazepine has been used for longer. There is good evidence of efficacy in mania (45,54) and there have been longer-term controlled studies which suggest benefit. Other anticonvulsants have also been tried in bipolar patients; lamotrigine is currently the most advanced in evaluation.
Acute treatment of depression
Psychological treatments: general issues
There is high public demand for psychotherapies for unipolar depression. Recently, the use of these interventions in bipolar disorder has also been advocated. (55) Guidelines for the use of psychotherapy in depression are less well developed than for pharmacotherapy and are based on less robust empirical data. Early research into the benefits of psychotherapy in depression comprised single case studies, small case series, and open or non-randomized treatment trials. The increase in randomized, controlled trials of psychotherapy for depression can be attributed both to the introduction of ‘manualized' (or ‘protocol-driven') therapies, enabling consistency of application (56) and valid and reliable evaluations, and to the emphasis on evidence-based medicine and cost-effectiveness. (57)
Almost all the controlled trials of psychotherapy for depression undertaken have employed manualized therapies. The interventions share the common characteristics of being time limited (less than 20 sessions), with primary targets symptom reduction and problem resolution. Cognitive therapy, interpersonal therapy, behavioural therapy, and some models of brief dynamic psychotherapy fall into this category. The largest volume of efficacy research has focused on cognitive therapy (about 50 studies), with fewer studies (about 30 in total) of interpersonal therapy, behavioural therapy, and other dynamic therapies. Sample sizes are often smaller than desirable and many studies have methodological weaknesses including the failure to include pill-placebo control groups.
Early meta-analyses were hampered by use in most most outcome studies of ‘completer' samples rather than ‘intent-to-treat' analyses. A meta-analysis of 81 studies of the treatment of neurotic disorders (mainly depression) (effect size 0.97) showed that specific psychological therapies, particularly cognitive therapy, were more effective than other verbal therapies (effect size 0.74) or waiting-list controls. (58) Other meta-analyses, restricted to acute depressive episodes, found similar trends for superiority of cognitive or behavioural approaches over other therapies. (59,60) Dobson (61) reviewed studies of cognitive therapy using the Beck Depression Inventory as the primary outcome measure. Cognitive therapy gave effect sizes of 2.15 compared to waiting-list controls, 0.46 compared to behavioural therapy, and 0.53 compared to pharmacotherapy. Robinson et al. (62) identified 58 outpatient depression treatment studies. Overall behavioural therapy and cognitive therapy showed moderate effect sizes, with cognitive therapy showing marginal superiority over behavioural therapy. Psychological therapies also showed a small but significant advantage when compared with pharmacotherapy (mean effect size 0.12). However, Robinson et al. (62) found that the results of their meta-analysis became less stable if the allegiance of the researcher to a particular therapeutic model was taken into account. Using regression analysis to partial out the effect of allegiance virtually extinguished differences in treatment outcome.
The most recent meta-analysis of 29 carefully selected controlled trials, employing intent-to-treat design, explored group and individual therapies for major depression, included the National Institute of Mental Health (NIMH) study, (63) and also incorporated interpersonal therapy studies for the first time. The study used categorical outcomes (recovered versus not recovered). The efficacies of individual cognitive therapy (response rate, 50 per cent), behavioural therapy (55 per cent), and interpersonal therapy (52 per cent) in the treatment of the acute episode were not significantly different and compared favourably with pharmacotherapy (58 per cent). Brief dynamic psychotherapies, mainly group therapies, were less effective (35 per cent) and only marginally superior towaiting-list controls (30 per cent). Cognitive therapy was less effective in a group format (39 per cent), behavioural therapy was equally effective, and interpersonal therapy was more beneficial when a significant other took part in therapy, rather than one individual alone.
Almost all trials of psychological therapies have been in outpatient depressives, not above moderate severity. Comparisons with pharmacotherapy must be interpreted in this light and do not represent severe or inpatient disorder.
Earlier studies of individual cognitive therapy suggested that it was at least as effective and acceptable as antidepressant drugs (or ‘treatment as usual') in the treatment of non-psychotic outpatient unipolar depressives in primary care and hospital outpatient settings (for reviews see Hollon et al. (64) and Scott (56) ). Furthermore, severity and endogenicity did not appear to be a contraindication to cognitive therapy. However, most of these studies had significant methodological flaws. The three-centre NIMH study (63) sought to overcome these. A total of 239 patients with major depression were randomly allocated to one of four treatments, imipramine with clinical management, pill placebo with clinical management, cognitive therapy, or interpersonal therapy. Treatments were undertaken by trained and supervised therapists. The primary analysis showed few differences between the active treatments. A secondary analysis which controlled for severity of depression, found that cognitive therapy was not as effective as pharmacotherapy in the more severe disorders within the outpatient range studied. The findings have been subject to debate, particularly over variations between sites and adequacy of therapist supervision. (64) Hollon et al. (65) undertook a well-designed controlled trial of cognitive therapy and pharmacotherapy in 107 patients. The primary and secondary analyses, again controlling for severity, did not demonstrate any significant between-group differences in treatment outcome.
Fewer outcome studies are available regarding the efficacy of interpersonal therapy, behavioural therapy, or brief dynamic psychotherapy. Most data are available for interpersonal therapy. The first randomized study in depressed women (66) found that only antidepressant prevented relapse, whilst interpersonal therapy, started 6 weeks after acute amitriptyline had a significant effect on social functioning. In a later study (67) interpersonal therapy was as effective as amitriptyline in acute treatment of outpatient depression. The NIMH study (63) is the only one that has compared interpersonal therapy with a pill-placebo control. Interpersonal therapy was nearest to the effectiveness of imipramine but a little weaker.
Few acute controlled trials of other therapies have been published. Two large-scale studies of individual behavioural therapy are available. In a comparison of behavioural therapy with insight-orientated therapy, antidepressant drugs, and relaxation, the behavioural approach was more effective than insight-orientated therapy (which tended to fair worst overall), but differences between treatments had largely disappeared at 3 months' follow-up. (68) Hersen et al. (69) randomly allocated 125 depressed females to antidepressant drug treatment, social skills training plus antidepressants, social skills training plus placebo or dynamic therapy plus placebo, and found similar outcome in all groups.
Few high-quality studies exist on marital and family models of psychotherapy. It is clear that cognitive therapy, interpersonal therapy, and brief dynamic psychotherapy can be applied to families, groups or couples, but the only published randomized controlled trials on marital therapy mainly draw on behavioural approaches. For example, O'Leary and Beach (70) demonstrated that behavioural marital therapy or cognitive therapy were both more effective than waiting-list controls in treating women with depression or dysthymia. Furthermore, Jacobson et al. (71) demonstrated an advantage for behavioural marital therapy over cognitive therapy in depressed individuals with marital discord.
Combined psychotherapy and pharmacotherapy
Data on whether the use of a combination of psychotherapy and pharmacotherapy bestows additional benefit over either treatment alone are not conclusive. Overall the studies suggest a small advantage at the level of severity usually studied. Conte et al. (72) in a meta-analysis suggested an advantage for combined treatments, but this review has been criticized. (57) Hollon et al. (64) found a non-significant trend for a higher response rate with a combination of pharmacotherapy and cognitive therapy as opposed to either treatment alone. A similar trend is reported in studies of interpersonal therapy plus medication as compared to either treatment alone. (66,67) However, when these data were included in a single meta-analysis of eight outcome studies, neither cognitive therapy, behavioural therapy, or interpersonal therapy added to antidepressants were any more effective than pharmacotherapy alone. (73)
These analyses have primarily used symptom outcomes. An equally important target of interpersonal therapy and dynamic psychotherapies may be improvement in interpersonal relationships and social adjustment. There is some evidence for interpersonal therapy of preferential benefit on such measures. (74) This may result in benefit from the combination, by effects on different measures.
There are few adequately designed studies examining the role of psychotherapy in the prevention of relapse or recurrence of depression. None is available on brief dynamic psychotherapy. Short-term follow-up studies of behavioural therapy (68,69) and interpersonal therapy (75) do not demonstrate any significant differences in outcome between these interventions and the other psychological or pharmacological treatments with which the approaches were compared.
Most cognitive therapy studies comprise naturalistic follow-ups of treatment responders in previously published acute depression studies, sometimes without adequate drug continuation. Better drug continuation was used in the study by Evans et al. (76) which prospectively followed up a cohort of patients treated in a randomized controlled trial of cognitive therapy and pharmacotherapy. (65) In this study the relapse rate in the cognitive therapy group (20 per cent) was no different from that in the drug continuation treatment group (27 per cent) and less than half that of the patients who had drug treatment withdrawn at the time the depression remitted (50 per cent). These findings support trends in the NIMH follow-up (77) and other naturalistic follow-up studies that cognitive therapy reduces relapse rates.
Continuation and maintenance trials
The use of continuation and maintenance psychotherapy is a new concept in psychological treatment studies. In a follow-up study Blackburn et al. (78) offered about five sessions of cognitive therapy over the following 6 months to subjects from an acute treatment study. At 2-year follow-up, the relapse rate in patients who had received acute pharmacotherapy was significantly higher than that in patients who had received cognitive–behavioural therapy either alone or in combination with medication. Blackburn and Moore (79) allocated subjects with recurrent major depression to 16 weeks of acute treatment and 2 years of maintenance treatment which comprised either antidepressants alone, cognitive therapy alone, or antidepressants followed by maintenance cognitive therapy. All groups improved in the acute phase and there were no differences in relapse rates in the maintenance phases, suggesting that cognitive therapy may be a viable alternative to maintenance medication.
Recently there have been two controlled trials designed to test reduction of relapse and recurrence rates by cognitive therapy given after the acute episode in patients with residual depressive symptoms after major depression. (80,81) Both studies compared cognitive therapy with clinical management in patients with residual depression following antidepressant treatment. Both studies found significant worthwhile reduction in relapse and recurrence rates.
There is evidence from a well-designed 3-year study of maintenance interpersonal therapy, undertaken at monthly intervals, that interpersonal therapy may reduce the risk of relapse. (82) However, benefit was much greater from imipramine than from interpersonal therapy. Effects of interpersonal therapy were more substantial where it was rated as of high quality.
Psychotherapy for bipolar disorders has not been systematically studied. No studies are available on psychological interventions in acute mania. Reviews by Scott (55) and by Roth and Fonagy (57) highlight that psychosocial interventions undertaken during other phases of bipolar disorder all resulted in greater symptomatic improvement and social adjustment than treatment with medication alone. However, the studies were poorly designed and the data are weak. The only controlled trial published (83) randomly assigned a small sample of 28 subjects to either six sessions of compliance-oriented cognitive therapy or standard clinic care. In the next 6 months lithium compliance appeared to be enhanced in the cognitive–behavioural therapy group, who also showed fewer hospitalizations. The most promising approaches to bipolar disorders appear to be cognitive therapy, interpersonal therapy–social rhythms therapy, and family therapy, and large-scale controlled trials of these therapies are now underway in the United Kingdom and the United States.
The goals of treatment of affective disorders are to alleviate acute symptoms, to restore psychosocial functioning, and to prevent relapse and recurrence. Crucial decisions in clinical management are the appropriate selection of an intervention and treatment setting. Research on which depressed patients will respond to a particular treatment offered in a particular setting does not give a good practical guide. (84) Pragmatic decisions regarding management usually focus on four key issues: the severity of the disorder (including risk of harm to self or others), the availability of effective treatments (either specific antidepressants or trained therapists), patient preference, and the nature of any associated difficulties.
Severe cases of depression with significant suicidal risk are often best managed in inpatient facilities to allow regular observation and careful monitoring of the patient's mental state. If risk of suicide is lower and the patient has appropriate social support it may be possible to manage severe cases with intensive community support, such as partial hospitalization, day care, or a combination of outpatient and home-based care. Moderate or mild cases of depression can usually be managed in outpatient settings, unless treatment is complicated by comorbidity of severe physical or other mental disorders (including drug or alcohol misuse) or non-response requires more detailed assessment.
Although severe cases of depression may respond to psychotherapy alone, the rate of recovery is slower than with drugs or ECT. (56) Psychotherapy may be used in addition to drugs or ECT, but should not be used alone. In mild or moderate depressions, treatment choice may be more balanced and depends partly on patient preference and, for psychotherapies, on availability, although when major depression criteria are reached antidepressants should not generally be withheld.
Most patients with affective disorders are treated in primary care or general medical settings. Cases seen by specialist mental health services are usually referred because the disorder is more severe, chronic, treatment resistant, or because other difficulties, such as alcohol misuse or marital difficulties, complicate the clinical picture. In these situations it may be necessary to use combinations of drugs and psychosocial approaches. The rest of this section gives an overview of physical and psychological treatments. Although these approaches are described separately, the treatment of affective disorders rarely involves simply prescribing medication. Education and support of a depressed patient and his or her family are important aspects of any clinical management package.
Medication and physical treatments
Acute treatment of unipolar disorder
The most important indications for use of medication are probably severity and persistence. Two studies (5,6) have shown a threshold a little below major depression at which tricyclic antidepressants start to show superiority over placebo in acute episodes of depression. There is not yet equivalent evidence for SSRIs. Tricyclics are also superior to placebo in dysthymia, (85) but most studies do not separate those dysthymics without added major depression. For mild acute depressive episodes highly reactive to major stress, and for acute grief, prognosis for spontaneous resolution is often good, and medication may be delayed, provided that improvement is occurring. Impairment of function and suicidal feelings in the context of the depressive syndrome are other indications to treat. Recent guidelines (73,86) recommend use in major depression, equivalent to ICD-10 depressive episode. For depressions reaching these criteria, antidepressants should be used irrespective of life stress or symptom pattern: counselling and psychotherapy may be combined with antidepressants where indicated.
Choice of antidepressant
Because the evidence of selective response is weak, and overall efficacy appears equivalent, choice of initial antidepressant legitimately varies considerably among clinicians and countries. Where cost is an important consideration, some older tricyclics are very inexpensive. Where cost minimization is less crucial, SSRIs and newer antidepressants often have advantages in side-effects and tolerability. Irrespective of first choice, troublesome side-effects indicate a change to an antidepressant with a different side-effect profile. Monoamine oxidase inhibitors are little used as first choices. Where there is a previous history of antidepressant response, the best first choice is the antidepressant to which the patient previously responded.
With a few exceptions clinical symptom pattern is not in practice a good guide to treatment. Effects of the tricyclics extend widely across the spectrum of depression and in to anxiety disorders. The place of SSRIs in very severe depression is still debated. On the other hand their lower incidence of side-effects and absence of sedation can render them easier to use in milder depression. Monoamine oxidase inhibitors are a reasonable first choice in atypical depression. A reversible inhibitor of monoamine oxidase A (moclobemide) is safer.
Comorbidity with anxiety is common in depression. Here the evidence is still too weak to determine treatment choice. For concomitant obsessive–compulsive disorder clomipramine, or the SSRIs, are preferable to noradrenergic antidepressants.
Some special situations require specific treatment choices. Major suicidal risk, particularly by overdose, points away from tricyclics, most of which carry considerable risk of death by cardiac arrhythmia. SSRIs and most newer antidepressants are comparatively safe in overdose.
Cardiac problems also indicate use of a non-tricyclic antidepressant. Although tricyclics can often be used without major problems, there is risk of arrhythmia, particularly partial or complete heart block, and orthostatic hypotension is common. Monoamine oxidase inhibitors lower blood pressure as a dose-related effect and are also better avoided.
Concomitant epilepsy can often easily be controlled by adjustment of anticonvulsant dose. Tricyclics are epileptogenic and should be avoided. Epileptic potential is usually less with newer antidepressants but is often not clear, and the only antidepressants clearly established to be free of epileptic potential are older monoamine oxidase inhibitors.
The elderly are particularly liable to anticholinergic side-effects, including confusion, and orthostatic hypotension may precipitate falls and fractures. SSRIs and newer antidepressants are preferable to tricyclics.
Antidepressant treatment of patients with medical disorders is often difficult, because of toxicity due to the medical disorder, high blood levels due to impaired metabolism, side-effects, and drug interactions. All antidepressants interact with some other medications, including SSRIs, which affect other medications metabolized by the cytochrome P-450 system. Choice of antidepressant depends on the specific situation.
The tricyclics have been used in pregnancy and do not carry risk of fetal malformation. For SSRIs and newer antidepressants thesituation is less clear as sufficient experience is lacking: they usually carry warnings against use in pregnancy. Accumulating experience suggests that fluoxetine is safe. (87) Mood stabilizers are contraindicated; lithium, carbamazepine, and valproate all have some risk of fetal malformation. Where antidepressants are used at the time of delivery there may be complications of anaesthesia and fetal sedation, and these should be anticipated. Most antidepressants and mood stabilizers appear in breast milk, but in small quantities. Breast feeding should be discussed with the patient.
Clinical use of antidepressants
There is a delay in clinical antidepressant effects of 1 to 3 weeks or longer, although some improvement may be seen earlier. Medication needs to be continued for a minimum duration of 6 weeks at adequate or high dose before treatment can be deemed ineffective.
For most antidepressants, side-effects are most apparent in the early weeks and some tolerance develops so that build-up of dose over 2 to 3 weeks is advisable. Newer drugs, better tolerated, allow more rapid dose escalation. For fluoxetine, the exceptionally long half-life of the active metabolite means that blood levels build up for some weeks, even on a standard dose.
Dose division during the day can be based on pharmacology. Half-lives of most antidepressants are such that, combined with delay in therapeutic effects, one dose per day is adequate, but for most, two doses per day is better; three doses are useful where daytime sedation is an advantage. For fluoxetine only a single dose is appropriate. Moclobemide, as a competitive monoamine oxidase inhibitor which is easily displaced and metabolized, should be given in three doses daily. For sedative antidepressants, administration of two-thirds of the dose at night is beneficial and enables avoidance of hypnotics, although it may leave a little morning ‘hangover' sedation. Doses at bedtime of the more stimulant antidepressants, including monoamine oxidase inhibitors and SSRIs, should be avoided.
Common side-effects of tricyclics clinically are sedation and anticholinergic side-effects of dry mouth, blurred near vision, urinary retention, orthostatic hypotension, and confusion in the elderly. Common side-effects of SSRIs are nausea, and other gastrointestinal disturbances, insomnia, and sometimes tension and restlessness.
Dose-limiting side-effects of monoamine oxidase inhibitors are hypotension, insomnia, and ankle oedema.
A common problem in use of antidepressants is low dosage. If response does not occur and side-effects are not severe, doses should be progressively increased until either response occurs, severity of side-effects precludes further increase, or dose becomes very high. In the United States, doses of older tricyclics used may be up to 300 mg daily, although in Europe 200 to 250 mg are more common maxima. Monitoring plasma levels of mood stabilizers is an essential part of good clinical practice, but the use of plasma drug levels for other drugs has equivocal support. (88) A single plasma level measurement is less likely to help in management decisions than a short series of two to three measurements, but monitoring may help in the following circumstances: (73) non-response or partial response to therapeutic doses of a particular drug; symptom breakthrough following full response; symptoms of toxicity at low or therapeutic doses; situations of altered metabolism (elderly people, pregnant women, patients with medical illness, psychiatric comorbidity, or receiving other drugs that affect antidepressant metabolism); potential non-compliance.
Extent of clinical use of ECT varies cross-nationally. Many psychiatrists, including ourselves, use it as a first choice treatment in severe depression with psychomotor retardation or mood-congruent depressive delusions. Alternatively an antidepressant may be tried, with a change to ECT if there is poor response or worsening. ECT is also appropriate for moderately severe depressions which have not responded to one or two courses of antidepressant.
An alternative to ECT for the treatment of psychotic (delusional) depression with mood-congruent delusions is combination of neuroleptic and antidepressant. Spiker et al. (89) report that only 35 per cent of psychotic depressions responded to tricyclics alone, but 80 per cent responded to tricyclics plus antipsychotic medications. Neuroleptic–antidepressant combinations are also indicated where there are non-mood-congruent delusions or schizoaffective symptoms.
In the United Kingdom, the Royal College of Psychiatrists (90) has made detailed recommendations on administration of ECT, including equipment, anaesthesia, and the use of stimulus dose titration to achieve a moderately suprathreshold dose.
Non-response and resistant depression
If the first choice of antidepressant medication fails, a change should be made to an antidepressant of a different class, or to ECT. There is little to support change to an alternative antidepressant of the same class. If the second choice fails, a third-class, ECT, or lithium augmentation (see below) are appropriate choices, depending on the circumstances.
If there is still limited response, a more systematic approach to resistant depression should be adopted.
1. Reassess the situation thoroughly, with full history, assessment, and laboratory investigation of thyroid function to ask the following questions.
a. Is the diagnosis correct? Wrong diagnosis is in practice unusual.
b. Are there perpetuating factors in personality, family environment, or the social setting? It is common where depression has been long term that secondary role loss (including work) and family adaptations to a non-functioning member mean there are no roles or relationships for the patient to return to and remission cannot occur, or is transient, unless psychotherapy, family therapy, and rehabilitation are employed to change the situation.
c. Is hypothyroidism impairing response? This may develop as a result of earlier use of lithium.
2. Consider previous treatment. Failure to use high-dose antidepressant is a common reason for apparently resistant depression, or at least was so in the past. (91)
3. Consider drug and other physical treatments.
4. As remission occurs, introduce psychotherapeutic, cognitive, and rehabilitative interventions.
The actual choices depend on what has been used before. A common sequence is to start with the most promising antidepressant suggested by the history and to push it to a very high dose. Clomipramine has in the past been used by many psychiatrists for this purpose. Our clinical experience suggests that venlafaxine, with similar actions but lower side-effects, is an appropriate substitute, with monitoring of blood pressure for elevation as high doses are reached. Whatever the antidepressant, doses in excess of officially recommended levels may be required.
The next intervention is to use an augmentation strategy. Lithium augmentation is the easiest and probably most effective. There is good evidence of efficacy. (92,93) Blood levels required for augmentation are not established, but are probably similar to those for maintenance. Tremor may be a troublesome side-effect with tricyclics, particularly clomipramine. If response occurs, it is our practice to continue the lithium for some months, but not as long as antidepressant, although controlled trial evidence is lacking. Care should be taken to monitor for a serotonin syndrome (excitability, restlessness, temperature elevation), particularly with SSRIs.
There is some evidence that L-tryptophan may potentiate monoamine oxidase inhibitors and the more serotoninergic uptake inhibitors. (94) This amino acid was withdrawn from the market because of eosinophilic myalgia, but is now available again in some countries. Its effect is weak, but may be combined with lithium potentiation.
Thyroid hormone, particularly tri-iodothyronine, (95) may also potentiate antidepressants. It is used less frequently in clinical practice; care must be exercised if there are cardiac problems.
There is accumulating evidence that pindolol, which has effects in blocking 5-HT1A autoreceptors, can accelerate speed of antidepressant response. (96) Augmentation of amount of response is less clear, but it may have a place in this circumstance.
At one time combinations between tricyclics and monoamine oxidase inhibitors were often used in resistant depression. Although two controlled trials suggested that the combination was not superior to single antidepressant, (97,98) subjects were not resistant cases. It occasionally still has a place, combined with lithium. Serotoninergic uptake inhibitors are contraindicated because of the risk of serotonin syndrome. Tricyclics other than clomipramine may be combined with older monoamine oxidase inhibitors or moclobemide, with gradual dose increase of both. In ordinary clinical practice 1 to 2 weeks should intervene between stopping an older monoamine oxidase inhibitor and starting a reuptake inhibitor, because of the risk of interaction until new monoamine oxidase is synthesized.
When vigorous medication regimens have still not produced a response, it is often helpful to add bilateral ECT to maximal drug therapy, even when ECT alone has not helped in the past. When all else fails in intractable severe chronic depression, psychosurgery still has an occasional place. In spite of the absence of controlled trials, it does appear sometimes to be helpful, when followed by active rehabilitation.
In view of the strong evidence from controlled trials, continuation for approximately 6 months is recommended as routine practice following response to acute treatment of major depression. (73,86) There is one trial in dysthymia showing similar benefit. (99) Although clear evidence is lacking, it should also probably be routine in milder acute episodes treated with antidepressants, unless there is strongly suggestive evidence that the response is non-pharmacological, for example occurring on very low dose, developing very early after treatment commencement, or closely related in timing and context to reversal of a major stress.
Continuation is particularly important where there has been partial remission with residual symptoms, or a history of previous relapse or recurrence. There is good evidence of high rates of relapse where residual symptoms are present. (100) One study showed particular superiority of drug over placebo in this situation; (101) in another study relapse after stopping antidepressant only occurred where 4 months completely free of symptoms had not supervened. Sometimes continuation antidepressant or lithium may be required after ECT, where relapse has occurred.
The dose used for continuation should initially be the same as the acute treatment dose. After 2 to 3 months this may be reduced if side-effects are a problem, but only by a small amount, to avoid symptom return.
The usual length of antidepressant continuation should be about 6 months after response. The patient should also be completely free of residual symptoms for 4 months. Withdrawal should then be carried out slowly, over 2 to 3 months, to minimize the risk of relapse, and of withdrawal symptoms.
In some patients, complete withdrawal, or achievement of a low dose, will be followed by return of depressive symptoms. This phenomenon usually reflects a genuine relapse, and in one study relapse rates on placebo withdrawal and open withdrawal to no drug were the same. (67) If symptoms persist, full dose should be resumed, followed by continuation for a further period of 9 months to a year. Some of these patients relapse again on later drug withdrawal, and long-term maintenance should then be considered.
Longer-term maintenance is indicated where there have been several recurrences. Various recommendations for initiating maintenance have been formulated, such as two episodes in the last 2 years, or three episodes in 5 years. (46,73) This also depends on the severity of episodes, their potential impact on personal life, family life, and career, and the patient's preference and willingness to commit to prolonged drug treatment. Discussion is required with the patient, and where appropriate the family, to reach a joint decision.
For most unipolar depressives the maintenance treatment choice will be whichever antidepressant has been effective and well tolerated. Where antidepressants have not been fully effective, lithium or combination are required. Antidepressant doses should be of the same order as those needed for acute treatment in the particular patient. The length of maintenance is harder to specify, and it depends on the previous history, but it should be at least 3 to 5 years, particularly where there has been a good acute response to antidepressant, persisting through continuation. (102) Drug withdrawal should be attempted at some point thereafter, unless there is clear evidence from previous history that further recurrence has followed previous withdrawal. Withdrawal of antidepressants, lithium, or other drugs after long-term maintenance should always be gradual. Where withdrawal is followed soon after by a recurrence, longer-term maintenance is indicated, and where this sequence has been repeated, lifelong treatment.
The treatment of bipolar depression is in principle similar to that of unipolar depression. Lithium may produce some benefit alone, but usually an antidepressant is required in addition. Antidepressants may precipitate mania, and rapid cycling, so that combination with a mood stabilizer is usually desirable. It is a clinical impression that rapid cycling may occur more readily with uptake inhibitors than with monoamine oxidase inhibiting agents including moclobemide. Bipolar depression is often characterized by increased sleep, one feature of an atypical depression. ECT may be indicated, in similar circumstances to those in unipolar depression, and does not appear to lead to rapid cycling.
Acute treatment of mania
A number of mood stabilizers are reported to have an acute antimanic effect, but the Expert Consensus Guideline on the Treatment of Bipolar Disorder (103) advocated either lithium or valproate as the drugs of first choice. Valproate is often preferred for patients with mixed states or rapid cycling disorder. Response to lithium or valproate is usually delayed by 7 to 14 days, so most clinicians also use other drugs such as neuroleptics or atypical antipsychotics. These are effective within a matter of days in controlling the acute symptoms of mania, particularly delusions, hallucinations, thought disorder, or severe agitation. The main problem with the classic combination of haloperidol and lithium is the need for close monitoring, as manic patients are at greater risk of neuroleptic malignant syndrome and a combined lithium–neuroleptic neurotoxicity syndrome has also been reported. Benzodiazepines such as lorazepam and clonazepam are frequently used to treat hyperactivity, insomnia, and agitation. (103)
The loss of insight, impaired judgement, and disinhibited behaviour of manic patients or the level of agitation and hyperactivity often mean that hospitalization is required to ensure the patient's safety and commence an appropriate treatment regimen. For severe cases of mania, ECT may occasionally be used as a first-line treatment.
Continuation and maintenance treatment
Continuation treatment is indicated for at least 6 months after acute bipolar episodes, using the single medication or combination of mood stabilizers, antidepressants, and neuroleptics that has been used in acute treatment. Since neuroleptics have the least specific effects and carry occasional risk of tardive dyskinesia even after short-term treatment, they should be terminated first.
Bipolar disorder is more recurrent than unipolar disorder, and the disinhibition of mania can have catastrophic long-term effects on personal life. The threshold for maintenance treatment is therefore lower than for unipolar disorder. There is a case for 1 to 2 years' maintenance following a first episode of mania.
Choice of mood stabilizer includes an increasingly wide range. Probably lithium is still the drug of first choice, in the absence of major side-effects or patient reluctance. It is usual to recommend doses to achieve blood levels 12 h after the last dose of 0.4 to 0.8 mmol/l. Sometimes higher levels may be necessary to prevent recurrences, and to reduce residual symptoms. (103) After some months of use blood levels are often very stable and only require very occasional monitoring. Advice needs to be given on circumstances which may disturb blood levels (e.g. dehydration, gastrointestinal upset, travel, hot climates). Thyroid function should be monitored every 6 to 12 months, in view of possible insidious onset of hypothyroidism.
Poor or partial responses are not uncommon, and carbamazepine or valproate should be added. They are alternatives as single drugs where the patient prefers. Valproate is increasingly a drug of first choice in the United States. Blood levels for bipolar disorder are not well established but it is usual to target blood levels in the anticonvulsant range. In treatment-resistant cases, there is an increasing trend toward the use of combinations of mood stabilizers (particularly lithium and valproate). The indications and precautions necessary when using such combinations are reviewed by Freeman and Stoll. (104)
Antidepressants can often be slowly withdrawn in bipolars after mood stabilizers are well established, but may be necessary to prevent depression; mood stabilizers, particularly lithium, appear to have better effects in preventing mania. Antidepressants should not usually be used alone for maintenance in bipolars in view of the risk of mania. Neuroleptics, although better avoided in the long term, are sometimes necessary in multiple drug combinations in highly recurrent bipolar disorder. Very occasionally depot neuroleptics are helpful in non-compliant subjects.
Length of maintenance treatment necessarily varies, from a few years, to lifelong where several recurrences have followed withdrawal. There have been fears that withdrawal of lithium might be followed by treatment resistance in recurrences, but a recent study suggested that this is not the case. (105) Withdrawal of lithium should always be slow, over 3 to 6 months, in view of the evidence for rebound mania. In the absence of evidence to the contrary for the anticonvulsants it is best to follow a similar practice.
Acute treatment of unipolar disorder
The psychological management of acute depression ranges from basic clinical management, supportive psychotherapy, psychoeducation sessions for the individual with their partner or family present, through to formal psychotherapy. Clinical management and family psychoeducation sessions will involve education about the nature of the disorder (including polarity, course, and prognosis), treatment options (including the advantages and disadvantages of psychotherapy, or in the use of drugs, the delay in benefits, and probable side-effects) and an early discussion about the planned length of treatment. These basic sessions can help build a strong alliance between the clinician and the patient, overcome misconceptions about the diagnosis and treatment (such as fears of addiction to antidepressants), reduce tension in interpersonal relationships and significantly reduce barriers to medication compliance.
For some individuals the reduction in symptoms that occurs after the introduction of medication restores them to their previous level of functioning and they are once again able to use their own coping skills to resolve personal problems. However, for others, the disorder is only partially resolved or the nature of problems is such that additional input is required over a longer period of time. Such cases may benefit from longer-term supportive psychotherapy. This may be provided in an outpatient clinic, but might also be provided through day services or visits by a community psychiatric nurse.
Formal psychotherapy may be offered as the only treatment to individuals with milder depressions or in combination with medication in those with moderate and severe disorders. More than 20 per cent of couples report marital discord in association with depressive disorders and so marital or family approaches should always be considered as an alternative to individual therapy. Individual treatments, such as cognitive therapy, may particularly benefit milder depressions. There are a number of features that identify potentially effective psychological approaches to depression. (56) The therapy should be highly structured and based on a coherent model. It should provide the patient with a clear rationale for the interventions made and the therapy should promote independent use of the skills learned. Change should be attributed to the individual's rather than the therapist's skillfulness and the therapy should enhance the individual's sense of self-efficacy. Clearly cognitive therapy, behavioural therapy, and interpersonal therapy conform to this description. The choice of which of these models to use is less dependent on the patient's presentation than on the availability of a trained and experienced therapist. Adherence to the therapy model, therapists' level of expertise and skill and the provision of regular and adequate supervision to the practitioner are important determinants of outcome and may account for some 30 per cent of the variance in patient's improvement. (57) Furthermore, the more severe or complex the case, the more important therapist factors become. (56,57) It is also likely that more severe or chronic disorders will require a more prolonged course of therapy. Scott and DeRubeis (106) reviewed studies using cognitive therapy plus drugs in patients with non-responsive depression and found that the average response rate (about 44 per cent) was about the same as that achieved with lithium augmentation, but tended to increase with expertise of the therapist and overall duration of treatment.
Acute treatment of mania
Psychotherapy has not been tested in manic patients, but it is important to use clinical management, supportive therapy, and psychoeducational sessions as described previously. Clarkin et al. (107) have demonstrated that the use of inpatient family interventions (about six sessions) with patients who have been stabilized in hospital can have beneficial effects extending beyond discharge.
In day-to-day practice, supportive therapy or other forms of psychological input may extend over considerable periods of time. In addition, people with affective disorders form about 15 to 20 per cent of the long-stay patient populations of mental hospitals in the United Kingdom and the United States. Rehabilitation techniques as applied to schizophrenia and other severe mental disorders are important for instilling hope and developing day-to-day living skills in people with chronic or recurrent affective disorders. Lastly, all individuals with chronic health problems are at high risk (about 50 per cent) of non-compliance with medication. (108) Jamison et al. (109) have identified the potentially critical role of psychotherapy in enhancing medication compliance in bipolar disorder and outlined an intervention programme. (47)
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