Evidence-based guidelines for treating depressive disorders with antidepressants continued

Alternatives to antidepressants

• Choice between drug and non-drug treatments for depression should be informed by evidence base, individual patient characteristics and choice, and treatment availability

Psychological and behavioural treatments

• For major depression of mild to moderate severity:
• cognitive behaviour therapy (CBT) is recommended especially if psychological treatment is used as monotherapy for recurrent depression
• behaviour therapy/activity scheduling (BT/AS)
• interpersonal psychotherapy (IPT)
• For severe major depression:
• psychological or behavioural treatment is not recommended as sole therapy, but routinely consider adding CBT or BT/AS to antidepressant treatment

• For major depression in children and adolescents:
• consider CBT for those not responding to initial structured supportive treatment
• combining CBT with selective serotonin reuptake inhibitors (SSRI) is not recommended routinely as first-line treatment for adolescents

Physical treatments

• Electroconvulsive therapy (ECT):
• consider as a first-line treatment for severe major depression in an emergency situation (e.g. not eating or drinking, depressive stupor, extreme distress, suicidality)
• is not recommended as a first-line treatment for depression in non-urgent circumstances
• consider for treating major depression where first-line treatments are not possible or feasible

• Light therapy:
• is a first-line treatment for the acute treatment of seasonal affective disorder, but effective prophylaxis against relapse is then needed, including consideration of an antidepressant
• is not a first-line alternative to antidepressants for non-seasonal major depression, but could be considered if first-line treatments are not feasible or tolerated
• routinely combining with antidepressants is not recommended

Complementary and other treatments

• St John’s Wort is not recommended as a first-line treatment for depression

• Omega-3 fatty acids are not recommended as a monotherapy treatment for major depression

Acute management

• Initially review patients every 1–2 weeks after commencing treatment and thereafter according to clinical situation and patient need—some reviews may be done by appropriately trained non-medical staff

• Educate patients about the nature of depressive disorders, the possibility of worsening or emerging suicidal thoughts, possible side-effects and benefits of medication, likely duration of treatment, and problems associated with stopping medication

• At each review, assess response, adherence to drug treatment, side-effects and suicidal risk. The use of simple, standardised rating scales is recommended. Lack of significant improvement after 2–4 weeks treatment substantially reduces the probability of eventual sustained response

• Consider limiting the total amount of antidepressant drug available (especially if from a more toxic class) to reduce the risk of death/medical complications if taken in overdose

• Therapeutic drug monitoring is mainly relevant to TCAs and should be considered where there is the potential for antidepressant toxicity; it is also an option for assessing treatment adherence and lack of efficacy at apparently adequate doses

• Manage side-effects that are likely to be transient (e.g. SSRI-induced nausea) by explanation and reassurance

• For persistent, severe, or distressing side-effects the options are:
• dose reduction and retitration
• switching to an antidepressant with a lower propensity to cause that side-effect
• non-drug management of the side-effect (e.g. diet and exercise for weight gain)
• symptomatic treatment with a second drug (e.g. benzodiazepines for agitation/anxiety/insomnia early in treatment, sidenafil for erectile dysfunction in men, modafinil for persisting sleepiness)

Evidence-based guidelines for treating depressive disorders with antidepressants continued

Next-step treatments following inadequate response

Treatment failure and treatment resistance

• Assess the efficacy and risks of each alternative next-step treatment option against the severity and risks associated with the individual’s depression, the degree of treatment resistance, and past treatments that have been tried

• Check the adequacy of treatment including dose and non-adherence; increase dose to recommended therapeutic dose if only a low or marginal dose has been achieved

• Review diagnosis including the possibility of other medical or psychiatric diagnoses, which should be treated in addition

• Consider social factors maintaining the depression and, if present, help the patient address them if possible

• Continue adequately dosed antidepressants for at least 4 weeks before changing treatment for lack of efficacy

• Assessment after 4 weeks adequate treatment:
• if there is at least some improvement continue treatment with the same antidepressant for another 2–4 weeks
• if there is no improvement undertake a next-step treatment; however, in patients who have failed a number of treatments consider longer trials before changing treatment

• Assessment after 6–8 weeks adequate treatment
• if there is moderate or greater improvement continue the same treatment
• if there is minimal improvement undertake a next-step treatment; however, in patients who have failed a number of treatments consider longer trials before changing treatment

Next-step drug treatment options

• Increase dose if:
• there are minimal side-effects and/or
• there has been some improvement on the antidepressant and/or
• the current antidepressant has a possible dose-response effect (e.g. venlafaxine, escitalopram, TCAs)

• Switch antidepressants:
• if there are troublesome or dose-limiting side-effects and/or there has been no improvement
• switching abruptly is generally preferable unless there is a potential drug interaction, in which case follow the recommended taper/washout period
• either within or between antidepressant class initially
• to a different antidepressant class after more than one failure with a specific class; consider venlafaxine after more than one SSRI failure

• Augment/combine with a second agent if:
• there is partial/insufficient response (and good tolerability) on the current antidepressant
• switching antidepressant has been unsuccessful

• Establish safety of proposed combination. Choose combinations with the best evidence-base first, these include augmenting antidepressants with lithium or atypical antipsychotics

Next-step psychological treatment options

• Consider adding:
• CBT to ongoing antidepressant treatment
• other psychological or behavioural treatments that have established acute treatment efficacy

Next-step physical treatment options

• ECT should be considered, especially in more severely ill patients in whom two or more treatments have failed

• Repetitive transcranial magnetic stimulation could be considered but should only be given in specialist centres

• Vagus nerve stimulation could be considered for patients with chronic treatment-resistant depression; this should only be given in specialist centres

Next-step other treatment options

• Consider adding omega-3 fatty acids, folate, or supervised physical exercise

Evidence-based guidelines for treating depressive disorders with antidepressants continued

Relapse prevention

• There is a high risk of relapse after a depressive episode, especially in the first 6 months, however, this risk declines with time in remission

• Assess risk factors for relapse:
• presence of residual symptoms
• number of previous episodes
• severity, duration, and degree of treatment resistance of the most recent episode

• Medication-responsive patients should have their medication continued at the acute treatment dose after remission with the duration determined by risk of relapse
• in patients at lower risk of relapse
  (e.g. first episode patients without other risk factors) the duration should be at least 6–9 months after full remission
• duration in other cases should be tailored to the individual relapse risk; consider a duration of at least 1 year after full remission in patients with any increased risk of relapse. In higher risk patients (e.g. more than five lifetime episodes and/or two episodes in the last few years) at least 2 years should be advised and for most long-term treatment should be considered

• Lithium:
• continue in patients who need lithium augmentation of antidepressants in acute treatment
• consider adding to antidepressants in patients at high risk of relapse or suicide
• do not routinely use as monotherapy for relapse prevention, but consider as a second-line alternative to antidepressants

• CBT:
• added to medication should be considered for patients with residual symptoms or at high risk of relapse
• in responders to acute phase CBT, continuation medication is not routinely recommended; in unstable or partial remitters consider continuation of CBT or antidepressants

• IPT is not recommended as a sole continuation treatment for relapse prevention unless acute response was to IPT monotherapy. Consider continuation IPT as an adjunct to antidepressants in patients with recurrent depression responding to acute phase IPT combined with antidepressants

• In responders to acute phase ECT, prophylactic medication should be continued/initiated; consider continuation ECT in patients with frequent relapses who have been refractory to prophylactic medication

Treatment of relapse while on continuation therapy

• Check the adequacy of treatment including dose and adherence

• Review diagnosis including the possibility of additional medical or psychiatric diagnoses, which should be treated in addition

• Be aware that relapses may be self-limiting and be cautious about frequent or too-early treatment changes

• Treatment options:
• if antidepressants have been stopped re-start the patient on an antidepressant at adequate dose; if the dose had been lowered re-establish the previous dose
• in a patient on an adequate dose of medication with a recent-onset relapse initially consider providing support and monitoring without changing the medication dose
• consider increasing the dose of antidepressant
• consider other next-step treatments as above

Evidence-based guidelines for treating depressive disorders with antidepressants continued

Stopping treatment

• Warn patients that discontinuation reactions may occur when treatment is abruptly stopped If a discontinuation reaction does occur:
• explain and reassure
• if this is not sufficient, and for more severe reactions, restart antidepressant and taper more slowly; for SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) consider switching to fluoxetine which can then be stopped after discontinuation symptoms have fully subsided

• When stopping antidepressant treatment after a period of prophylaxis, match the timing to both risk and consequences of relapse. Warn the patient that the highest period of risk is in the 6 months after stopping

• Judge the rate of taper against clinical situation; serious adverse events may warrant rapid discontinuation; otherwise a minimum period of 4 weeks taper is advised after longer-term treatment. A period of some months may be appropriate for planned treatment withdrawal after long-term prophylaxis

Special considerations

Age

• Age-related factors that may influence treatment with antidepressants:
• increased incidence of deliberate self harm in adolescents and young adults
• smaller antidepressant–placebo difference when treating depression in children and adolescents compared with adults
• decreased tolerability of antidepressants in the elderly
• high risk of depressive relapse in the elderly with comorbid medical illness

Comorbidities

• Increasing severity of comorbid medical illness and painful conditions are associated with poorer response to antidepressants and a greater risk of depressive relapse

• Be aware of potential:
• drug–drug interactions. Routinely choose antidepressants with a lower risk of interaction in patients on multiple medications
• interaction between the medical illness and adverse effects of the drug when choosing an antidepressant

• Where possible avoid TCAs in patients at high risk of cardiovascular disease, arrhythmias and cardiac failure

• In acute coronary syndromes, choose drugs which do not increase the risk of subsequent cardiac events; there is best evidence for SSRIs, mirtazapine, and bupropion

• In patients with bleeding disorders, choose antidepressants that are not serotonin reuptake inhibitors (SRI) in preference to those that are (e.g. SSRIs, SNRIs)

• In patients on aspirin/non-steroidal anti-inflammatory drugs requiring an antidepressant, choose a non-SRI antidepressant or combine an SRI with an ulcer-protective drug

Pregnancy and breastfeeding

• Inform women taking prophylactic antidepressants who are pregnant, or planning to get pregnant, about the risk of relapse if they are stopped and about potential risks to the baby (including neonatal behavioural syndrome)

• In women needing treatment for depression while pregnant choose alternatives to antidepressants where possible
• consider treatment with an antidepressant when there is a favourable risk–benefit balance:
• choose antidepressants for which there is most evidence for a lack of adverse outcomes, these include most SSRIs and TCAs
• avoid the use of paroxetine

• If mothers wish to breastfeed while taking antidepressants, where possible choose drugs which do not accumulate in the baby:
• sertraline and nortriptyline have undetectable levels
• fluoxetine and citalopram may lead to significant levels in the infant
• lithium should be avoided where possible

full guidelines available from…
The British Association for Psychopharmacology, 36 Cambridge Place, Hills Road, Cambridge CB2 1NS (Tel –01223 358428)

Anderson IM, Ferrier IN, Baldwin RC et al. Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008; 22(4): 343–396.