Evidence-based Guidelines for Treating Depressive Disorders with Antidepressants

Overview

This guideline is primarily concerned with the use of antidepressant drugs to treat the most common (unipolar) depressive disorders in adults. The content of this guideline is relevant for all doctors seeing and treating patients with depressive disorders, but the recommendations included in this summary are only those relevant to primary care. For a full set of recommendations, refer to the original guideline.

Diagnosis

• All clinicians should:
  • have a working knowledge of the criteria for major depression (DSM-5; equivalent to ICD-10 moderate or severe depressive episode, i.e. five or more depressive symptoms)
  • determine the duration, severity, and symptom profile of depression to guide treatment choice
  • routinely check for a history of hypomania, mania, mixed affective, or psychotic symptoms in patients diagnosed with depression
• For the purposes of this guideline four grades of severity are used:
  • subthreshold depression—significant depressive symptoms below the threshold for DSM-5 major depression, including ICD-10 mild depressive episode with only four symptoms
  • mild major depression—few symptoms beyond the minimum and mild functional impairment
  • moderate major depression—more than minimum number of symptoms and moderate functional impairment
  • severe major depression—most symptoms are present and marked or greater functional impairment
• Treatment of major depression with antidepressants in primary care should ideally be in the context of case management, or collaborative care to improve outcomes. This should include:
  • scheduled follow-up
  • routine assessment of depression severity to monitor progress
  • an effective strategy to enhance adherence to medication
  • standardised assessment of symptoms
  • access to a mental health specialist when required
• Case managers should ideally have a mental health background, and receive supervision. Case management can be delivered over the telephone to enhance access and efficiency, and can be integrated with Improving Access to Psychological Therapies services.

When to Refer

• Referral to psychiatric services should occur:
  • if there is a significant perceived risk of suicide, of harm to others, or of severe self-neglect
  • if there are psychotic symptoms
  • if there is a history, or clinical suspicion, of bipolar disorder
  • in all cases where a child or adolescent is presenting with major depression
• Consultation with, or referral, to a psychiatrist or a specialist is appropriate:
  • when the GP feels insufficiently experienced to assess or manage a patient's condition
  • if two or more attempts to treat a patient's depressive disorder with medication have failed, or resulted in insufficient response.

Acute Treatment

Indications for Antidepressants

• Antidepressants are a first-line treatment for:
  • moderate and severe major depression in adults irrespective of environmental factors and depression symptom profile
  • depression of any severity that has persisted for 2 years or more
• Antidepressants are a treatment option in short-duration mild major depression in adults and should be considered if there is a prior history of moderate to severe recurrent depression or the depression persists for more than 2–3 months
• Antidepressants are not a first-line treatment for:
  • short-duration subthreshold depression in adults, but should be considered if the depression persists for more than 2–3 months, or there is a prior history of moderate to severe recurrent depression
  • major depression in children and adolescents, but should be considered when there has been a partial, or no response to other treatment, where the depression is severe, or there is a history of moderate to severe recurrent depression.

Choice of Antidepressant Drug

• Match choice of antidepressant drug to individual patient requirements, taking into account likely short-term and long-term effects
• In the absence of special factors, choose antidepressants that are better tolerated and safer in overdose. There is most evidence for selective serotonin reuptake inhibitors (SSRIs) which, together with other newer antidepressants, are first-line choices
• In psychotic depression, combine an antidepressant with an antipsychotic initially in preference to treating with an antidepressant alone or an antipsychotic alone
• Other factors to consider in choosing an antidepressant include:
  • patient preference
  • associated psychiatric disorder that may specifically respond to a particular class of antidepressant (e.g. obsessive–compulsive disorder and SSRIs)
  • previous treatment response to a particular drug
  • tolerability and adverse effects of a previously given drug
  • likely side-effect profile (e.g. sedation, sexual side-effects, weight gain)
  • low lethality in overdose if history or likelihood of overdose
  • concurrent medical illness or condition that may make the antidepressant more noxious or less well tolerated
  • concurrent medication that may interact with the antidepressant drug
  • a family history of differential antidepressant response if choosing between a tricyclic antidepressant (TCA) and monoamine oxidase inhibitors
  • presence of atypical features (responds less well to imipramine than phenelzine)
  • in children and adolescents, the side-effect and benefit profile are different to those in adults, meaning that generally only SSRIs should be used although in older adolescents TCAs may also be effective.

Alternatives to Antidepressants for Acute Treatment

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

Psychological and Behavioural Treatments

• Psychological and behavioural treatments should be administered by appropriately trained practitioners
• For major depression of mild to moderate severity:
  • cognitive behaviour therapy (CBT) is recommended if psychological treatment is used as monotherapy for recurrent depression
  • behavioural activation (BA)
  • interpersonal psychotherapy (IPT)
• For severe major depression:
  • psychological or behavioural treatment is not recommended as sole therapy but routinely consider adding CBT or BA to antidepressant treatment
• For major depression in the elderly:
  • the overall effect size for psychotherapy may be higher than for antidepressants
  • problem-solving therapy may be particularly suitable when treating depression associated with prominent executive dysfunction
• For major depression in children and adolescents:
  • consider CBT or IPT for those not responding to initial structured supportive treatment
  • combining drug and non-drug treatments is not recommended routinely as first-line treatment for adolescents
• Other alternatives or adjuncts to antidepressants in selected circumstances include:
  • computerised CBT and guided bibliotherapy
  • supervised high-intensity exercise.

Physical Treatments

• Electroconvulsive therapy (ECT):
  • should be considered as a first-line treatment for major depression in urgent and emergency situations (e.g. depressive stupor, high risk of suicide, extreme levels of distress, and poor fluid intake)
  • is not recommended as a first-line treatment for major depression in non-urgent circumstances
  • should be considered for treating major depression where first-line treatments are not possible or feasible
  • should be followed by continuation pharmacotherapy to reduce the risk of relapse or recurrence
• Light therapy:
  • is an effective option for the acute treatment of seasonal affective disorder; effective prophylaxis against relapse is then needed, including consideration of an antidepressant
  • is more effective when given in the morning
  • 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 light therapy 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, S-adenosyl methionine (SAMe), folate, or L-methylfolate 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 to the patient (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
• In older people, response to antidepressants may take longer
• 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 if possible
  • 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; sildenafil or tadafinil for erectile dysfunction, and bupropion for sexual dysfunction, in men; bupropion or sildenafil for sexual dysfunction in women; and modafinil for persisting sleepiness).

Next-step Treatments Following Inadequate Treatment 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 of 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 of 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

• Consider increasing 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 (there is modest evidence for venlafaxine, escitalopram, and TCAs)
• Consider switching antidepressant 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
  • switch either within, or between antidepressant class initially
  • consider a different antidepressant class after more than one failure with a specific class; consider venlafaxine after more than one SSRI failure
• Consider adding a second agent especially if:
  • there is partial/insufficient response on the current antidepressant and
  • there is good tolerability of current antidepressant
  • switching antidepressant has been unsuccessful
• Establish the safety of the proposed combination. Choose the combinations with the best evidence base first
• Consider adding quetiapine, aripiprazole, or lithium as first-line treatments, and risperidone olanzapine, tri-iodothyronine, or mirtazapine as second-line treatments, being aware that the evidence derives mainly from studies in which lithium and tri-iodothyronine were added to TCAs and the other drugs added to SSRI/serotonin-norepinephrine reuptake inhibitors (SNRIs).

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 as an option for patients who have not responded to other treatments
• Other physical treatment options with only limited evidence of efficacy include:
  • transcranial direct current stimulation
  • repetitive transcranial magnetic stimulation
  • vagus nerve stimulation
  • deep brain stimulation
  • ablative neurosurgery.

Next-step Other Treatment Options

• Consider adding omega-3 fatty acids, SAMe, L-methylfolate, or supervised physical exercise.

Relapse Prevention

• There is a high risk of relapse after a depressive episode, especially in the first 6 months, and this risk declines with time in remission
• Assess patients for risk factors for relapse. The most important are 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
• Other treatment options include:
  • CBT
  • IPT
  • mindfulness-based cognitive therapy
  • maintenance ECT.

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
• Consider social factors and, where present, help the patient address them if possible
• 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, subject to the limitations described above
  • consider other next-step treatments as above.

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 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 include:
  • increased incidence of deliberate self-harm in adolescents and young adults
  • smaller antidepressant–placebo difference when treating depression in children and (to a lesser extent) adolescents compared with adults and so a different cost–benefit balance applies
  • decreased tolerability of the elderly to antidepressants
  • high risk of depressive relapse in the elderly with comorbid medical illness.

Comorbid Medical Illness

• Increasing severity of comorbid medical illness and painful conditions are associated with poorer response to antidepressants and a greater risk of depressive relapse
• For patients on multiple medications, routinely choose antidepressants with a lower risk of drug–drug interaction
• Consider the potential interaction between the medical illness and adverse effects of the drug when choosing an antidepressant:
  • avoid TCAs in patients at high risk of cardiovascular disease, arrhythmias, and cardiac failure
  • in patients with acute coronary syndrome, 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 potent 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.