Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): non-pregnant

1st line – urgent psychiatric referral ± hospitalisation

Back
ACUTE
|
at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): non-pregnant
1st line – 

urgent psychiatric referral ± hospitalisation

These people are at increased risk for suicide, impulsive and potentially self-destructive behaviour, and health complications due to poor self-care and immobility.

Refer urgently to a psychiatrist. Suicide risk mitigation is critical. Consider hospitalisation for people: with significant suicidal ideation or intent who lack adequate safeguards in their family environment; with intent to hurt others; who are unable to care for themselves and adhere to their treatment; who have psychotic symptoms, or uncontrolled agitation accompanied by the risk of impulsive behaviour.​[165][181][182] If the individual is unwilling to be hospitalised, engage family support and, if necessary, exercise legal means to compel treatment.

Specialist referral, hospitalisation, constant observation, tranquilisation, and/or electroconvulsive therapy may be required to ensure safety until definitive antidepressant therapy can take effect.

People with agitation require high levels of care because of their enhanced emotional distress and the risk of impulsive violence. Severe impairment of the activities of daily living due to catatonia or psychomotor retardation increases the severity of depression, as people who are inert and bedbound, or not taking adequate sustenance, run the risk of a deterioration in health while awaiting a response to pharmacotherapy. These people may require supportive nursing care.

Plus – antidepressant

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ACUTE
|
at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): non-pregnant
Plus – 

antidepressant

Treatment recommended for ALL patients in selected patient group

Antidepressant therapy is usually the first-line option in most patients. Electroconvulsive therapy (ECT) is the first-line treatment in some people with severe depression, but when immediate ECT is either not indicated or not an option, antidepressant pharmacotherapy is crucial.

US guidance recommends that initial pharmacological treatment should be with a second-generation antidepressant. This may include a selective serotonin-reuptake inhibitor (SSRI; e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline); a serotonin-noradrenaline reuptake inhibitor (SNRIs; e.g., desvenlafaxine, duloxetine, levomilnacipran, venlafaxine); bupropion (a dopamine-reuptake inhibitor); mirtazapine (a 5-HT2 receptor antagonist); vilazodone (an SSRI and partial 5-HT1A receptor agonist); vortioxetine (a serotonin-reuptake inhibitor with serotonin receptor modulation properties).[197]​ UK guidance recommends offering an SSRI as first-line treatment for most people with depression for whom pharmacological treatment is suitable.[165] SNRIs are recommended by NICE as a later-line option.[165] According to UK guidance, clinicians should only consider prescribing vortioxetine when there has been no or limited response to at least 2 previous antidepressants.[165]

No consistent differences in safety or efficacy have been demonstrated between antidepressants.​[202][203]​​ While a few meta-analyses of comparative treatment efficacy have favoured one drug over others, by and large they are comparable in efficacy.[204][205] [ Cochrane Clinical Answers logo ]

Choice of drug should be based on patient preference, tolerability, and past evidence of effectiveness in the patient.[181]

Depressed patients with undiagnosed bipolar affective disorder may convert to frank mania if they receive antidepressants. Ask patients about a prior history of manic episodes (e.g., periods of days to weeks marked by unusually high energy, euphoria, insomnia, hyperactivity, or impaired judgment) before starting antidepressant therapy.

There is some evidence of increased suicidal thoughts and behaviour in the first weeks of treatment, particularly in teenagers and young adults, and in those on relatively high starting doses.[210][211][212][213]​​ This association is not necessarily causal and may instead be attributable to confounding factors.[214]​ Close monitoring and risk management is recommended when prescribing an antidepressant to a person under the age of 25 years, or to anybody thought to be at increased risk for suicide.[165]

Follow up patients 1-2 weeks after initiating therapy, then monthly for the next 12 weeks. If you prefer systematic assessment, use the Patient Health Questionnaire-9 (PHQ-9) to assess changes in symptom severity. Titrate the antidepressant dose to the maximum tolerated in patients who experience a partial response after 2-4 weeks. Patients may begin to show a response within the first 1-2 weeks of treatment; however, one fifth of those who have not previously responded may begin to respond after week 5.[216] Successful antidepressant therapy to the point of remission of all symptoms may be expected to take 6-8 weeks. A 50% decrease in symptom score constitutes an adequate response, and a 25% to 50% change in symptom score may indicate the need to modify treatment.

Continue successful antidepressant treatment for 6-12 months following remission, before considering discontinuation.[165][322]​ However, some treatment guidelines recommend that patients with frequent recurrences and relapses, who respond successfully to antidepressant treatment, may require longer-term or indefinite pharmacological therapy, following shared decision-making.[332]​​

The specific drug regimens listed are examples of commonly used regimens only. Consult local guidance for other examples and preferred options.

Primary options

citalopram: 20 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day

OR

escitalopram: 10 mg orally once daily initially, increase gradually according to response, maximum 20 mg/day

OR

fluoxetine: 20 mg orally (immediate-release) once daily initially, increase gradually according to response, maximum 80 mg/day; doses >20 mg/day may be given in 2 divided doses

More

OR

paroxetine: 20 mg orally (immediate-release) once daily initially, increase gradually according to response, maximum 50 mg/day; 25 mg orally (controlled-release) once daily initially, increase gradually according to response, maximum 62.5 mg/day

OR

sertraline: 50 mg orally once daily initially, increase gradually according to response, maximum 200 mg/day

OR

desvenlafaxine: 50 mg orally once daily initially, increase gradually according to response, maximum 400 mg/day; doses >50 mg/day have not shown additional benefit

OR

duloxetine: 40-60 mg/day orally initially given in 1-2 divided doses, increase gradually according to response, maximum 120 mg/day; doses >60 mg/day have not shown additional benefit

OR

levomilnacipran: 20 mg orally once daily initially for 2 days, increase to 40 mg once daily, then increase gradually according to response, maximum 120 mg/day

OR

venlafaxine: 75 mg/day orally (immediate-release) initially given in 2-3 divided doses, increase gradually according to response, maximum 225 mg/day; 75 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 225 mg/day

OR

bupropion: 100 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 450 mg/day given in 2-3 divided doses; 150 mg orally (sustained-release) once daily initially, increase gradually according to response, maximum 400 mg/day given in 2 divided doses; 150 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 450 mg/day

OR

mirtazapine: 15 mg orally once daily initially, increase gradually according to response, maximum 45 mg/day

OR

vilazodone: 10 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day

OR

vortioxetine: 5-10 mg orally once daily initially, increase gradually according to response, maximum 20 mg/day

Consider – immediate symptom management with benzodiazepine ± antipsychotic

Back
ACUTE
|
at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): non-pregnant
Consider – 

immediate symptom management with benzodiazepine ± antipsychotic

Additional treatment recommended for SOME patients in selected patient group

Emergency treatment of mood disorder symptoms aims to stabilise a situation that otherwise leaves the patient in danger from suicidal impulses or extreme self-neglect, and leaves third parties in danger due to unpredictable, impulsive, or aggressive behaviour. Short-term treatment with a benzodiazepine and/or antipsychotic may also bring immediate relief from insomnia, anxiety, agitation, and persistent ruminative thinking while waiting the expected several weeks for significant symptom remission from the antidepressant.[186]

Because antipsychotics tend to have significant clinical effects more rapidly than antidepressants, the decision to employ one is more urgent than to use an antidepressant. Have a lower threshold for adding an antipsychotic to antidepressant treatment in patients with severe depression under several circumstances. Antidepressants alone may not effectively address psychotic symptoms, such as delusions or hallucinations.[184]

People with catatonia can be treated with a benzodiazepine (e.g., lorazepam, clonazepam), sometimes in combination with an antipsychotic and ECT.[187]​ Patients with psychosis or severe agitation can be treated with an antipsychotic (e.g., risperidone, olanzapine, quetiapine, fluphenazine). Patients with mild agitation or severe anxiety can be treated with a benzodiazepine and/or an antipsychotic. Patients with insomnia can be treated with quetiapine or trazodone. Antipsychotics are more appropriate where there is risk of benzodiazepine dependence. 

Dose to effectiveness: if the benzodiazepine or antipsychotic fails to produce an effect and is tolerated, increase the dose with caution up to the recommended maximum. If it fails at the maximum dose or leads to intolerable adverse effects at lower doses, switch to another agent.

The specific drug regimens listed are examples of commonly used regimens only. Consult local guidance for other examples and preferred options.

Primary options

lorazepam: consult specialist for guidance on dose

OR

clonazepam: consult specialist for guidance on dose

OR

risperidone: consult specialist for guidance on dose

OR

olanzapine: consult specialist for guidance on dose

OR

quetiapine: consult specialist for guidance on dose

OR

fluphenazine: consult specialist for guidance on dose

OR

trazodone: consult specialist for guidance on dose

Consider – esketamine nasal spray

Back
ACUTE
|
at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): non-pregnant
Consider – 

esketamine nasal spray

Additional treatment recommended for SOME patients in selected patient group

Esketamine (an active isomer of ketamine, an N-methyl-D-aspartate [NMDA] receptor antagonist) may be considered by a consultant for depression with acute suicidal ideation or behaviour, as an adjunct to an oral antidepressant.

Although esketamine is being used more frequently in clinical practice, questions remain about which patients respond best to it, how long therapeutical effects might persist, and over what duration to continue treatment. While no longer considered a last resort treatment, esketamine is not a first- or second-line treatment.

Availability of esketamine varies according to country of practice and relevant regulatory approval. In the US, the drug is only available through a restricted distribution programme.

The drug must be self-administered by the patient, who is supervised by a health care provider in a certified medical office, and the patient monitored for at least 2 hours because of the risk of sedation, respiratory depression, difficulty with attention, judgement and thinking (dissociation), suicidal thoughts and behaviours, and the potential for drug misuse. Monitor respiratory status and blood pressure during treatment.

Be aware that patients with poorly controlled hypertension or pre-existing aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects. Esketamine is contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, or intracerebral haemorrhage.

Use of esketamine nasal spray beyond 4 weeks is not currently supported by evidence, given that its effectiveness beyond 4 weeks has not yet been evaluated.

Primary options

esketamine nasal: (28 mg/device) 84 mg intranasally twice weekly for 4 weeks, may decrease dose to 56 mg twice weekly based on tolerability

More

Consider – electroconvulsive therapy (ECT)

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ACUTE
|
at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): non-pregnant
Consider – 

electroconvulsive therapy (ECT)

Additional treatment recommended for SOME patients in selected patient group

In certain patients with severe depression who have psychotic features, active suicidal thoughts, catotonia or who are unresponsive to or intolerant of antidepressants, or who have had a previous positive response to ECT, ECT may be considered early in the course of treatment.[39][177] ECT is often the treatment of choice for severely depressed older patients because it is effective, and avoids the complications that may arise from pharmacological intolerance and drug interactions associated with treatment for comorbid physical conditions.[178]

ECT is performed under general anaesthesia, typically 2 or 3 times a week for a total of 6-12 treatments.[188]

Patient and clinician must be fully informed of the potential risks, including the risks associated with not having ECT, so that the patient can provide informed consent.[165]​ The mortality rate of ECT is estimated to be about 2 deaths per 100,000 treatments, meaning that it is one of the safer procedures performed under general anaesthetic.[189][190]​​ Overall, there is no increase in risk of medical complications in patients receiving ECT versus equally depressed patients not receiving ECT.[191] ECT affects heart rate and blood pressure. Chest pain, arrhythmias, persistent hypertension, and ECG changes have been reported as complications, particularly in patients with pre-existing cardiac disease.[192] Cardiovascular conditions should be stabilised before administering ECT.[192] The majority of patients report adverse cognitive effects during and shortly after treatment, most commonly memory loss (both anterograde and retrograde amnesia).[194] This impairment seems to be short-lived according to objective assessment, although a significant proportion of patients report persistent memory loss following ECT.[193][194] This potential risk must be balanced against the evidence in favour of its efficacy, especially in patients with severe depression. If a person with depression cannot give informed consent for ECT, it should only be given when it does not conflict with a valid advance treatment decision made by the person.[165]

ECT treatment effects are temporary; following successful treatment, the effect must be maintained by the use of antidepressants and/or maintenance electroconvulsive treatments (typically once per week to once every 4 weeks or longer, titrated to stability).[195] Combined with antidepressants, lithium has been shown to reduce the risk for relapse post-ECT.[319]

2nd line – increase dose or switch to alternative antidepressant

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ACUTE
|
at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): non-pregnant
2nd line – 

increase dose or switch to alternative antidepressant

If the response to first-line therapy is inadequate, initial steps include reassessing the diagnosis, evaluating comorbidities, and exploring adherence to treatment.[277]

Continue treatment if there has been some improvement for at least the full 6-8 weeks. If the response is still incomplete, and if the drug is well-tolerated, and not already above the threshold of safe dose, consider increasing the dose. But do not continue prescribing a drug providing inadequate benefit indefinitely. Of note, in patients with no initial improvement to treatment with fluoxetine, one study showed the likelihood of converting to a positive response decreased the longer patients remained unimproved.[278]

Another option to consider is switching to an alternative antidepressant.[279][280]​ By the end of four different medication trials, 60% to 70% of patients are likely to respond to treatment. Switching may be appropriate if no improvement in symptoms has occurred within the first 2 weeks of treatment.[281][282]​ However, early response may be, but is not necessarily, a reliable indicator of continued response.[283][284]

Consider a change in drug class; if a patient was on a selective serotonin-reuptake inhibitor, then try a serotonin noradrenaline-reuptake inhibitor. If treatment was not tolerated due to adverse effects, retry with an agent with fewer or different adverse effects. If an agent is switched, resume weekly follow-up until a response is apparent.

Caution is required when switching from one antidepressant to another due to the risk of drug interactions, serotonin syndrome, withdrawal symptoms, or relapse.

The timeframe required for safely switching depends on various factors, including the pharmacokinetic properties of the drugs and possible interactions between them, as well as patient characteristics such as age, sensitivity to adverse effects, and the capacity to wait to begin a new course of treatment. In some situations, it is possible to give both drugs for a short period of time while the changeover is occurring; however, this should only be done under specialist guidance. In other cases, it is safer to take a more conservative approach. This involves slowly tapering the dose of the first drug before stopping it, and then waiting a period of time before starting the second drug (known as a washout period, which is usually five half-lives of the first drug). Drugs with longer half-lives (e.g., fluoxetine) require longer washout periods (e.g., up to 5-6 weeks) when combined with a drug with which the combination is contraindicated (e.g., monoamine oxidase inhibitors with fluoxetine). Specific recommendations for switching from one antidepressant to another, along with suitable washout periods, are available and local guidance should be consulted. When in doubt, in the absence of such guidelines, as a general principle perform a drug interaction check to be sure there are no absolute contraindications, and then 'start low and go slow' until safety can be ascertained.

Continue successful antidepressant treatment for 6-12 months following remission, before considering discontinuation.[165]​​[322]​ However, some treatment guidelines recommend that patients with frequent previous recurrences and relapses, who respond successfully to antidepressant treatment, may require longer-term or indefinite pharmacological indefinite therapy, following shared decision-making.[332]​​

If there is an inadequate response to two (or more) full-dose and duration antidepressants, the patient’s depression might be considered treatment resistant or refractory, and warrants a more complex approach.

at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): pregnant

1st line – urgent psychiatric referral ± hospitalisation (with psychiatric and obstetric involvement)

Back
ACUTE
|
at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): pregnant
1st line – 

urgent psychiatric referral ± hospitalisation (with psychiatric and obstetric involvement)

These people are at increased risk for suicide, impulsive and potentially self-destructive behaviour, and health complications due to poor self-care and immobility.

Refer urgently to a psychiatrist; joint psychiatric and obstetric involvement is required to ensure the safety of both mother and fetus. Suicide risk mitigation is critical. Consider hospitalisation for people: with significant suicidal ideation or intent who lack adequate safeguards in their family environment; with intent to hurt others; who are unable to care for themselves and adhere to their treatment; who have psychotic symptoms, or uncontrolled agitation accompanied by the risk of impulsive behaviour.[165][181][182] If the individual is unwilling to be hospitalised, engage family support and, if necessary, exercise legal means to compel treatment.

Specialist referral, hospitalisation, constant observation, and/or electroconvulsive therapy (ECT) may be required to ensure safety until definitive antidepressant therapy can take effect.

People with agitation require high levels of care because of their enhanced emotional distress and the risk of impulsive violence. Severe impairment of the activities of daily living due to catatonia or psychomotor retardation increases the severity of depression, as people who are inert and bedbound, or not taking adequate sustenance, run the risk of a deterioration in health while awaiting a response to pharmacotherapy. These people may require supportive nursing care.

Severity of depressive symptoms may influence treatment choice. In very severe depression in pregnancy, ECT may the treatment of choice when the severity of illness puts the patient and/or fetus at risk either due to poor maternal self-care or suicide. There is no known risk to the fetus from ECT.[359][360]

Antidepressants may be considered, following shared decision-making based on individualised risk:benefit assessment: In the US, such discussions are frequently carried out by an obstetrician; obstetricians in the US may seek further specialist treatment advice from Perinatal Psychiatry Access Programs where available.[358] In other locations (e.g., the UK) input from a specialist with experience in perinatal mental health is typically required. The American College of Obstetricians and Gynecologists (ACOG) recommends that if pharmacological treatment is required for perinatal depression, selective serotonin-reuptake inhibitors (SSRIs) may be used as first-line pharmacotherapy, and serotonin-noradrenaline reuptake inhibitors (SNRIs) are reasonable alternatives.[358] Despite the lack of consistent evidence of harmful effects of antidepressants to fetal and infant health and development, caution is required.

Some classes of antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), are not routinely used for depression in pregnancy, owing to concerns about potential risks to the mother and baby.[358]​ Esketamine nasal spray is a relatively new drug and is not recommended in pregnancy, as studies involving pregnant animals treated with ketamine indicate that esketamine may cause harm to the fetus when used during pregnancy.

Updated information about potential harms from antidepressants and other pharmaceuticals can be found at various resources. UK Teratology Information Service Opens in new window

more severe depression (PHQ score ≥16): non-pregnant

1st line – antidepressant and/or psychological therapy

Back
ACUTE
|
more severe depression (PHQ score ≥16): non-pregnant
1st line – 

antidepressant and/or psychological therapy

More severe depression has been defined by NICE in the UK as a Patient Health Questionnaire (PHQ) score of 16 or more.[165] This category includes both moderate and severe depression, as defined by DSM-5-TR.[165] 

Treatment decisions are informed by a number of important real-world considerations, including access to psychological treatment, which may be limited or non-existent in some locations. Furthermore, people with depression may have a strong preference for psychological therapy or pharmacotherapy. Research to guide evidence-based individualised treatment is at an early stage.[179]​ Choice of treatment is therefore highly individualised and empirically validated.

Treatment options for more severe depression include pharmacotherapy and psychological therapy, either alone or in combination.[165][197] Both pharmacotherapy and psychological therapy have shown effectiveness when used alone, and yield similar results in randomised trials.

Results from one meta-analysis of antidepressant treatment for adults with depression suggest numbers needed to treat (NNT) values of 16, 11, and 4 for the mild-to-moderate, severe, and very-severe subgroups, respectively.[166]

Although monotherapy with a psychological therapy is one potential option as endorsed by some treatment guidelines, the author notes that evidence to support this approach is limited.[165][197][198][199]​​​ In the absence of definitive evidence supporting psychological treatment as monotherapy for more severe depression, clinicians should consider patient preferences or other individual factors to guide this decision. A stepped care model may be considered, whereby those who do not respond adequately to psychological treatment alone are offered timely add-on pharmacological treatment.[198] 

The World Health Organization (WHO) recommends that psychological interventions are included within the treatment regimen whenever possible for all adults with moderate-to-severe depression.[198]

The combination of psychological therapy plus pharmacotherapy has been demonstrated to be more effective than either treatment alone for those with more severe depression.[171][172][173][174]​ Furthermore, the addition of psychological therapy to the treatment regimen is associated with a more enduring treatment effect than when pharmacotherapy is used alone.[169][175]​​[377]

Psychological treatments may be delivered via different methods and settings, and may include individual, group, or virtual sessions. No clear differences in efficacy have been found among different types of psychological therapies used for depression.[217]

Published treatment guidelines recommend a range of psychological therapies as first-line options more severe depression, including cognitive behavioural therapy, behavioural activation, short-term psychodynamic therapy, interpersonal psychotherapy, and problem-solving therapy.[165][218] However guidance from the American College of Physicians only recommends CBT, citing insufficient evidence to support other types of psychological therapies.[197]

Cognitive behavioural therapy (CBT) has shown greater efficacy than pharmacological placebo across levels of severity.[219] Treatment response to CBT is comparable with antidepressant response in some studies.[170][Evidence B]​ Staged treatment trials suggest that CBT may be particularly beneficial when used during the continuation phase of treatment; CBT reduces the risk of relapse/recurrence at least as well as, and perhaps better than, antidepressant continuation.[175][335][336][337]​​

US guidance recommends that initial pharmacological treatment should be with a second-generation antidepressant. This may include a selective serotonin-reuptake inhibitor (SSRI; e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline); a serotonin-noradrenaline reuptake inhibitor (SNRIs; e.g., desvenlafaxine, duloxetine, levomilnacipran, venlafaxine); bupropion (a dopamine-reuptake inhibitor); mirtazapine (a 5-HT2 receptor antagonist); vilazodone (an SSRI and partial 5-HT1A receptor agonist); vortioxetine (a serotonin-reuptake inhibitor with serotonin receptor modulation properties).[197] UK guidance recommends offering an SSRI as first-line treatment for most people with depression for whom pharmacological treatment is suitable.[165] SNRIs are recommended by NICE as a later-line option.[165] According to UK guidance, clinicians should only consider prescribing vortioxetine when there has been no or limited response to at least 2 previous antidepressants.[165]

No consistent differences in safety or efficacy have been demonstrated between antidepressants.[202][203]​ While a few meta-analyses of comparative treatment efficacy have favoured one drug over others, by and large they are comparable in efficacy.[204][205] [ Cochrane Clinical Answers logo ]

Choice of drug should be based on patient preference, tolerability, safety in overdose, presence of other psychiatric illness, and past evidence of effectiveness in the patient.[181]

Depressed patients with undiagnosed bipolar affective disorder may convert to frank mania if they receive antidepressants. Ask patients about a prior history of manic episodes (e.g., periods of days to weeks marked by unusually high energy, euphoria, insomnia, hyperactivity, or impaired judgement) before starting antidepressant therapy.

There is some evidence of increased suicidal thoughts and behaviour in the first weeks of treatment, particularly in teenagers and young adults, and in those on relatively high starting doses.​[210][211][212][213]​​​ This association is not necessarily causal and may instead be attributable to confounding factors.[214] Close monitoring and risk management is recommended when prescribing an antidepressant to a person under the age of 25 years, or to anybody thought to be at increased risk for suicide.[165]

Follow up patients 1-2 weeks after initiating therapy, regardless of treatment type, then monthly for the next 12 weeks. If you prefer systematic assessment, use the Patient Health Questionnaire-9 (PHQ-9) to assess changes in symptom severity.

For people taking antidepressants, titrate the dose to the maximum tolerated in patients who experience a partial response after 2-4 weeks. Patients may begin to show a response within the first 1-2 weeks of treatment; however, one fifth of those who have not previously responded may begin to respond after week 5.[216] Successful antidepressant therapy to the point of remission of all symptoms may be expected to take 6-8 weeks. A 50% decrease in symptom score constitutes an adequate response, and a 25% to 50% change in symptom score may indicate the need to modify treatment.

Continue successful antidepressant treatment for 6-12 months following remission, before considering discontinuation.[165][322]​ However, some treatment guidelines recommend that patients with frequent recurrences and relapses, who respond successfully to antidepressant treatment, may require longer-term or indefinite pharmacological therapy, following shared decision-making.[332]​​

The specific drug regimens listed are examples of commonly used regimens only. Consult local guidance for other examples and preferred options.

Primary options

citalopram: 20 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day

OR

escitalopram: 10 mg orally once daily initially, increase gradually according to response, maximum 20 mg/day

OR

fluoxetine: 20 mg orally (immediate-release) once daily initially, increase gradually according to response, maximum 80 mg/day; doses >20 mg/day may be given in 2 divided doses

More

OR

paroxetine: 20 mg orally (immediate-release) once daily initially, increase gradually according to response, maximum 50 mg/day; 25 mg orally (controlled-release) once daily initially, increase gradually according to response, maximum 62.5 mg/day

OR

sertraline: 50 mg orally once daily initially, increase gradually according to response, maximum 200 mg/day

OR

desvenlafaxine: 50 mg orally once daily initially, increase gradually according to response, maximum 400 mg/day; doses >50 mg/day have not shown additional benefit

OR

duloxetine: 40-60 mg/day orally initially given in 1-2 divided doses, increase gradually according to response, maximum 120 mg/day; doses >60 mg/day have not shown additional benefit

OR

levomilnacipran: 20 mg orally once daily initially for 2 days, increase to 40 mg once daily, then increase gradually according to response, maximum 120 mg/day

OR

venlafaxine: 75 mg/day orally (immediate-release) initially given in 2-3 divided doses, increase gradually according to response, maximum 225 mg/day; 75 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 225 mg/day

OR

bupropion: 100 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 450 mg/day given in 2-3 divided doses; 150 mg orally (sustained-release) once daily initially, increase gradually according to response, maximum 400 mg/day given in 2 divided doses; 150 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 450 mg/day

OR

mirtazapine: 15 mg orally once daily initially, increase gradually according to response, maximum 45 mg/day

OR

vilazodone: 10 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day

OR

vortioxetine: 5-10 mg orally once daily initially, increase gradually according to response, maximum 20 mg/day

Plus – psychoeducation and lifestyle advice

Back
ACUTE
|
more severe depression (PHQ score ≥16): non-pregnant
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165] Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

Consider – immediate symptom management with benzodiazepine ± antipsychotic

Back
ACUTE
|
more severe depression (PHQ score ≥16): non-pregnant
Consider – 

immediate symptom management with benzodiazepine ± antipsychotic

Additional treatment recommended for SOME patients in selected patient group

Patients with mild agitation or severe anxiety can be treated with the short-term use of a benzodiazepine (e.g., lorazepam, clonazepam) and/or an antipsychotic (e.g., quetiapine). However, one cohort study reported increased mortality risk in patients receiving augmentation with an antipsychotic for depression compared with patients receiving augmentation with a second antidepressant.[308] Patients with insomnia can be treated with quetiapine or trazodone. Antipsychotics are more appropriate where there is risk of benzodiazepine dependence.

Dose to effectiveness: if the benzodiazepine or antipsychotic fails to produce an effect and is tolerated, increase the dose with caution up to the recommended maximum. If it fails at the maximum dose or leads to intolerable adverse effects at lower doses, switch to another agent.

The specific drug regimens listed are examples of commonly used regimens only. Consult local guidance for other examples and preferred options.

Primary options

lorazepam: consult specialist for guidance on dose

OR

clonazepam: consult specialist for guidance on dose

OR

quetiapine: consult specialist for guidance on dose

OR

trazodone: consult specialist for guidance on dose

Consider – esketamine nasal spray

Back
ACUTE
|
more severe depression (PHQ score ≥16): non-pregnant
Consider – 

esketamine nasal spray

Additional treatment recommended for SOME patients in selected patient group

Esketamine (an active isomer of ketamine, an N-methyl-D-aspartate [NMDA] receptor antagonist) may be considered by a consultant for depression with acute suicidal ideation or behaviour, as an adjunct to an oral antidepressant.

Although esketamine is being used more frequently in clinical practice, questions remain about which patients respond best to it, how long therapeutical effects might persist, and over what duration to continue treatment. While no longer considered a last resort treatment, esketamine is not a first- or second-line treatment.

Availability of esketamine varies according to country of practice and relevant regulatory approval. In the US, the drug is only available through a restricted distribution programme.

The drug must be self-administered by the patient, who is supervised by a health care provider in a certified medical office, and the patient monitored for at least 2 hours because of the risk of sedation, respiratory depression, difficulty with attention, judgement and thinking (dissociation), suicidal thoughts and behaviours, and the potential for drug misuse. Monitor respiratory status and blood pressure during treatment.

Be aware that patients with poorly controlled hypertension or pre-existing aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects. Esketamine is contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, or intracerebral haemorrhage.

Use of esketamine nasal spray beyond 4 weeks is not currently supported by evidence, given that its effectiveness beyond 4 weeks has not yet been evaluated.

Primary options

esketamine nasal: (28 mg/device) 84 mg intranasally twice weekly for 4 weeks, may decrease dose to 56 mg twice weekly based on tolerability

More

Consider – electroconvulsive therapy (ECT)

Back
ACUTE
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more severe depression (PHQ score ≥16): non-pregnant
Consider – 

electroconvulsive therapy (ECT)

Additional treatment recommended for SOME patients in selected patient group

Electroconvulsive therapy (ECT) may be an option for those who have not responded to, or cannot tolerate, antidepressants.[165] The response rate is better for patients with severe major depression than for moderate or mild depression.[177]​ The potential impact on memory and cognition, which may reduce functioning during active treatment, make ECT less desirable for patients with milder depression. ECT is often the treatment of choice for severely depressed people with late-life depression, because it is effective, and avoids complications that may arise from pharmacological intolerance and drug interactions associated with treatment for comorbid physical conditions.[178]

ECT is performed under general anesthesia, typically 2 or 3 times a week for a total of 6-12 treatments.[188]

Patient and clinician must be fully informed of the potential risks, including the risks associated with not having ECT, so that the patient can provide informed consent.[165] The mortality rate of ECT is estimated to be about 2 deaths per 100,000 treatments, meaning that it is one of the safer procedures performed under general anesthetic.[189][190] Overall, there is no increase in risk of medical complications in patients receiving ECT versus equally depressed patients not receiving ECT.[191]​ ECT affects heart rate and blood pressure. Chest pain, arrhythmias, persistent hypertension, and ECG changes have been reported as complications, particularly in patients with pre-existing cardiac disease.[192]​ Cardiovascular conditions should be stabilised before administering ECT.[192] The majority of patients report adverse cognitive effects during and shortly after treatment, most commonly memory loss (both anterograde and retrograde amnesia).[194]​ This impairment seems to be short-lived according to objective assessment, although a significant proportion of patients report persistent memory loss following ECT.[193][194] This potential risk must be balanced against the evidence in favour of its efficacy, especially in patients with severe depression. If a person with depression cannot give informed consent for ECT, it should only be given when it does not conflict with a valid advance treatment decision made by the person.[165]

ECT treatment effects are temporary; following successful treatment, the effect must be maintained by the use of antidepressants and/or maintenance electroconvulsive treatments (typically once per week to once every 4 weeks or longer, titrated to stability).[195]​ Combined with antidepressants, lithium has been shown to reduce the risk for relapse post-ECT.[319]

2nd line – increase antidepressant dose or switch to alternative treatment or combination therapy

Back
ACUTE
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more severe depression (PHQ score ≥16): non-pregnant
2nd line – 

increase antidepressant dose or switch to alternative treatment or combination therapy

If the response to first-line therapy is inadequate, initial steps include reassessing the diagnosis, evaluating comorbidities, and exploring adherence to treatment.[277]

For those already being treated with an antidepressant, continue treatment if there has been some improvement for at least the full 6-8 weeks. If the response is still incomplete, and if the drug is well-tolerated, and not already above the threshold of safe dose, consider increasing the dose. But do not continue prescribing a drug providing inadequate benefit indefinitely. Of note, in patients with no initial improvement to treatment with fluoxetine, one study showed the likelihood of converting to a positive response decreased the longer patients remained unimproved.[278]

Augmentation with psychological therapy is a good option to consider if there is a partial improvement with first-line pharmacotherapy, given that the evidence suggests that combined therapy works better than either treatment alone owing to a synergistic effect of using both.[173][174][197]​​​​​​​ Likewise, patients who do not respond adequately to psychological treatment alone may be offered add-on pharmacological treatment.[198]​ Switching from pharmacotherapy to a psychological therapy, or from a pharmacological therapy to pharmacotherapy, may be another reasonable option to consider, as guided by patient preference and access to CBT.[197]

Another option to consider for those already receiving pharmacotherapy is switching to an alternative antidepressant.[279][280] Switching may be appropriate if no improvement in symptoms has occurred within the first 2 weeks of treatment.[281][282]​ However, early response may be, but is not necessarily, a reliable indicator of continued response.[283][284]

Switching between antidepressants within a class may be considered initially (e.g., from one selective serotonin-reuptake inhibitor [SSRI] to another SSRI).[181] Next consider a change in drug class; for example, if a patient was on an SSRI, then consider a serotonin noradrenaline-reuptake inhibitor (SNRI).[181] If treatment was not tolerated due to adverse effects, retry with an agent with fewer or different adverse effects. If an agent is switched, resume weekly follow-up until a response is apparent.

Caution is required when switching from one antidepressant to another due to the risk of drug interactions, serotonin syndrome, withdrawal symptoms, or relapse. See Serotonin syndrome.

The timeframe required for safely switching depends on various factors, including the pharmacokinetic properties of the drugs and possible interactions between them, as well as patient characteristics such as age, sensitivity to adverse effects, and the capacity to wait to begin a new course of treatment. In some situations, it is possible to give both drugs for a short period of time while the changeover is occurring; however, this should only be done under specialist guidance. In other cases, it is safer to take a more conservative approach. This involves slowly tapering the dose of the first drug before stopping it, and then waiting a period of time before starting the second drug (known as a washout period, which is usually five half-lives of the first drug). Drugs with longer half-lives (e.g., fluoxetine) require longer washout periods (e.g., up to 5-6 weeks) when combined with a drug with which the combination is contraindicated (e.g., monoamine oxidase inhibitors with fluoxetine). Specific recommendations for switching from one antidepressant to another, along with suitable washout periods, are available and local guidance should be consulted. When in doubt, in the absence of such guidelines, as a general principle perform a drug interaction check to be sure there are no absolute contraindications, and then 'start low and go slow' until safety can be ascertained.

Continue successful antidepressant treatment for 6-12 months following remission, before considering discontinuation.[165][322]​​ However, some physicians recommend that patients with frequent previous recurrences and relapses, who respond successfully to antidepressant treatment, may require longer-term or indefinite indefinite pharmacological therapy, following shared decision-making.[332]​​

If there is an inadequate response to two (or more) full-dose and duration antidepressants, the patient’s depression might be considered treatment resistant or refractory, and warrants a more complex approach.

Plus – psychoeducation and lifestyle advice

Back
ACUTE
|
more severe depression (PHQ score ≥16): non-pregnant
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165]​ Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

Consider – esketamine nasal spray

Back
ACUTE
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more severe depression (PHQ score ≥16): non-pregnant
Consider – 

esketamine nasal spray

Additional treatment recommended for SOME patients in selected patient group

Esketamine (an active isomer of ketamine, an N-methyl-D-aspartate [NMDA] receptor antagonist) may be considered by a consultant for depression with acute suicidal ideation or behaviour, as an adjunct to an oral antidepressant.

Although esketamine is being used more frequently in clinical practice, questions remain about which patients respond best to it, how long therapeutical effects might persist, and over what duration to continue treatment. While no longer considered a last resort treatment, esketamine is not a first- or second-line treatment.

Availability of esketamine varies according to country of practice and relevant regulatory approval. In the US, the drug is only available through a restricted distribution programme.

The drug must be self-administered by the patient, who is supervised by a health care provider in a certified medical office, and the patient monitored for at least 2 hours because of the risk of sedation, respiratory depression, difficulty with attention, judgement and thinking (dissociation), suicidal thoughts and behaviours, and the potential for drug misuse. Monitor respiratory status and blood pressure during treatment.

Be aware that patients with poorly controlled hypertension or pre-existing aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects. Esketamine is contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, or intracerebral haemorrhage.

Use of esketamine nasal spray beyond 4 weeks is not currently supported by evidence, given that its effectiveness beyond 4 weeks has not yet been evaluated.

Primary options

esketamine nasal: (28 mg/device) 84 mg intranasally twice weekly for 4 weeks, may decrease dose to 56 mg twice weekly based on tolerability

More

Consider – electroconvulsive therapy (ECT)

Back
ACUTE
|
more severe depression (PHQ score ≥16): non-pregnant
Consider – 

electroconvulsive therapy (ECT)

Additional treatment recommended for SOME patients in selected patient group

ECT may be an option for those who have not responded to, or cannot tolerate, antidepressants.[165]  The response rate is better for patients with severe major depression than for moderate or mild depression.[177]​ The potential impact on memory and cognition, which may reduce functioning during active treatment, make ECT less desirable for patients with milder depression. ECT is often the treatment of choice for severely depressed people with late-life depression, because it is effective, and avoids complications that may arise from pharmacological intolerance and drug interactions associated with treatment for comorbid physical conditions.[178]

ECT is performed under general anesthesia, typically 2 or 3 times a week for a total of 6-12 treatments.[188] 

Patient and clinician must be fully informed of the potential risks, including the risks associated with not having ECT, so that the patient can provide informed consent.[165] The mortality rate of ECT is estimated to be about 2 deaths per 100,000 treatments, meaning that it is one of the safer procedures performed under general anesthetic.[189][190] Overall, there is no increase in risk of medical complications in patients receiving ECT versus equally depressed patients not receiving ECT.[191] ECT affects heart rate and blood pressure. Chest pain, arrhythmias, persistent hypertension, and ECG changes have been reported as complications, particularly in patients with pre-existing cardiac disease.[192] Cardiovascular conditions should be stabilised before administering ECT.[192] The majority of patients report adverse cognitive effects during and shortly after treatment, most commonly memory loss (both anterograde and retrograde amnesia).[194] This impairment seems to be short-lived according to objective assessment, although a significant proportion of patients report persistent memory loss following ECT.[193][194] This potential risk must be balanced against the evidence in favour of its efficacy, especially in patients with severe depression. If a person with depression cannot give informed consent for ECT, it should only be given when it does not conflict with a valid advance treatment decision made by the person.[165]

ECT treatment effects are temporary; following successful treatment, the effect must be maintained by the use of antidepressants and/or maintenance electroconvulsive treatments (typically once per week to once every 4 weeks or longer, titrated to stability).[195]​ Combined with antidepressants, lithium has been shown to reduce the risk for relapse post-ECT.[319] 

less severe depression (PHQ <16): non-pregnant

1st line – active monitoring

Back
ACUTE
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less severe depression (PHQ <16): non-pregnant
1st line – 

active monitoring

‘Less severe depression’ has been defined by NICE in the UK as a Patient Health Questionnaire (PHQ) score of less than 16.[165]​ This category includes both subthreshold and mild symptoms.

Treatment decisions are informed by a number of important real-world considerations, including access to psychological treatment, which may be limited or non-existent in some locations. Furthermore, people with depression may have a strong preference for psychological therapy or pharmacotherapy. Research to guide evidence-based individualised treatment is at an early stage.[179] Choice of treatment is therefore highly individualised and empirically validated.

For people with subthreshold and mild symptoms, the prognosis is often good without the need for pharmacotherapy or formal psychological therapy.[176][229] For people with less severe depression who do not want treatment, or who feel that their depressive symptoms are improving, an initial period of active monitoring may be appropriate, with review after 2-4 weeks, with advice given to seek medical input if symptoms worsen, and the option to consider treatment at any time if needed.[165] This approach may facilitate further assessment, monitoring and shared decision-making.

Plus – psychoeducation and lifestyle advice

Back
ACUTE
|
less severe depression (PHQ <16): non-pregnant
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

Psychoeducation alone can achieve remission for some people with less severe depression.[230]

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165] Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

1st line – supportive interventions

Back
ACUTE
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less severe depression (PHQ <16): non-pregnant
1st line – 

supportive interventions

'Less severe depression’ has been defined by NICE in the UK as a Patient Health Questionnaire (PHQ) score of less than 16.[165] This category includes both subthreshold and mild symptoms.

Treatment decisions are informed by a number of important real-world considerations, including access to psychological treatment, which may be limited or non-existent in some locations. Furthermore, people with depression may have a strong preference for psychological therapy or pharmacotherapy. Research to guide evidence-based individualised treatment is at an early stage.[179] Choice of treatment is therefore highly individualised and empirically validated.

For people with less severe depression who wish to consider treatment, guidelines typically recommend non-pharmacological therapies as first-line, based on the assessment that the risk:benefit ratio does not justify the use of pharmacotherapy for mild depression.[165][197]

For some patients who have milder symptoms, the degree of impairment or distress from these symptoms might not outweigh the stigma the patients attach to accepting any form of psychiatric treatment; in these patients a focus directly on symptom management may be the optimal strategy.[254] Bibliotherapy, a programme of self-help by reading, may have long-term benefits for some patients.[231]

Yoga interventions may have a beneficial effect on depressive disorders, but there are significant variations in interventions, reporting, and feasibility.[255]

Other supportive interventions include relaxation training, light therapy, exercise, tai chi, music therapy, and acupuncture.​[232][233][234][235][236]​​​​[237][238][239][240][241][242]​​ [ Cochrane Clinical Answers logo ] ​​​ In patients with depression, higher remission rates were observed in a higher-dose exercise group plus continuation of serotonin noradrenaline-reuptake inhibitor treatment compared with low-dose exercise plus selective serotonin-reuptake inhibitors.[238] Conversely, cessation of exercise may worsen depressive symptoms.[260][261] [ Cochrane Clinical Answers logo ]

Plus – psychoeducation and lifestyle advice

Back
ACUTE
|
less severe depression (PHQ <16): non-pregnant
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165] Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180] 

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

1st line – computer-based interventions

Back
ACUTE
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less severe depression (PHQ <16): non-pregnant
1st line – 

computer-based interventions

'Less severe depression’ has been defined by NICE in the UK as a Patient Health Questionnaire (PHQ) score of less than 16.[165] This category includes both subthreshold and mild symptoms.

Treatment decisions are informed by a number of important real-world considerations, including access to psychological treatment, which may be limited or non-existent in some locations. Furthermore, people with depression may have a strong preference for psychological therapy or pharmacotherapy. Research to guide evidence-based individualised treatment is at an early stage.[179]​ Choice of treatment is therefore highly individualised and empirically validated.

For people with less severe depression who wish to consider treatment, guidelines typically recommend non-pharmacological therapies as first-line, based on the assessment that the risk:benefit ratio does not justify the use of pharmacotherapy for mild depression.[165][197]

Internet- and mobile-based interventions are a promising and rapidly emerging development, and demonstrate efficacy. They may be a useful intervention for people who cannot access or afford or schedule individual or group face-to-face CBT.

Digital interventions have the potential to widen access to evidence-based care for depression by reaching underserved populations, and may also increase the quality of care by augmenting face-to-face treatment. They may facilitate collaborative care, and shared decision-making.[243][244][245][246][247][248][249]​​​[250]

The evidence is greatest for internet CBT (iCBT), and suggests that guided iCBT (iCBT supported by human guidance) is as effective as face-to-face CBT.[262][263]

Unguided CBT also demonstrates efficacy, but with smaller treatment effect sizes.[244] There may be an increasing role for other types of self-help and self-guided interventions such as behavioural activation strategies, particularly for those with less severe symptoms of depression.[250][264][265]​​[266]​ 

Several key barriers to digital interventions have been noted, including concerns about reduced access to care for people with lower levels of digital literacy; appropriate patient selection is therefore required. There is evidence to suggest that patients with a lower educational level may be at increased risk of symptom deterioration with internet-based guided-self-help than patients with higher education.[268]

Plus – psychoeducation and lifestyle advice

Back
ACUTE
|
less severe depression (PHQ <16): non-pregnant
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165] Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.​[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

1st line – psychological therapy

Back
ACUTE
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less severe depression (PHQ <16): non-pregnant
1st line – 

psychological therapy

'Less severe depression’ has been defined by NICE in the UK as a Patient Health Questionnaire (PHQ) score of less than 16.[165] This category includes both subthreshold and mild symptoms.

Treatment decisions are informed by a number of important real-world considerations, including access to psychological treatment, which may be limited or non-existent in some locations. Furthermore, people with depression may have a strong preference for psychological therapy or pharmacotherapy. Research to guide evidence-based individualised treatment is at an early stage.[179] Choice of treatment is therefore highly individualised and empirically validated.

For people with less severe depression who wish to consider treatment, guidelines typically recommend non-pharmacological therapies as first-line, based on the assessment that the risk:benefit ratio does not justify the use of pharmacotherapy for mild depression.[165][197]

Psychological therapy appears to have a positive impact on the quality of life of patients with depression, beyond measurable reductions in depressive symptom severity.[269] Mild depression treated with psychotherapy may be less likely to progress to severe depression.[271]

Psychological treatments may be delivered via different methods and settings, and may include individual, group, or virtual sessions. No clear differences in efficacy have been found among different types of psychological therapies used for depression.[217] Less intensive psychological therapies such as guided self-help and group CBT or behavioural activation may be reasonable initial options in this group.[165]

Note that US-based guidance from the American College of Physicians only recommends CBT, citing insufficient evidence to support other types of psychological therapies.[197]

Cognitive behavioural therapy (CBT) has shown greater efficacy than pharmacological placebo across levels of severity.[219] Treatment response to CBT is comparable with antidepressant response in some studies.[170][Evidence B]​ Staged treatment trials suggest that CBT may be particularly beneficial when used during the continuation phase of treatment; CBT reduces the risk of relapse/recurrence at least as well as, and perhaps better than, antidepressant continuation.[335][336][337]​ In pooled clinical trials, mindfulness-based CBT was found to be particularly useful in relapse prevention.[338] CBT appears to have an enduring effect that reduces subsequent risk after treatment ends.[175] Adjunctive CBT has also been found to improve outcomes for depression treatment in the primary care setting.[220]

Other types of psychological therapy for less severe depression include interpersonal psychotherapy (IPT), problem-solving therapy (PST), behavioural activation, and mindfulness-based therapy.[165]

IPT requires the patient to have psychological insight.[221] Frequency for both CBT and IPT is determined by the healthcare provider. The time to response is approximately 12 weeks. IPT may improve interpersonal functioning, and also appears effective for relapse prevention.[222] PST focuses on training in adaptive problem-solving attitudes and skills.[223][224][225]​ Results from PST are comparable to those from CBT in primary care settings.[226]

Plus – psychoeducation and lifestyle advice

Back
ACUTE
|
less severe depression (PHQ <16): non-pregnant
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165]​ Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

1st line – antidepressant

Back
ACUTE
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less severe depression (PHQ <16): non-pregnant
1st line – 

antidepressant

'Less severe depression’ has been defined by NICE in the UK as a Patient Health Questionnaire (PHQ) score of less than 16.[165] This category includes both subthreshold and mild symptoms.

For people with less severe depression who wish to consider treatment, guidelines typically recommend non-pharmacological therapies as first-line, based on the assessment that the risk:benefit ratio does not justify the use of pharmacotherapy for mild depression.[165][197]​ However note that, as for all patients with depression, there may be reasons to consider pharmacological treatment from the offset in this group in certain specific circumstances (e.g., when there is a history of severe depression, where there is a lack of access to psychological treatment, when the patient has a preference for pharmacotherapy, or when there is a history of a previous positive treatment response to pharmacotherapy). An antidepressant may be preferable in some patients as it may offer a more rapid response than a non-pharmacological treatment.

Treatment decisions are informed by a number of important real-world considerations, including access to psychological treatment, which may be limited or non-existent in some locations. Furthermore, people with depression may have a strong preference for psychological therapy or pharmacotherapy. Research to guide evidence-based individualised treatment is at an early stage.[179] Choice of treatment is therefore highly individualised and empirically validated.

US guidance recommends that initial pharmacological treatment should be with a second-generation antidepressant. This may include a selective serotonin-reuptake inhibitor (SSRI; e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline); a serotonin-noradrenaline reuptake inhibitor (SNRIs; e.g., desvenlafaxine, duloxetine, levomilnacipran, venlafaxine); bupropion (a dopamine-reuptake inhibitor); mirtazapine (a 5-HT2 receptor antagonist); vilazodone (an SSRI and partial 5-HT1A receptor agonist); vortioxetine (a serotonin-reuptake inhibitor with serotonin receptor modulation properties).[197] UK guidance recommends offering an SSRI as first-line treatment for most people with depression for whom pharmacological treatment is suitable.[165] SNRIs are recommended by NICE as a later-line option.[165] According to UK guidance, clinicians should only consider prescribing vortioxetine when there has been no or limited response to at least 2 previous antidepressants.[165]

The most commonly prescribed antidepressants, SSRIs and SNRIs, offer similar response rates and can be used first line as monotherapy in mild to moderate depression.[378] No consistent differences in safety or efficacy have been demonstrated between antidepressants.[202][203]​ While a few meta-analyses of comparative treatment efficacy have favoured one drug over others, by and large they are comparable in efficacy.[204][205] [ Cochrane Clinical Answers logo ]

Choice of drug should be based on patient preference, tolerability, safety in overdose, presence of other psychiatric illness, and past evidence of effectiveness in the patient.[181]

Depressed patients with undiagnosed bipolar affective disorder may convert to frank mania if they receive antidepressants. Ask patients about a prior history of manic episodes (e.g., periods of days to weeks marked by unusually high energy, euphoria, insomnia, hyperactivity, or impaired judgement) before starting antidepressant therapy.

There is some evidence of increased suicidal thoughts and behaviour in the first weeks of treatment, particularly in teenagers and young adults, and in those on relatively high starting doses.​[210][211][212][213]​​​ This association is not necessarily causal and may instead be attributable to confounding factors.[214] Close monitoring and risk management is recommended when prescribing an antidepressant to a person under the age of 25 years, or to anybody thought to be at increased risk for suicide.[165]

Follow up patients 1-2 weeks after initiating therapy, then monthly for the next 12 weeks. If you prefer systematic assessment, use the Patient Health Questionnaire-9 (PHQ-9) to assess changes in symptom severity. Titrate the antidepressant dose to the maximum tolerated in patients who experience a partial response after 2-4 weeks. Patients may begin to show a response within the first 1-2 weeks of treatment; however, one fifth of those who have not previously responded may begin to respond after week 5.[216] Successful antidepressant therapy to the point of remission of all symptoms may be expected to take 6-8 weeks. A 50% decrease in symptom score constitutes an adequate response, and a 25% to 50% change in symptom score may indicate the need to modify treatment.

​Continue successful antidepressant treatment for 6-12 months following remission, before considering discontinuation.[165][322]​​ However, some treatment guidelines recommend that patients with frequent recurrences and relapses, who respond successfully to antidepressant treatment, may require longer-term or indefinite pharmacological therapy, following shared decision-making.[332]​​

The specific drug regimens listed are examples of commonly used regimens only. Consult local guidance for other examples and preferred options.

Primary options

citalopram: 20 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day

OR

escitalopram: 10 mg orally once daily initially, increase gradually according to response, maximum 20 mg/day

OR

fluoxetine: 20 mg orally (immediate-release) once daily initially, increase gradually according to response, maximum 80 mg/day; doses >20 mg/day may be given in 2 divided doses

More

OR

paroxetine: 20 mg orally (immediate-release) once daily initially, increase gradually according to response, maximum 50 mg/day; 25 mg orally (controlled-release) once daily initially, increase gradually according to response, maximum 62.5 mg/day

OR

sertraline: 50 mg orally once daily initially, increase gradually according to response, maximum 200 mg/day

OR

desvenlafaxine: 50 mg orally once daily initially, increase gradually according to response, maximum 400 mg/day; doses >50 mg/day have not shown additional benefit

OR

duloxetine: 40-60 mg/day orally initially given in 1-2 divided doses, increase gradually according to response, maximum 120 mg/day; doses >60 mg/day have not shown additional benefit

OR

levomilnacipran: 20 mg orally once daily initially for 2 days, increase to 40 mg once daily, then increase gradually according to response, maximum 120 mg/day

OR

venlafaxine: 75 mg/day orally (immediate-release) initially given in 2-3 divided doses, increase gradually according to response, maximum 225 mg/day; 75 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 225 mg/day

OR

bupropion: 100 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 450 mg/day given in 2-3 divided doses; 150 mg orally (sustained-release) once daily initially, increase gradually according to response, maximum 400 mg/day given in 2 divided doses; 150 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 450 mg/day

OR

mirtazapine: 15 mg orally once daily initially, increase gradually according to response, maximum 45 mg/day

OR

vilazodone: 10 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day

OR

vortioxetine: 5-10 mg orally once daily initially, increase gradually according to response, maximum 20 mg/day

Plus – psychoeducation and lifestyle advice

Back
ACUTE
|
less severe depression (PHQ <16): non-pregnant
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165]​ Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

2nd line – increase antidepressant dose or switch to alternative treatment

Back
ACUTE
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less severe depression (PHQ <16): non-pregnant
2nd line – 

increase antidepressant dose or switch to alternative treatment

If the response to first-line therapy is inadequate, initial steps include reassessing the diagnosis, evaluating comorbidities, and exploring adherence to treatment.[277]

For those already being treated with an antidepressant, continue treatment if there has been some improvement for at least the full 6-8 weeks. If the response is still incomplete, and if the drug is well-tolerated, and not already above the threshold of safe dose, consider increasing the dose. But do not continue prescribing a drug providing inadequate benefit indefinitely. Of note, in patients with no initial improvement to treatment with fluoxetine, one study showed the likelihood of converting to a positive response decreased the longer patients remained unimproved.[278]

Another option to consider for those already receiving pharmacotherapy is switching to an alternative antidepressant.[279][280]​ Switching may be appropriate if no improvement in symptoms has occurred within the first 2 weeks of treatment.[281][282]​ However, early response may be, but is not necessarily, a reliable indicator of continued response.[283][284]

Switching between antidepressants within a class may be considered initially (e.g., from one selective serotonin-reuptake inhibitor [SSRI] to another SSRI).[181] Next consider a change in drug class; for example, if a patient was on an SSRI, then consider a serotonin-noradrenaline reuptake inhibitor [SNRI].[181] If treatment was not tolerated due to adverse effects, retry with an agent with fewer or different adverse effects. If an agent is switched, resume weekly follow-up until a response is apparent.

Caution is required when switching from one antidepressant to another due to the risk of drug interactions, serotonin syndrome, withdrawal symptoms, or relapse. See Serotonin syndrome.

The timeframe required for safely switching depends on various factors, including the pharmacokinetic properties of the drugs and possible interactions between them, as well as patient characteristics such as age, sensitivity to adverse effects, and the capacity to wait to begin a new course of treatment. In some situations, it is possible to give both drugs for a short period of time while the changeover is occurring; however, this should only be done under specialist guidance. In other cases, it is safer to take a more conservative approach. This involves slowly tapering the dose of the first drug before stopping it, and then waiting a period of time before starting the second drug (known as a washout period, which is usually five half-lives of the first drug). Drugs with longer half-lives (e.g., fluoxetine) require longer washout periods (e.g., up to 5-6 weeks) when combined with a drug with which the combination is contraindicated (e.g., monoamine oxidase inhibitors with fluoxetine). Specific recommendations for switching from one antidepressant to another, along with suitable washout periods, are available and local guidance should be consulted. When in doubt, in the absence of such guidelines, as a general principle perform a drug interaction check to be sure there are no absolute contraindications, and then 'start low and go slow' until safety can be ascertained.

Switching from pharmacotherapy to a psychological therapy, or from a pharmacological therapy to pharmacotherapy, may be another reasonable option to consider, as guided by patient preference and access to CBT.[197]

Continue successful antidepressant treatment for 6-12 months following remission, before continuing discontinuation.[165][322]​​ However, some treatment guidelines recommend that patients with frequent previous recurrences and relapses, who respond successfully to antidepressant treatment, may require longer-term or indefinite pharmacological therapy, following shared decision-making.[332]​​

If there is an inadequate response to two (or more) full-dose and duration antidepressants, the patient’s depression might be considered treatment resistant or refractory, and warrants a more complex approach.

Plus – psychoeducation and lifestyle advice

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less severe depression (PHQ <16): non-pregnant
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165] Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

treatment-resistant/refractory depression

1st line – reassess and switch to alternative antidepressant or combination therapy

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treatment-resistant/refractory depression
1st line – 

reassess and switch to alternative antidepressant or combination therapy

Evidence to guide treatment decisions when people with depression do not respond to initial treatments is very limited.[285][286] The majority of patients with depression do not reach full remission after their first antidepressant trial, but a substantial proportion of those will respond to a second or third antidepressant.[280] The terms ‘treatment-refractory’ or ‘treatment-resistant’ depression have been used variously, and somewhat inconsistently, to denote depressive illness that has not remitted after two antidepressant trials of adequate dose and duration.[287][288]​ An alternative term has been proposed to emphasise less the binary response of remission or non-remission and more the common scenario of partial, or inconsistent, treatment response: 'difficult-to-treat depression'.[289]

Guidelines typically recommend that primary care physicians seek specialist input after two unsuccessful treatment interventions, where feasible.​[182][290]​​ Comorbid medical conditions, and psychosocial factors such as temperamental vulnerabilities, behaviour patterns, and life circumstances, may all make depression more difficult to treat.

Reassessment can be useful after an apparently failed course of treatment, because some of the residual symptoms of depression (e.g., social avoidance, sleep/wake reversal, feelings of hopelessness) can reflect behavioural adaptations to depression, rather than the depression itself. In such cases, symptoms may best be ameliorated through behavioural intervention or psychological therapy rather than a new medication trial. Cognitive deficits after remission of symptoms are common.[292]​ These may warrant monitoring and, if appropriate, the patient may benefit from reassurance that there may be continued improvement over time.

With intermittent, brief follow-up visits it is also easy to miss mood-cycling that may occur between sessions that would indicate a bipolar spectrum disorder rather than pure major depression. Consider diagnostic re-evaluation or whether there may have been issues around adherence with treatment, or if factors such as substance use, medication adverse effects, or medical illness may have interfered with treatment.

Assuming major depressive disorder continues to be the most salient clinical problem, alternative options for treatment-resistant/refractory depression within the antidepressant class include monotherapy with a third (or fourth or fifth) selective serotonin-reuptake inhibitor (SSRI), serotonin noradrenaline-reuptake inhibitors (SNRI), or an atypical agent (e.g., bupropion, mirtazapine, vilazodone, vortioxetine, reboxetine, and agomelatine). The process of switching antidepressants, if undertaken, provides a window of opportunity for combined antidepressant therapy (i.e., an SSRI or SNRI plus bupropion or mirtazapine) while crossing over from one to the other. However, there are little data to support the efficacy of antidepressant combinations.[294][295][296][297]​ One notable exception to these observations is an apparently synergistic effect when the second antidepressant adds presynaptic alpha-2 receptor antagonism (e.g., mirtazapine, trazodone); however, as in other combination strategies, patient retention in treatment drops when additional drugs are added.[298]

A specialist may prescribe two (or in rare cases more) antidepressants as a way of making optimal use of adverse effects (e.g., adding mirtazapine to an SNRI to facilitate sleep, or bupropion to an SSRI to try to improve sexual functioning). There is some evidence that failure on one or several antidepressants does not preclude later success.[279][280]​ Although the general rule of thumb is to give antidepressants for at least 6-8 weeks, if there is no improvement at all in the first 2 weeks, switching may be appropriate at that point.[282]

When selecting a third (or fourth or fifth) medication to switch to, consider not only another SSRI, SNRI, or atypical agent, but also a tricyclic antidepressant (TCA) (e.g., amitriptyline, desipramine, doxepin, imipramine, or nortriptyline). Historically the first-line pharmacotherapy for depression, TCAs have fallen somewhat out of favour because of their adverse effects, the need for gradual dose increases, and their potential lethality in overdose. However, they remain effective and useful for many patients. Dose TCAs according to therapeutic blood monitoring. For most TCAs there is a minimum therapeutic level; for nortriptyline, uniquely, there is a therapeutic window delineating a range of effective levels. UK guidance states that TCAs should only be prescribed for depression by a specialist clinician (e.g., psychiatrist) working in secondary care.[165]

Esketamine (an active isomer of ketamine, an N-methyl-D-aspartate [NMDA] receptor antagonist) may be considered by a consultant as monotherapy for treatment-resistant depression. Evidence has demonstrated the rapid efficacy of esketamine monotherapy; within one randomised controlled trial (RCT), within the first 24 hours of the initial dose, participants experienced significant improvements in their Montgomery-Asberg Depression Rating Scale (MADRS) total score, with the effects persisting for at least 4 weeks. By the fourth week, 22.5% of patients receiving esketamine had achieved remission (MADRS total score ≤12), compared to 7.6% in the placebo group.[379]​ Although esketamine is being used more frequently in clinical practice, a cautious approach is advised, questions remain about which patients respond best to it, how long therapeutical effects might persist, and over what duration to continue treatment. While no longer considered a last resort treatment, esketamine is not a first- or second-line treatment. Availability of esketamine varies according to country of practice and relevant regulatory approval. In the US, the drug is only available through a restricted distribution programme. The drug must be self-administered by the patient, who is supervised by a health care provider in a certified medical office, and the patient monitored for at least 2 hours because of the risk of sedation, respiratory depression, difficulty with attention, judgement and thinking (dissociation), suicidal thoughts and behaviours, and the potential for drug misuse. Monitor respiratory status and blood pressure during treatment. Be aware that patients with poorly controlled hypertension or pre-existing aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects. Esketamine is contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, or intracerebral haemorrhage.

In cases where nothing else has worked and the patient can tolerate a washout period from their current antidepressant, monotherapy with a monoamine oxidase inhibitor (MAOI) (e.g., isocarboxazid, phenelzine, selegiline, tranylcypromine) can be uniquely effective, even though it is associated with a more severe adverse effect profile and recommended only when other options prove ineffective.[299][300]​ The washout period depends on the half-life of the antidepressant the patient is currently on and can range from 1 to 5 weeks. MAOIs inhibit monoamine oxidase, causing an increase in monoamine neurotransmitters (e.g., serotonin, adrenaline, and dopamine). MAOIs are rarely used as they have many drug-drug and drug-food interactions, and should not be used in patients with hypertension. The combination of a MAOI with another antidepressant is not recommended, and certain combinations are contraindicated, owing to severe risks (e.g., serotonin syndrome). They are generally not used in primary care; do not use an MAOI without consulting a psychiatrist first.[165]

Caution is required when switching from one antidepressant to another due to the risk of drug interactions, serotonin syndrome, withdrawal symptoms, or relapse. The timeframe required for safely switching depends on various factors, including the pharmacokinetical properties of the drugs and possible interactions between them, as well as patient characteristics such as age, sensitivity to adverse effects, and the capacity to wait to begin a new course of treatment. In some situations, it is possible to give both drugs for a short period of time while the changeover is occurring; however, this should only be done under specialist guidance. In other cases, it is safer to take a more conservative approach. This involves slowly tapering the dose of the first drug before stopping it, and then waiting a period of time before starting the second drug (known as a washout period, which is usually five half-lives of the first drug). Drugs with longer half-lives (e.g., fluoxetine) require longer washout periods (e.g., up to 5-6 weeks) when combined with a drug with which the combination is contraindicated (e.g., monoamine oxidase inhibitors with fluoxetine). Specific recommendations for switching from one antidepressant to another, along with suitable washout periods, are available and local guidance should be consulted. When in doubt, in the absence of such guidelines, as a general principle perform a drug interaction check to be sure there are no absolute contraindications, and then 'start low and go slow' until safety can be ascertained.

Continue successful antidepressant treatment for 6-12 months following remission, before considering discontinuation.[165][322]​​​​ A possible exception is the use of esketamine nasal spray, as current evidence on longer-term use is limited and its effectiveness beyond 4 weeks has not yet been evaluated.

Some physicians recommend that patients with frequent previous recurrences and relapses, who respond successfully to antidepressant treatment, may require longer-term or indefinite therapy, following shared decision-making.[332]​​

The specific drug regimens listed are examples of commonly used regimens only. Consult local guidance for other examples and preferred options.

Primary options

citalopram: 20 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day

OR

escitalopram: 10 mg orally once daily initially, increase gradually according to response, maximum 20 mg/day

OR

fluoxetine: 20 mg orally (immediate-release) once daily initially, increase gradually according to response, maximum 80 mg/day; doses >20 mg/day may be given in 2 divided doses

More

OR

paroxetine: 20 mg orally (immediate-release) once daily initially, increase gradually according to response, maximum 50 mg/day; 25 mg orally (controlled-release) once daily initially, increase gradually according to response, maximum 62.5 mg/day

OR

sertraline: 50 mg orally once daily initially, increase gradually according to response, maximum 200 mg/day

OR

desvenlafaxine: 50 mg orally once daily initially, increase gradually according to response, maximum 400 mg/day; doses >50 mg/day have not shown additional benefit

OR

duloxetine: 40-60 mg/day orally initially given in 1-2 divided doses, increase gradually according to response, maximum 120 mg/day; doses >60 mg/day have not shown additional benefit

OR

levomilnacipran: 20 mg orally once daily initially for 2 days, increase to 40 mg once daily, then increase gradually according to response, maximum 120 mg/day

OR

venlafaxine: 75 mg/day orally (immediate-release) initially given in 2-3 divided doses, increase gradually according to response, maximum 225 mg/day; 75 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 225 mg/day

OR

bupropion: 100 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 450 mg/day given in 2-3 divided doses; 150 mg orally (sustained-release) once daily initially, increase gradually according to response, maximum 400 mg/day given in 2 divided doses; 150 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 450 mg/day

OR

mirtazapine: 15 mg orally once daily initially, increase gradually according to response, maximum 45 mg/day

OR

vilazodone: 10 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day

OR

vortioxetine: 5-10 mg orally once daily initially, increase gradually according to response, maximum 20 mg/day

OR

amitriptyline: 25 mg orally once daily at bedtime initially, increase gradually according to response, maximum 150-300 mg/day (may give in divided doses)

OR

desipramine: 50-75 mg orally once daily at bedtime initially, increase gradually according to response, maximum 200-300 mg/day (may give in divided doses)

OR

doxepin: 25-75 mg orally once daily at bedtime initially, increase gradually according to response, maximum 150-300 mg/day (may give in divided doses)

OR

imipramine: 25-75 mg orally once daily at bedtime initially, increase gradually according to response, maximum 150-300 mg/day (may give in divided doses)

OR

nortriptyline: 25-50 mg orally once daily at bedtime initially, increase gradually according to response, maximum 150 mg/day (may give in divided doses)

Secondary options

esketamine nasal: (28 mg/device) induction phase: 56-84 mg intranasally twice weekly for 4 weeks, adjust dose based on response and tolerability; maintenance phase: 56-84 mg intranasally once weekly for 4 weeks, followed by 56-84 mg every 1-2 weeks

More

OR

isocarboxazid: 10 mg orally twice daily initially, increase gradually according to response, maximum 60 mg/day given in 2-4 divided doses

OR

phenelzine: 15 mg orally three times daily initially, increase gradually according to response, maximum 60-90 mg/day; reduce dose gradually over several weeks to lowest effective dose after clinical response

OR

selegiline transdermal: 6 mg/24 hours patch once daily initially, increase gradually according to response, maximum 12 mg/24 hours

OR

tranylcypromine: 10 mg orally three times daily initially for 2 weeks, increase gradually according to response, maximum 60 mg/day

Plus – consider augmentation pharmacotherapy

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ACUTE
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treatment-resistant/refractory depression
Plus – 

consider augmentation pharmacotherapy

Treatment recommended for ALL patients in selected patient group

In patients who have not responded to conventional antidepressants, lithium augmentation is an evidence-based approach.[302] Lithium augmentation is initiated by a psychiatrist because of its narrow therapeutic index and risks of inadvertent toxicity from excessive dosing and drug-drug interactions. Augmentation with some antipsychotic agents may improve outcomes.[304][305][380] [ Cochrane Clinical Answers logo ] ​ However, one cohort study reported increased mortality risk in general associated with adding an antipsychotic versus adding a second antidepressant.[308] It is unclear whether this is a pharmacological effect of antipsychotics or a reflection of the likelihood that antipsychotics tend to be prescribed to patients who are at higher risk for mortality for other reasons. Because of this potential risk, augmentation with an antipsychotic for treatment-resistant depression should typically be overseen by a psychiatrist who can determine the clinical necessity of choosing it over other strategies. 

Evidence better supports short-term versus long-term use of adjunctive antipsychotics.[309] Long-term use exposes patients to common antipsychotic side effects such as weight gain, akathisia, and, rarely, tardive dyskinesia. This concern applies as well to new agents such as brexpiprazole, which are similar to antipsychotics structurally but are marked specifically for use in treatment-resistant depression. Although deemed effective (in a small number of studies), the side effects are similar to other antipsychotics, and so it is important to consider whether benefits outweigh risks in people without psychosis.[310][311][312][313][314]

If the patient is not already on esketamine nasal spray monotherapy first line, it may be considered by a consultant as an augmentation strategy (to be used with an oral antidepressant) for treatment-resistant depression.

Other augmentation strategies may be used by specialists.[316][317][318]

The specific drug regimens listed are examples of commonly used regimens only. Consult local guidance for other examples and preferred options.

Primary options

lithium: consult specialist for guidance on dose

OR

aripiprazole: consult specialist for guidance on dose

OR

olanzapine/fluoxetine: consult specialist for guidance on dose

OR

brexpiprazole: consult specialist for guidance on dose

OR

cariprazine: consult specialist for guidance on dose

Plus – psychological therapy or other non-pharmacological treatment

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ACUTE
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treatment-resistant/refractory depression
Plus – 

psychological therapy or other non-pharmacological treatment

Treatment recommended for ALL patients in selected patient group

Check and ensure that the patient has started psychological therapy if multiple pharmacological agents have been unsuccessful; in particular, cognitive behavioural therapy (CBT) appears to be effective at reducing symptoms in treatment-resistant depression with long-lasting results (up to at least 1 year).[293]

Psychological therapy has been shown to be both effective and cost-effective in reducing depressive symptoms.[167][168]​ Psychological therapy is as efficacious as pharmacotherapy and reduces the risk of relapse when added to pharmacotherapy.[169][377]​ Psychological interventions may reduce the number of sickness absence days from work, whether this is face to face or online.[163]

CBT has shown greater efficacy than pharmacological placebo across levels of severity.[219] Treatment response to CBT is comparable with antidepressant response in some studies.[170][Evidence B] Staged treatment trials suggest that CBT may be particularly beneficial when used during the continuation phase of treatment; CBT reduces the risk of relapse/recurrence at least as well as, and perhaps better than, antidepressant continuation.[335][336][337] In pooled clinical trials, mindfulness-based CBT was found to be particularly useful in relapse prevention.[338] CBT appears to have an enduring effect that reduces subsequent risk after treatment ends.[175]​ Adjunctive CBT has also been found to improve outcomes for depression treatment in the primary care setting.[220]

Other types of psychological therapy for depression include interpersonal psychotherapy (IPT), problem-solving therapy (PST), behavioural activation, and bibliotherapy. IPT requires the patient to have psychological insight.[221] Frequency for both CBT and IPT is determined by the healthcare provider. The time to response is approximately 12 weeks. IPT may improve interpersonal functioning, and also appears effective for relapse prevention.[222] PST focuses on training in adaptive problem-solving attitudes and skills.[223][224][225]​ Results from PST are comparable to those from CBT in primary care settings.[226]

Behavioural activation is a less cerebral, more behavioural alternative to CBT. It actively promotes a return to functioning and has the advantage of not requiring doctoral-level therapists to administer it. A Cochrane review found it to be equally effective to CBT for adults with depression, albeit with a low level of certainty given the evidence available.[227] [ Cochrane Clinical Answers logo ]

Bibliotherapy, a programme of self-help by reading, may have long-term benefits for some patients.[231]

Plus – psychoeducation and lifestyle advice

Back
ACUTE
|
treatment-resistant/refractory depression
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165] Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

2nd line – electroconvulsive therapy (ECT)

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ACUTE
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treatment-resistant/refractory depression
2nd line – 

electroconvulsive therapy (ECT)

ECT may be an option for those who have not responded to, or cannot tolerate, antidepressants.[165] Although listed here as a secondary option, note that treatment decisions are highly individualised, and ECT may be considered early in the course of treatment in some people with severe depression. Indications for early use include treatment for depression with psychotic symptoms, suicidality, or catatonia, or where there has been a previous positive treatment response to ECT.[165][177]

The response rate is better for patients with severe major depression than for moderate or mild depression.[177] The potential impact on memory and cognition, which may reduce functioning during active treatment, make ECT less desirable for patients with milder depression. ECT is often the treatment of choice for severely depressed people with late-life depression, because it is effective, and avoids complications that may arise from pharmacological intolerance and drug interactions associated with treatment for comorbid physical conditions.[178]

ECT is performed under general anesthesia, typically 2 or 3 times a week for a total of 6-12 treatments.[188]

Patient and clinician must be fully informed of the potential risks, including the risks associated with not having ECT, so that the patient can provide informed consent.[165] The mortality rate of ECT is estimated to be about 2 deaths per 100,000 treatments, meaning that it is one of the safer procedures performed under general anesthetic.[189][190] Overall, there is no increase in risk of medical complications in patients receiving ECT versus equally depressed patients not receiving ECT.[191] ECT affects heart rate and blood pressure. Chest pain, arrhythmias, persistent hypertension, and ECG changes have been reported as complications, particularly in patients with pre-existing cardiac disease.[192] Cardiovascular conditions should be stabilised before administering ECT.[192] The majority of patients report adverse cognitive effects during and shortly after treatment, most commonly memory loss (both anterograde and retrograde amnesia).[194] This impairment seems to be short-lived according to objective assessment, although a significant proportion of patients report persistent memory loss following ECT.[193][194] This potential risk must be balanced against the evidence in favour of its efficacy, especially in patients with severe depression. If a person with depression cannot give informed consent for ECT, it should only be given when it does not conflict with a valid advance treatment decision made by the person.[165]

ECT treatment effects are temporary; following successful treatment, the effect must be maintained by the use of antidepressants and/or maintenance electroconvulsive treatments (typically once per week to once every 4 weeks or longer, titrated to stability).[195] Combined with antidepressants, lithium has been shown to reduce the risk for relapse post-ECT.[319]

Plus – psychological therapy or other non-pharmacological treatment

Back
ACUTE
|
treatment-resistant/refractory depression
Plus – 

psychological therapy or other non-pharmacological treatment

Treatment recommended for ALL patients in selected patient group

Check and ensure that the patient has started psychological therapy if multiple pharmacological agents have been unsuccessful; in particular, cognitive behavioural therapy (CBT) appears to be effective at reducing symptoms in treatment-resistant depression with long-lasting results (up to at least 1 year).[293]

Psychological therapy has been shown to be both effective and cost-effective in reducing depressive symptoms.[167][168]​ Psychological therapy is as efficacious as pharmacotherapy and reduces the risk of relapse when added to pharmacotherapy.[169][377]​ Psychological interventions may reduce the number of sickness absence days from work, whether this is face to face or online.[163]

CBT has shown greater efficacy than pharmacological placebo across levels of severity.[219] Treatment response to CBT is comparable with antidepressant response in some studies.[170][Evidence B] Staged treatment trials suggest that CBT may be particularly beneficial when used during the continuation phase of treatment; CBT reduces the risk of relapse/recurrence at least as well as, and perhaps better than, antidepressant continuation.[335][336][337] In pooled clinical trials, mindfulness-based CBT was found to be particularly useful in relapse prevention.[338] CBT appears to have an enduring effect that reduces subsequent risk after treatment ends.[175]​ Adjunctive CBT has also been found to improve outcomes for depression treatment in the primary care setting.[220]

Other types of psychological treatment for depression include interpersonal psychotherapy (IPT), problem-solving therapy (PST), behavioural activation, and bibliotherapy. IPT requires the patient to have the capacity for psychological insight.[221] Frequency for both CBT and IPT is determined by the healthcare provider. The time to response is approximately 12 weeks. IPT may improve interpersonal functioning, and also appears effective for relapse prevention.[222] PST focuses on training in adaptive problem-solving attitudes and skills.[223][224]​ Results from PST are comparable to those from CBT in primary care settings.[226]

Behavioural activation is a less cerebral, more behavioural alternative to CBT. It actively promotes a return to functioning and has the advantage of not requiring doctoral-level therapists to administer it. A Cochrane review found it to be equally effective to CBT for adults with depression, albeit with a low level of certainty given the evidence available.[227] [ Cochrane Clinical Answers logo ]

Bibliotherapy, a programme of self-help by reading, may have long-term benefits for some patients.[231]

Plus – psychoeducation and lifestyle advice

Back
ACUTE
|
treatment-resistant/refractory depression
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be re-inforced during treatment, as required.[165]​ Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as 'laziness' or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

pregnant

1st line – active monitoring and/or antidepressant and/or electroconvulsive therapy (ECT)

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ACUTE
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pregnant
1st line – 

active monitoring and/or antidepressant and/or electroconvulsive therapy (ECT)

Less severe depression: when the maternal and fetal risk of untreated depression is low, the risk/benefit balance may tip in favour of non-pharmacological therapies, as reflected in several treatment guidelines worldwide.[358][362]​​

More severe depression: studies of the safety of antidepressant use in pregnancy for the most part add up to minimal risk to the fetus.[340][341]​ There is little controlled trial evidence. Consistent data to support fully informed decision-making are lacking.​ Cohort studies have reported a small increased risk of pre-eclampsia, postnatal haemorrhage, and gestational diabetes in women who continue antidepressants throughout pregnancy.[342][343]​ Based on mixed evidence for an increased risk of postnatal haemorrhage associated with antidepressants, the UK government has advised caution.[344]

Women who stop their antidepressant are more likely to have a relapse of depression during their pregnancy.[345][346]​​ UK national enquiry data show that in women in contact with UK psychiatric services, peinatal suicides are more likely to occur in those with a depression diagnosis and no active treatment at the time of death.[347]

Depression itself may negatively affect fetal development (e.g., causing hyperactivity and irregular fetal heart rate), increase infants’ cortisol levels, impact on infant temperament, and influence behaviour in later childhood and adolescence.[348]

For infants exposed to antidepressants during pregnancy, evidence as to whether there is an increased risk of preterm birth and low birth weight compared to infants of mothers with untreated depression is mixed.[343][349][350][351]​​​[352]​ There is a small increased risk of persistent pulmonary hypertension of the newborn with maternal SSRI and SNRI use in any trimester (number needed to harm = 100).[356][357]​ 

Clinicians and patients should carefully discuss the risks of remaining on antidepressant treatment during pregnancy, against the risks of stopping or avoiding antidepressants and exposing the fetus to the harmful effects of prepartum depression. In the US, such discussions are frequently carried out by the patient’s obstetrician; obstetricians in the US may seek further specialist treatment advice from Perinatal Psychiatry Access Programs where available.[358]​ In other locations (e.g., the UK) clinicians should consult a specialist with experience in perinatal mental health as part of this process. The American College of Obstetricians and Gynecologists (ACOG) recommends that if pharmacological treatment is required for perinatal depression, selective serotonin-reuptake inhibitors (SSRIs) may be used as first-line pharmacotherapy, and serotonin-noradrenaline reuptake inhibitors (SNRIs) are reasonable alternatives.[358]

Some classes of antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), are not routinely used for depression in pregnancy, owing to concerns about potential risks to the mother and baby.[358]​ Esketamine nasal spray is a relatively new drug and is not recommended in pregnancy, as studies involving pregnant animals treated with ketamine indicate that esketamine may cause harm to the fetus when used during pregnancy.

Despite the lack of consistent evidence of harmful effects of antidepressants to fetal and infant health and development, caution is required. Updated information about potential harms from antidepressants and other pharmaceuticals can be found at various resources. UK Teratology Information Service Opens in new window

Severity of depressive symptoms may influence treatment choice. In very severe depression in pregnancy, electroconvulsive therapy (ECT) may the treatment of choice when the severity of illness puts the fetus at risk either due to poor maternal self-care or suicide. There is no known risk to the fetus from ECT.[359][360]

Plus – psychological therapy

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ACUTE
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pregnant
Plus – 

psychological therapy

Treatment recommended for ALL patients in selected patient group

Psychological treatments have essentially no risk of side effects and may be offered as monotherapy as one first-line option for depression occurring in pregnancy, particularly for those with less severe depression, or as adjunctive therapy for people receiving other treatments.[358]

Cognitive behavioural therapy (CBT) is associated with a robust moderate treatment effect for major depressive disorder during pregnancy. Interpersonal psychotherapy also appears to have a treatment effect, but to a lesser extent than CBT.[364]

Plus – psychoeducation and lifestyle advice

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ACUTE
|
pregnant
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165]​ Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

ONGOING

treatment responsive

1st line – maintenance antidepressant and/or psychological therapy

Back
ONGOING
|
treatment responsive
1st line – 

maintenance antidepressant and/or psychological therapy

For patients established on antidepressants, regularly review their antidepressant use to assess efficacy and the presence of any adverse effects, and to ensure that long-term use remains clinically indicated.[272]

Shared decision-making is recommended; options for those already taking an antidepressant who have achieved full or partial remission are; continuing antidepressant treatment; switching to a psychological treatment for relapse prevention; or continuing with the same antidepressant and adding on a psychological treatment for relapse prevention.[165]

Maintenance on antidepressants following remission does not guarantee protection from relapse, but there is evidence of at least a modest benefit.[331] Continue the antidepressant regimen that led to remission for 6-12 months following remission.[165][322]​​ The World Federation of Societies of Biological Psychiatry (WFSBP) supports the use of maintenance treatment for recurrent depression in some circumstances; WFSBP recommends maintenance treatment for 5-10 years, or indefinitely, for those people at greater risk of recurrent depression, particularly when two or three attempts to withdraw pharmacotherapy have been followed by another episode within a year.[322]

There is a growing body of evidence to support the use of psychological therapy for prevention of relapse and recurrence, both used alone and in combination with pharmacotherapy.[175][333]​ Specific modalities with demonstrated efficacy for relapse prevention include preventive CBT, mindfulness-based CBT, and interpersonal therapy (IPT).[165][334]​ Staged treatment trials suggest that CBT may be particularly beneficial when used during the continuation phase of treatment; CBT reduces the risk of relapse/recurrence at least as well as, and perhaps better than, antidepressant continuation.[335][336][337]​​​​ In pooled clinical trials, mindfulness-based CBT was found to be particularly useful in relapse prevention.[338]

Continued psychotherapy with antidepressant management is an effective option when continued through both acute and ongoing phases of treatment.[173]

There is evidence that switching in the maintenance phase from pharmacotherapy to psychotherapy can be at least as effective in preventing relapse as staying with pharmacotherapy.[182][333][339]​​

Computerised CBT is recommended by some international guidelines for relapse prevention in patients with mild depression.[182]

If discontinuation of a selective serotonin-reuptake inhibitor (SSRI) or a serotonin-noradrenaline reuptake inhibitor (SNRI) is required, the most immediate concern when removing a patient from antidepressant therapy is the possibility of rapid relapse. Beyond that, some antidepressants, particularly those in the SSRI or SNRI classes, are associated with a 'discontinuation syndrome'. Typical are flu-like symptoms, hyperarousal, insomnia, vertigo, and sensory disturbances (e.g., 'brain zaps'). Patients will often know how vulnerable they are to these symptoms, if they have ever skipped a dose or run out of their medication.

Slowly decrease the dose to reduce the risk of unpleasant discontinuation symptoms; this can usually be done over several weeks, but in some cases may take several months or longer in particularly susceptible patients.[324][328]

Drugs with shorter half-lives (e.g., paroxetine, venlafaxine) may require longer periods of taper.[329] A proportionate method of tapering is recommended by some treatment guidelines; this involves reductions as a proportion of the previous dose (e.g. 25%) rather than reducing the dose by a fixed increment each time.[165] If the required dose is not available in tablet form, a liquid preparation may be required (if available).

Be aware that people’s experiences of withdrawal symptoms can vary substantially from mild and transient to longer-lasting and more severe. Anticipatory discussion with the patient is important, including when and how to seek support from a healthcare professional in the event of discontinuation symptoms.[329] Closely monitor the patient to ensure that any apparent emerging discontinuation symptoms do not in fact represent a relapse of their depression.[272][330]

Plus – psychoeducation and lifestyle advice

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ONGOING
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treatment responsive
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165]​ Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

recurrent episode

1st line – repeat of remission-inducing regimen or long-term therapy

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recurrent episode
1st line – 

repeat of remission-inducing regimen or long-term therapy

Recurrent episodes of major depression should be treated with the same regimen that previously led to remission, provided that the recurrence did not occur while under adequate maintenance treatment with such medication.

The World Federation of Societies of Biological Psychiatry (WFSBP) supports the use of pharmacological maintenance treatment for recurrent depression in some circumstances; WFSBP recommends maintenance treatment for 5-10 years, or indefinitely, for those people at greater risk of recurrent depression, particularly when two or three attempts to withdraw pharmacotherapy have been followed by another episode within a year.[332]​ The selection and success of these treatments depends on the type and severity of depressive symptoms, but most often relies on trial and error.

There is a growing body of evidence to support the use of psychological therapy for prevention of relapse and recurrence, both used alone and in combination with pharmacotherapy.[175][333] Specific modalities with demonstrated efficacy for relapse prevention include preventive CBT, mindfulness-based CBT, and interpersonal therapy (IPT).[165][334] Staged treatment trials suggest that CBT may be particularly beneficial when used during the continuation phase of treatment; CBT reduces the risk of relapse/recurrence at least as well as, and perhaps better than, antidepressant continuation.[335][336][337]​​​ In pooled clinical trials, mindfulness-based CBT was found to be particularly useful in relapse prevention.[338]

Continued psychotherapy with antidepressant management is an effective option when continued through both acute and ongoing phases of treatment.[173]

There is evidence that switching in the maintenance phase from pharmacotherapy to psychotherapy can be at least as effective in preventing relapse as staying with pharmacotherapy.[182][333][339]​​

Computerised CBT is recommended by some international guidelines for relapse prevention in patients with mild depression.[182]

Plus – psychoeducation and lifestyle advice

Back
ONGOING
|
recurrent episode
Plus – 

psychoeducation and lifestyle advice

Treatment recommended for ALL patients in selected patient group

For all people with depression, psychoeducation and lifestyle advice is recommended at the start of treatment, and may be reinforced during treatment, as required.[165] Psychoeducation entails educating about the nature of the illness and may be beneficial to involve family members whenever feasible. This involvement allows them to gain a better understanding of behaviours like lack of motivation or drive, which might otherwise be misconstrued as ‘laziness’ or disinterest.[180]

Lifestyle advice encompasses instruction on the following: sleep hygiene, and setting appropriate times for sleeping and waking; healthy diet and exercise; cessation of smoking, excess intake of alcohol and substance misuse including cannabis use (if cessation is not possible, then advice on moderation is required).[180]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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