Depression in adults

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The goals of treatment are to eradicate symptoms of depression, improve daily functioning and quality of life, improve workplace functioning, reduce suicidality, minimise treatment adverse effects, and prevent relapse.[161][162][163]

The initial priority is to identify and mitigate against any immediate risks for harm to self or others, including consideration of the need for inpatient admission (see Acute and urgent considerations).

For people with depression who can be safely managed outside of a hospital setting, first-line treatment options include:[164][165]

Psychological therapy (e.g., cognitive behavioural therapy [CBT])
Pharmacotherapy (e.g., antidepressants)
The combination of psychological therapy and pharmacotherapy

Both antidepressants 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] Psychological treatments have been shown to be both effective and cost-effective in reducing depressive symptoms, and may reduce the number of sickness absence days from work, whether this is face to face or online.[163][167][168][169] Treatment response to CBT is comparable with antidepressant response in some studies.[170][Evidence B]What are the effects of cognitive behavioural therapy (CBT) versus second-generation antidepressants (e.g., selective serotonin-reuptake inhibitors or serotonin-noradrenaline reuptake inhibitors) in adults with major depressive disorder?[170] For those with more severe depression, the combination of psychological therapy plus pharmacotherapy has demonstrated greater efficacy than either treatment alone.[171][172][173][174] Psychological therapy, both used alone or used in combination with pharmacotherapy, has a more enduring treatment effect than pharmacotherapy alone.[175] It should be noted that for people with subthreshold or mild symptoms, the prognosis is often good without the need for pharmacotherapy or psychological therapy.[176]

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 less severe 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-drug interactions associated with treatment for comorbid physical conditions.[178]

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 either 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 all patients 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 it 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 encompassess instruction on the following:[180]

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

Urgent and acute considerations

Features indicating a need for urgent management include psychosis, suicidal ideation, catatonia, severe psychomotor retardation impeding activities of daily living, and severe agitation.[165][181][182] These people are at increased risk for suicide, impulsive and potentially self-destructive behaviour, and health complications due to poor self-care and immobility.

Consultant referral, hospitalisation, constant observation, tranquilisation, and/or ECT may be required to ensure safety until definitive antidepressant therapy can take effect. The pharmacological and non-pharmacological treatment options used in these patients, once the risks have been stabilised, are discussed in Moore severe depression.

Urgent consultant referral is indicated and hospitalisation should be considered for people:[165][181][182]

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
With psychotic symptoms
With uncontrolled agitation accompanied by the risk of impulsive behaviour.

Suicide risk mitigation

Suicide risk mitigation is critical, especially as the risk may increase early in treatment. Routinely asking people about suicidal ideation and reducing access to lethal means (especially firearms) can reduce the risk of suicide.[129] Close telephone follow-up by a trained psychiatrist may help reduce the risk of death by suicide after a previous suicide attempt.[183] See Suicide risk mitigation.

Pharmacotherapy

Antidepressant therapy: usually the first-line option in most people with severe depression requiring an urgent management approach. General principles of prescribing antidepressants are described in 'More severe depression'.
Psychosis: antidepressants alone may not effectively address psychotic symptoms, such as delusions or hallucinations; therefore, clinicians should have a lower threshold for adding an antipsychotic to antidepressant treatment in people with psychosis.[165][184][185]
Agitation: for people who have severe agitation as a depressive symptom, antipsychotics can directly tranquilise the distress associated with this form of severe depression. People with agitation may also benefit from short-term treatment with a benzodiazepine, or possibly both an antipsychotic and a benzodiazepine, until definitive antidepressant therapy takes effect.[186] [ ] Patients with mild agitation or severe anxiety can be treated with a benzodiazepine and/or an antipsychotic.
Catatonia: people with catatonia are usually treated with a benzodiazepine, sometimes in combination with an antipsychotic: ECT may also be considered.[187]
Suicidality: esketamine nasal spray (an active isomer of ketamine, an N-methyl-D-aspartate [NMDA] receptor antagonist) may be considered by a consultant for those with depression with acute suicidal ideation or behaviour, as an adjunct therapy 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, and it is typically reserved for people with persistent suicidal ideation. 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. 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. Esketamine may also be considered for some people with treatment-resistant depression (see below).

Electroconvulsive therapy (ECT)

Indication: although most people referred for ECT have tried other antidepressant treatments, ECT may be considered early in the course of treatment in certain people with severe depression. It may be used early in treatment for depression with psychotic symptoms, suicidality, or catatonia, or where there has been a previous positive treatment response to ECT.[165][177]
General procedure: ECT is performed under general anaesthesia, typically 2 or 3 times a week for a total of 6-12 treatments.[188]
Risks: 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). 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]
After-effects: 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]

Supportive care

Agitated patients 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 patients 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 patients may require supportive nursing care.

Psychological therapy

These patients are unlikely to find other talking treatments effective, and it may worsen their outlook. Limit psychotherapy to the support necessary to manage the patient safely and to encourage the patient to accept definitive treatment.

More severe depression

‘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]

While it is important to assess the severity of depression using valid diagnostic criteria, the author uses a somewhat broader approach when determining severity of depressive symptoms. Thus the author notes that, within their own clinical practice, the following factors might sway the judegment towards considering a specific depressive episode to be 'more severe':

Symptoms suggestive of high clinical risk, for example, suicidal ideation
Symptoms that are highly specific for depression and/or that might impede normal coping strategies, for example, lack of interest[196]
Symptoms that are present on a daily or near-daily basis
A substantial lack of motivation where the person is unable to distract themselves from their depressive symptoms

For people with more severe depression who can be safely managed outside of a hospital setting, treatment options include pharmacotherapy and psychological therapy, either alone or in combination.[165][197] Efficacy of antidepressants is more pronounced with increasing severity of depression.[166] The combination of psychological therapy plus pharmacotherapy has demonstrated greater efficacy for this patient group than either treatment alone.[171][172][173][174] The World Health Organization (WHO) recommends psychological interventions whenever possible for all adults with moderate-to-severe depression, either with or without pharmacotherapy.[198] 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 this approach, clinicians should consider patient preferences or other individual factors when deciding whether to offer psychological therapy alone to people with more severe depression. 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]

Regardless of treatment type, close follow-up and at minimum supportive or educational interventions during the onset of treatment can improve treatment adherence and may also reduce the risk of self-injury or suicide that can emerge in the very early phases of recovery, when energy and arousal have increased but mood remains depressed.

Antidepressants for more severe depression

Antidepressants are more efficacious than placebo in patients with moderate or severe depression.[200][201]

Choice of antidepressant

The main antidepressant options include:

Selective serotonin-reuptake inhibitors (SSRIs) (e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline)
Serotonin-noradrenaline reuptake inhibitors (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)
Agomelatine (a melatonin receptor agonist and 5-HT2c receptor antagonist
Reboxetine (a noradrenaline-reuptake inhibitor)

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] [ ]

US guidance recommends that initial pharmacological treatment should be with a second-generation antidepressant (e.g., SSRI, SNRI, bupropion, mirtazapine, vilazodone, vortioxetine).[197] UK guidance recommends offering an SSRI as first-line treatment for most people with depression for whom pharmacological treatment is suitable.[165] Later-line options recommended by NICE include an SNRI or (in secondary-care only) a tricyclic antidepressant or a monoamine oxidase inhibitor (MAOI).[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]

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]

Determine antidepressant dose based on the known target dose range. Within the recommended ranges for several commonly used second-generation antidepressants (SSRIs, venlafaxine, and mirtazapine) it has been shown that across a population, the correlation between dose and efficacy flattens or declines at around the midpoint, in part because of diminished tolerability at higher doses.[206] High-dose SSRI treatment for depression in patients refractory to medium-dose treatment is not supported by evidence and is not recommended.[207][208][209]

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.

Antidepressants and suicide risk

Although the net result of antidepressant response is a significant reduction in suicidal ideation, 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] The results of one large meta-analysis suggest that in adults under the age of 25 years, the risk of both emergence and worsening of suicidality may be raised in weeks 3-6 of treatment (but not in weeks 1-2).[215] Close monitoring and suicide risk mitigation 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]

Assessing antidepressant response

Follow up patients 1-2 weeks after initiating therapy, then monthly for the next 12 weeks. The Patient Health Questionnaire-9 (PHQ-9) may be used 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.

Psychological treatments for more severe depression

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 more severe depression, including cognitive behavioural therapy (CBT), 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]

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]What are the effects of cognitive behavioural therapy (CBT) versus second-generation antidepressants (e.g., selective serotonin-reuptake inhibitors or serotonin-noradrenaline reuptake inhibitors) in adults with major depressive disorder?[170] CBT has 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 psychological modalities for more severe depression include include the following.[165][218]

Interpersonal psychotherapy (IPT): requires the patient to have psychological insight.[221] Frequency for 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]
Problem-solving therapy (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: 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] [ ]
Short-term psychodynamic psychotherapy: may be useful for people with emotional and developmental difficulties in relationships contributing to their depression.[165][228]

Less severe depression

‘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. Patients with less severe depression have low to moderate severity symptoms, partial impairment, no psychotic symptoms, no suicidal ideation, and no psychomotor retardation or agitation.

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. Psychoeducation and lifestyle advice is recommended for all people with depression of any severity. Psychoeducation alone can achieve remission for some people with less severe depression.[230]

For people with less severe depression who wish to consider treatment, guidelines typically recommend non-pharmacological therapies first line, based on the assessment that the risk:benefit ratio does not justify the use of pharmacotherapy for mild depression.[165][197] Less intensive options such as guided self-help and group CBT or behavioural activation may be a reasonable initial option in this group.[165] However it is important to note that, as for all patients with depression, treatment is individualised, and there may be reasons to consider pharmacological treatment from the offset in this group in certain 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).

Combination psychological therapy and pharmacotherapy offers no demonstrated short-term advantage in this group. However, continued psychological therapy with antidepressant management is an effective option when continued through both acute and ongoing phases of treatment.[173]

The initial choice of therapy should be guided by patient preference. Options include:

Supportive interventions: self-help books, yoga, relaxation training, light therapy, exercise, tai chi, music therapy, and acupuncture[231][232][233][234][235][236][237][238][239][240][241][242] [ ]
Computer-based treatment: CBT, PST, and stress management.[243][244][245][246][247][248][249][250]
Antidepressant treatment
Psychological therapy: CBT, IPT, PST, or a mindfulness-based intervention[251][252][253]

Supportive interventions

For some people who have milder symptoms, the degree of impairment or distress from these symptoms might not outweigh the stigma the person attaches to accepting any form of psychiatric treatment; for these people a focus directly on symptom management may be the optimal strategy.[254]
Self-help books are popular and may have long-term benefits for some patients.[231]
Yoga 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][256][257][258][259] [ ] In people with depression, higher remission rates were observed in a higher-dose exercise group plus continuation of SSRI treatment compared with low-dose exercise plus SSRIs.[238] Conversely, cessation of exercise may worsen depressive symptoms.[260][261] [ ]

Computer-based treatment

Internet- and mobile-based interventions are a promising and rapidly emerging development, and demonstrate efficacy. 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]
They may be useful for people who cannot access or afford or schedule individual or group face-to-face CBT.
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]
Smartphone-based iCBT and novel app-based approaches are increasingly popular with patients; evidence of efficacy has not been established, although preliminary evidence as to their feasibility and efficacy looks promising.[267]
Several key barriers to digital interventions have been noted, including concerns about reduced access to care for people with lower levels of digital literacy, which may include older people. 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]

Psychological therapy

Psychological therapy (CBT, IPT, or PST) is also considered a first-line option in less severe depression. Psychological therapy appears to have a positive impact on the quality of life of people with depression, beyond measurable reductions in depressive symptom severity.[269] As a general guide, the psychological interventions listed above in the section on ‘more severe depression’ are also suitable for people with ‘less severe depression'.[165] UK-based guidance from NICE also lists mindfulness-based therapy as a potential additional option in this group.[165][270]
Less severe depression treated with psychological therapy may be less likely to progress to more severe depression.[271]

Antidepressant treatment

The routine use of antidepressants for patients with mild depression has been questioned based on weaker evidence for efficacy in people with milder symptomatology.[272] Some analyses have not consistently determined that mild depression responds less well to antidepressants than severe depression, although the evidence on this is mixed overall; other studies suggest an increasing magnitude of benefit of antidepressants with higher levels of depressive symptomatology.[166][273][274][275][276]
In the absence of definitive evidence, clinicians should therefore be guided by patient preference or other patient-specific factors in deciding whether to offer pharmacotherapy for less severe depression.
If antidepressants are used, follow the same principles as for more severe depression (above).

Depression unresponsive to initial therapy

Regardless of depression severity, 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 receiving antidepressants, 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, with a synergistic effect of using both.[173][174][197] Switching from pharmacotherapy to a psychological therapy may be another reasonable option to consider, particularly for those with less severe depression (e.g., if the patient expresses this as a preference and can access CBT).[197]

Another option to consider if an antidepressant has been prescribed 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; however, be aware that early response may be, but is not necessarily, a reliable indicator of continued response.[281][282][283][284]

Switching between antidepressants within a class may be considered initially (e.g., from one SSRI to another SSRI).[181] Next consider a change in drug class; for example, if a patient was on an SSRI, then consider an 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.

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.

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 treatment-refractory, and warrants a more complex approach, as outlined in the 'Treatment-resistant/refractory depression' section.

Treatment-resistant/refractory depression

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] Regardless of the terminology, guidelines typically suggest that clinicians working in primary care should request input from a psychiatrist after two unsuccessful treatment interventions; however, in practice this may need to be balanced against barriers to referral such as lack of specialist access.[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.

New symptoms, attributed to medication side effects, commonly interrupt pharmacotherapy attempts; however, somatic symptoms are a common correlate of depressive disorder. Many perceived medication side effects, such as cognitive impairment, weight gain, and headache, occur just as frequently in study patients taking placebo.[291]

Reassessment

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 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.

Psychological treatment

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

Antidepressant treatment

Switching antidepressants: 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) SSRI, SNRI, or an atypical agent (e.g., bupropion, mirtazapine, vilazodone, vortioxetine). One caveat about this approach, however, is that there are little high-quality clinical trials data to support switching antidepressants as opposed to continuing with the first (and raising the dose or trying augmentation strategies).[285]
Combining antidepressants: 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]
Choice of alternative antidepressants: when selecting a third (or fourth or fifth) medication to switch to, consider not only another SSRI, SNRI, or atypical agent (e.g., bupropion, mirtazapine), 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]
Monoamine oxidase inhibitors (MAOIs): in cases where nothing else has worked and the patient can tolerate a washout period from their current antidepressant, an 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 1-5 weeks. Do not use an MAOI without consulting a psychiatrist first.[165]
Lithium augmentation: some studies show that combinations of antidepressants with other classes of medication are better than just a combination of different antidepressants alone.[301] In patients who have not responded to conventional antidepressants, lithium augmentation is an evidence-based approach.[302][303] 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.
Antipsychotic augmentation: augmentation with some agents is becoming more common practice and may improve outcomes, including in older adults.[303][304][305][306] [ ] However, intolerability and treatment discontinuation are more common with the majority of adjunctive antipsychotics compared to with placebo.[307] 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] 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 marketed 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][315]
Esketamine nasal spray: may be considered by a consultant either as monotherapy or as an augmentation strategy (to be used with an oral antidepressant) for treatment-resistant depression. 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. A key practical consideration is the logistical and occupational commitments required of patients; for example, the need to take time away from work and to arrange necessary transport and support. 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. 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.
Other augmentation strategies may be used by specialists (e.g., thyroid hormone, pindolol, and modafinil, as well as emerging treatments such as ketamine and transcranial magnetic stimulation).[316][317][318]

ECT

When depression is severe enough to cause danger, significant distress, or functional impairment, the superior efficacy of ECT makes it a reliable and reasonable rescue treatment. The transient impact on memory and cognition, which may reduce functioning during active treatment, make ECT less desirable for patients with milder depression. It is important to remember that the effects of ECT generally last only a few weeks, so pharmacotherapy is necessary to sustain its effects or act as maintenance therapy. Combined with antidepressants, lithium has been shown to reduce the risk for relapse post-ECT.[319]

Duration of pharmacological treatment

Duration of antidepressant treatment following the remission of symptoms depends on the prior course of illness. Data on treatment outcomes beyond the initial weeks of treatment are limited, although one systematic review suggests that the efficacy of antidepressants compared with placebo is stable over at least the first 6 months of treatment.[320] In general, there appears to be a reduced risk of relapse when antidepressants are continued for 6 months or over.[321][322][323]

Based on this, it is advisable to continue successful antidepressant treatment for at least 6-12 months following remission.[165][322]

For people prescribed an antipsychotic for depression with psychotic symptoms, UK guidance recommends continuing antipsychotic treatment for a number of months after remission, if tolerated. NICE recommends that the decision about if and when to stop an antipsychotic should be made by, or in consultation with, specialist psychiatric services.[165]

Discontinuation of antidepressant treatment has consistently been associated with a greater risk of relapse than does continuing treatment, and is therefore a complex clinical decision.[324][325][326] While the risk of relapse over a population of patients increases off treatment, a substantial proportion of patients may stop antidepressants without consequence.[327] For some people at increased risk of relapse, continuation of treatment beyond this period may be considered. Shared decision-making is recommended. See Maintenance treatment and relapse prevention.

Discontinuation of medication for depression

The most immediate concern when removing a patient from antidepressant treatment is the possibility of rapid relapse, if in fact the antidepressant was still serving its purpose. 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. Clinicians should 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 discontinuation 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 such 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]

UK guidance advises that antipsychotics for psychotic depression should only be stopped in specialist mental health services, or following specialist mental health advice. When stopping an antipsychotic, reduce the dose gradually over at least 4 weeks, and in proportion to the length of treatment.[165]

Maintenance treatment and relapse prevention

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:[165]

Continuing antidepressant treatment
Switching to a psychological treatment for relapse prevention
Continuing with the same antidepressant and adding on a psychological treatment for relapse prevention.

Maintenance on antidepressants following remission does not guarantee protection from relapse, but there is evidence of at least a modest benefit.[331]

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.[332]Bauer M, Severus E, Köhler S, et al.; World Federation of Societies of Biological Psychiatry (WFSBF) Task Force on Treatment Guidelines for Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 2: maintenance treatment of major depressive disorder - update 2015. World J Biol Psychiatry. 2015 Feb;16(2):76-95.

The selection and success of treatment for relapse prevention depends on the type and severity of depressive symptoms, but most often relies on trial and error.

There is a growing body of evidence supporting the use of psychological therapy for prevention of relapse and recurrence, both when 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] 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.[333][339] Psychological therapy in patients who suffer from recurrent episodes may be well aimed if it addresses the despair patients often feel when they see recovery as only a temporary respite from suffering, and if it educates patients about ways to cope with and possibly prevent recurrences.

Recurrent episodes

Recurrent episodes of major depression should be treated with the same antidepressant that previously induced remission, provided that the recurrences do not occur while under adequate maintenance treatment with such medication.

Pregnancy

Depression coinciding with pregnancy creates a significant clinical dilemma. On the one hand, the fetus is exposed to a potential for harm by the increased likelihood of maternal substance misuse, neglect of health, or suicide. On the other hand, all antidepressants cross the placental barrier, with the potential to cause iatrogenic harm to the fetus. 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.

Obstetric risks of antidepressant use during pregnancy

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]

Psychiatric risks of antidepressant discontinuation

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]

Effects on the fetus and child

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][353][354]

Transient irritability and other symptoms reminiscent of antidepressant discontinuation syndromes affect a substantial proportion of neonates exposed to antidepressants in utero up to the time of delivery.[355]

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]

Recommendations for management

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 consultant treatment advice from Perinatal Psychiatry Access Programs where available.[358] In other locations (e.g., the UK) clinicians should consult a consultant 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, SSRIs may be used as first-line pharmacotherapy, and 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 TCAs and 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

Severity of depressive symptoms may influence treatment choice. For women with very severe major depression in pregnancy, ECT may be the treatment of choice as it does not expose the fetus to any known risk.[359][360] For more severe depression, the risk to the fetus from the potentially harmful effects of the mother’s untreated depression on her health might outweigh any detectable risk to the fetus from antidepressants.[340][341][361] Where the maternal and fetal risk of untreated depression is low, as in mild to moderate depression, the risk/benefit balance may tip in favour of non-pharmacological therapies, as reflected in several treatment guidelines worldwide.[358][362]

Psychological treatments have essentially no risk of side effects and may be offered as one first-line option for depression occurring in pregnancy, particularly for those with less severe depression.[358] CBT is associated with a 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.[363][364]

It is important to consider and address any coexisting psychosocial problems, such as intimate partner violence.

Postnatal depression

See Postnatal depression.

Older adults with depression (age >65 years)

The treatment of depression in older adults is broadly similar to that in younger adult patients, and antidepressants are an effective treatment for depression in this group.[11] Collaborative care models may be particularly useful for this patient group.[365][366] There is evidence of efficacy for psychological treatments for older people with depression, including older adults residing in long-term care settings, although the evidence is uncertain.[367] [ ] Suicide risk mitigation is an important consideration, given the relatively higher rates of suicidal ideation in this age-group.[368]

Caution is required when prescribing for older patients with depression (as with any pharmacological treatment in older people) due to an increased risk of side effects and increased use of concurrent medication in this population. Clinicians should typically start at the lowest dose and titrate up slowly when prescribing any drug treatment in older adults, and be aware of potential drug interactions. However, if older adults are unresponsive to a low dose of antidepressants, a higher dose may be required; many older patients ultimately require the same doses of antidepressant that are used for younger adults.

The Screening Tool of Older Persons Prescriptions and Screening Tool to Alert doctors to Right Treatment (STOPP/START) criteria is a reliable screening tool enabling prescribers to avoid potentially inappropriate treatment (and under-treatment) in adults over the age of 65 years.[11] STOPP-START Opens in new window

ECT may be a suitable treatment for older patients with severe depression and avoids complications arising from drug-related adverse effects.[178]

Comorbidities

Antidepressants may be effective in reducing depression and alcohol consumption in patients with comorbid depression and alcohol dependence.[369] Antidepressant use in depressed patients who are on opioid agonist therapy is not well supported.[370] Available evidence on the use of antidepressants with depression comorbid with dementia is poor, suggesting their potential value may be outweighed in many cases by the potential for adverse effects.[371] There is some evidence for CBT-based treatments added to usual care in this patient group.[372] Evidence from one Cochrane review concluded that CBT-based treatments added to usual care probably have a small positive effect on symptoms of depression and quality of life when added to usual care for people with dementia and mild cognitive impairment.[372] One large-scale meta-analysis concluded that psychological interventions may be superior to pharmacological treatment in patients with dementia.[373] Evidence is also low quality, but more favourable, for antidepressants in patients with depression and HIV infection.[374] Support for antidepressants for depression comorbid with cancer is mixed.[155][375] Non-pharmacological approaches for the management of depressive symptoms both during and after cancer treatment (e.g., mindfulness-based interventions, yoga, music therapy, relaxation, reflexology and tai chi, and/or qigong) have been recommended according to integrative oncology treatment guidelines.[376]

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