Schizophrenia in adults: Assessment and treatment of co-occurring depression

INTRODUCTION — 

Depression is commonly seen in individuals with schizophrenia and is associated with less favorable patient course and poorer outcomes compared with individuals without depression.

The onset of depression in an individual diagnosed with schizophrenia may be due to many causes including a prodrome of an emerging psychosis, effects of co-occurring medical or substance use and disorder, adverse effects of antipsychotic medications, negative symptoms of schizophrenia, and disappointment reactions. Furthermore, the onset of a depression may indicate an alternative diagnosis, such as schizoaffective disorder [1].

This topic discusses the epidemiology, clinical manifestations, differential diagnosis, and treatment of depression in patients with schizophrenia. Discussion of the diagnosis and treatment of non-comorbid major depression, schizophrenia, and schizoaffective disorder are discussed separately.

●(See "Major depressive disorder in adults: Approach to initial management" and "Schizophrenia in adults: Clinical features, assessment, and diagnosis".)

●(See "Approach to the adult patient with suspected depression".)

●(See "Major depressive disorder in adults: Approach to initial management" and "Schizophrenia in adults: Clinical features, assessment, and diagnosis".)

●(See "Depression in adults: Course of illness".)

TERMINOLOGY — 

The term "depression" is used to describe several different phenomena. It can refer to an affect, a symptom, or a syndrome [2].

●As an affect, "depression" refers to a nonpathologic, transient feeling state of low mood.

●As a symptom, "depression" refers to an exaggerated feeling of low mood, exaggerated in that it occurs in the absence of sufficient stimulus, and is more severe or lasts longer than would be expected.

●As a syndrome, "depression" refers to a persisting clinical condition that features low mood or anhedonia along with elements such as low energy, self-reproach, impaired concentration, pessimism, guilt, lack of confidence, sleep or appetite disturbances, psychomotor agitation or retardation, or notions of self-harm, death, and suicide [1]. Diagnostic criteria for major depression are on the associated table (table 1).

As is the case for individuals who do not have schizophrenia, patients with schizophrenia can have "depression" in any of these three senses of the term. This topic refers to individuals with schizophrenia with co-occurring depressive symptoms or a syndrome of major depression. (See "Approach to the adult patient with suspected depression".)

EPIDEMIOLOGY — 

Estimates of the lifetime prevalence of depression in schizophrenia vary widely (from 6 to 75 percent) based on differing study characteristics including varying definitions of depression, patient settings, and durations of observation [3-8].

Risk factors for depression in schizophrenia include family history of depressive disorder, high levels of family and personal expectations for success in life, critical family attitudes, high levels of family-expressed emotion, stigma associated with psychiatric disorders, insight into the disorder and its psychosocial effects, multiple hospitalizations, recent hospital discharge, and lack or loss of psychosocial support or support of self-esteem [9-11].

CLINICAL FEATURES — 

Individuals with schizophrenia may develop depression at any time during their illness [3,12,13]. Symptoms of depression are heterogenous and may include emotional symptoms (loss of interest, depressed mood, anxiety), physical symptoms (change in appetite or sleep), and cognitive symptoms (impaired concentration, feelings of worthlessness). Suicidal ideation or behaviors may be present [11].

Commonly, depressive symptoms represent a prodromal psychosis. In this case, the psychosis typically emerges within one to two weeks of the onset of the depression.

Depression may present during an acute psychotic episode; however, it is often less dramatic than the psychotic symptoms and may be overlooked. The depression frequently remits as the psychosis subsides in response to an antipsychotic agent. However, a depressive syndrome may persist (and consequently appear to emerge) as the psychosis improves.

Depression may also present subsequent to or temporally unrelated to symptoms of psychosis.

The course of depression varies based on the presence of stressors, coping skills, presence of a support system, and the effect of treatment. In individuals with schizophrenia, depression appears to be associated with a variety of undesirable outcomes [3,5,14]. These include:

●Increased rate of suicide attempts and completed suicides, the latter estimated at between 4 and 12 percent [15-18]

●Higher rate of relapse and early rehospitalization

●Longer duration of hospitalization

●Poor response to psychologic and pharmacologic interventions

●Greater impairment in cognitive functioning

●Greater impairments in social and vocational functioning

●More personal suffering

●Increased family and community burden

EVALUATION

Assess for suicidality — Our initial step in the assessment of individuals with schizophrenia who present with a new onset of depression is to assess for suicidality. Depression in the context of schizophrenia is associated with increased rate of suicide attempts and death by suicide [15-17]. We encourage involvement of family members and other caregivers for collateral information regarding safety concerns. We refer individuals with an increase in suicidality for an urgent safety evaluation in an emergency department. (See 'Management' below and "Suicidal ideation and behavior in adults".)

Assess for and treat co-occurring disorders — Depression may be secondary to general medical disorders or co-occurring substance use or disorder. Once suicidal ideation has been ruled out or appropriately addressed, we review past medical history and address co-occurring disorders that may be contributing to the onset of depression.

We review prior medical history and past history of substance use and address each of these as indicated. In cases where the worsening symptoms may be due to substance use there is typically a temporal relationship between the symptoms and substance use. The associated table reviews general medical conditions and agents that may cause or contribute to depression (table 2) [19]. These are discussed further elsewhere. (See "Unipolar depression: Pathogenesis", section on 'Secondary depression'.)

Negative symptoms of schizophrenia — The "negative symptoms" syndrome of schizophrenia includes a number of features that are similar to components of the depression syndrome [20-22]. These features include anhedonia (lack of pleasure), anergia (lack of energy), alogia (lack of having things to say or lack of content in what is said), blunted affect, social withdrawal, and loss of drive or motivation.

A depressive syndrome may be distinguished from negative symptoms in schizophrenia by the presence of cognitive features more commonly seen with depressive syndromes (guilt, shame, low self-esteem, ideas of worthlessness, notions of helplessness, pessimism, and suicidal thoughts) and the prominent affective manifestations of depressed mood (such as intense low mood or tearfulness). Alogia and blunted affect are common negative symptoms of schizophrenia [23].

Minimal data support the pharmacologic management of negative symptoms of schizophrenia [24,25]. Further discussion of negative symptoms of schizophrenia is found elsewhere. (See "Schizophrenia in adults: Clinical features, assessment, and diagnosis", section on 'Negative symptoms'.)

Monitor for emergence of psychosis — We monitor for the onset of a new psychotic episode with weekly visits for a period of at least two weeks. Depressive symptoms in an individual with schizophrenia may represent symptoms of a prodromal psychosis. Studies report that current and lifetime depressive disorders are highly prevalent (60 percent) in the prodrome of a psychotic episode [26].

In individuals who manifest a new onset of psychosis, we consider the depression to have been a prodromal syndrome and treat the psychosis accordingly. (See 'Diagnosis' below.)

If the depression remits and the patient returns to their prior level of functioning, we consider the depression to be the response to psychosocial stressors, or a disappointment reaction. (See 'Diagnosis' below.)

If the depression persists at the end of this two week monitoring period, we treat the symptoms either by adjusting the antipsychotic regimen or treating with an antidepressant. (See 'Diagnosis' below and 'Management' below.)

DIAGNOSIS — 

The diagnosis and management of depression in patients with schizophrenia are closely intertwined and guided by the differential diagnosis. Diagnostic possibilities are guided by the patient's clinical state at the end of the monitoring period (see 'Monitor for emergence of psychosis' above):

●If symptoms of psychosis emerge, we consider the depression to have been a prodrome to recurrent psychosis and address the psychosis with antipsychotic medication. There does not appear to be an advantage to treating symptoms of depression with antidepressant medications in an individual with schizophrenia during an acute psychosis. Treatment of recurrent psychosis in individuals with schizophrenia is discussed elsewhere. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Medication adjustments'.)

●If the depression remits and the patient returns to their prior level of functioning, we consider the symptoms to have been a disappointment reaction or difficulty coping with a stressor. An acute disappointment reaction can occur in response to a loss or failure of plans to work out. Additionally, chronic disappointment (also called “demoralization” syndrome) can occur in response to ongoing symptoms and psychosocial limitations [27-33]. These may present with dysphoria, depressed mood, negativity, chronic discouragement, pessimism, loss of control, avoidance, and may further limit psychosocial functioning. Additionally, in these circumstances, "insight" into their situation can be a contributing factor as well [28]. These syndromes may respond favorably to interventions incorporating skill-building, success experiences, and exercises in positive thinking that are often a component of cognitive-behavioral therapy and motivational interviewing. (See 'Monitor for emergence of psychosis' above.)

●If the depression persists without other clinical changes (ie, psychosis) and the symptoms are not thought to be due to negative symptoms of schizophrenia, we address the depressive symptoms with psychosocial and pharmacologic interventions. (See 'Management' below and 'Negative symptoms of schizophrenia' above.)

Depending on the time course of symptoms, a new onset of major depression in an individual with schizophrenia may be cause for consideration of alternative diagnosis such as schizoaffective disorder. (See "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis".)

MANAGEMENT — 

If co-occurring disorders have been ruled out, there has not been a new onset of psychosis, and depression or other symptoms persist after two weeks of monitoring, we begin treatment of the depression. We encourage psychosocial intervention for all (if not already done) and consider adjustments to psychiatric medications or treatment of the depression with an antidepressant.

Psychosocial intervention for all — We encourage psychosocial intervention in all patients with schizophrenia or depression who are willing to engage in psychotherapy and stand to benefit from the treatment.

Schizophrenia is commonly associated with impairments in psychosocial or occupational functioning. These might contribute to depression. Psychosocial interventions such as supportive therapy, cognitive-behavioral therapy, family-based interventions, social skills training, cognitive remediation, or multimodal interventions may be effective in improving some patient outcomes [33-36]. The choice of intervention is selected based on specific patient characteristics and circumstances. These are discussed further elsewhere. (See "Schizophrenia in adults: Psychosocial management".)

Pharmacotherapeutic considerations — In individuals with schizophrenia, we are extremely cautious in making changes to antipsychotic regimens for fear of exacerbation of symptoms

Approach to patients with difficult to control psychosis — We do not make changes to the antipsychotic medication in individuals whose psychosis was difficult to treat (eg, needed multiple agents prior to response), those with a history of severe symptoms (ie, suicidality), or those whose symptoms require treatment with clozapine.

In these cases, our preference is to treat the depression with an antidepressant rather than making changes to the antipsychotic regimen. (See 'Treatment of major depression' below.)

Approach to others — In those individuals in which adjustment or change to antipsychotic regimen is clinically reasonable we do the following:

Address adverse effects of antipsychotic agents — Adverse effects of antipsychotic medications may present with symptoms similar to depression. These are discussed below and on the table (table 3). Our preference is to assess for and use adjunctive medications to treat adverse effects of antipsychotic medication prior to making changes to the antipsychotic regimen.

●Extrapyramidal symptoms – Extrapyramidal symptoms such as akinesia or akathisia may mimic or lead to symptoms that may be similar to those seen in depression. First- and second-generation antipsychotics are known to produce the extrapyramidal symptoms of akinesia and akathisia. While blatant forms of akinesia and akathisia are distinctive, more subtle forms can be difficult to distinguish from depression. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation and other antipsychotic medications: Pharmacology, administration, and side effects" and "Schizophrenia in adults: Maintenance therapy and side effect management".)

The subtle form of akinesia affects small muscle groups, typically the facial muscles of expression, producing an expressionless or "mask-like" appearance, and the larynx, decreasing voice tone and expressiveness. Akinesia can also adversely affect the part of the basal ganglia responsible for initiating and sustaining motor behavior. Such patients behave as if their "starter motor" is broken, appearing to be nonspontaneous. The patient's subjective experience is that activities are "not worth the effort;" they often perceive themselves self-critically as being "lazy," which contributes to a negative effect on mood. It is easy to see how this combination of factors could lead to a combination of depression and depression-like symptoms on both a psychologic and physiologic basis [37,38].

Patients with akathisia are fidgety and feel unable to stop moving; they can find the experience to be intensely dysphoric [39]. In a subtle manifestation of akathisia, patients may be observed to be "action-prone," overtalkative, and/or have the tendency to wander into other people's space [40]. A dysphoric, subtle akathisia can be difficult to distinguish from the syndrome of depression. Akathisia has also been noted to be a possible risk factor for suicide [41]. Treatment of antipsychotic effects that may mimic depression are discussed below and in more detail elsewhere. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Side effect management'.)

●Dysphoria – Antipsychotic medications have been observed to produce dysphoria (or a state of feeling unwell or unhappy) as a side effect [3,5,42]. We differentiate antipsychotic drug-induced dysphoria from depression in schizophrenia by reviewing the time frame of the dysphoria and its relationship to medication changes.

This has been reported particularly with first-generation antipsychotic compounds but has also been found to occur with second-generation antipsychotic agents. All antipsychotic medications interfere with dopamine neurotransmission as a component of their activity, and dopamine neurotransmission has been found to figure prominently in pleasure/reward pathways in the brain [5,43,44]. Blocking of dopamine transmission by antipsychotics may be responsible, at least in part, for the dysphoria experienced by a proportion of patients taking the medication. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation and other antipsychotic medications: Pharmacology, administration, and side effects" and "Schizophrenia in adults: Maintenance therapy and side effect management".)

Discussion of addressing side effects of antipsychotic agents is found elsewhere. (See "Schizophrenia in adults: Maintenance therapy and side effect management".)

Change to antipsychotic regimen — In individuals whose symptoms persist despite addressing adverse effects with adjunctive pharmacotherapy, we consider changes to the antipsychotic regimen. We weigh the potential benefit of changes to antipsychotic regimen against the possibility of exacerbation of symptoms, and take the following steps:

●Careful decrease in medication dose – If the individual is stable and receiving more than the minimally recommended antipsychotic dose, or, if their history is known, and they are receiving more than the minimal dose that has been historically required to control their psychotic symptoms, we attempt a cautious downward titration of their medication. We are extremely cautious in making this change and monitor on a weekly basis or more frequently. We do this in small steps (eg, lower medication by 10 percent every few weeks) while monitoring closely for exacerbation of symptoms.

●Change to an agent with a more favorable side effect profile – If careful lowering of the medication does not improve the adverse effects, we agree to change the agent to one with a more favorable side effect profile, if available. For example, in a patient who is being treated with risperidone 4 mg, we might change to an antipsychotic with a lower risk of extrapyramidal symptoms (eg, quetiapine). One small trial showed superiority of extended release quetiapine over risperidone for depressive symptoms in schizophrenia [45]. If sedation is thought to be the major contributing factor, we change to another agent with less propensity to cause sedation [4,46-49].

For patients being treated with first-generation antipsychotics, our preference is switching to a second-generation antipsychotic agent. We do this in individuals whose psychosis is not acute and who are agreeable to the change and can be monitored at least weekly. We do this by lowering the dose of the first-generation agent while titrating the second-generation agent at the same rate. Typically, this can be done over one to two weeks. For example, in an individual who is on haloperidol 10 mg per day, we would switch to aripiprazole at a similar dose over one to two weeks. Some data suggest a moderate efficacy for second-generation antipsychotics in relieving depressive symptoms in participants with schizophrenia. However, studies are few and results are heterogenous [50]. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation and other antipsychotic medications: Pharmacology, administration, and side effects".)

Treatment of major depression — In individuals with schizophrenia who are not acutely psychotic and whose symptoms of depression persist despite the clinically appropriate measures above, we suggest treatment with adjunctive antidepressant medication.

Choosing, initiating and titrating antidepressant

●For most patients – We typically choose from among antidepressants for those with schizophrenia and depression using the same factors as we do in choosing an antidepressant in the treatment of isolated major depression. Major factors include efficacy of specific classes of medication, co-occurring medical conditions, prior history of treatment, family history, side effect profile, and clinician and patient preference [51-54]. The treatment of major depression including choice of antidepressant is discussed elsewhere. (See "Major depressive disorder in adults: Initial treatment with antidepressants" and "Major depressive disorder in adults: Approach to initial management".)

In most cases, we choose a selective serotonin reuptake inhibitor (SSRI). We begin treatment with the chosen antidepressant at the same starting dose we use in the treatment of major depression. For example, when adding sertraline we begin at 50 mg per day. If tolerated, we titrate weekly by 50 mg/day until we reach a typical dose range of 100 to 200 mg. We continue to medication at the highest tolerated dose within the maintenance dose range for a minimum of six weeks prior to further changes.

During the antidepressant trial, we continue antipsychotic medications because antidepressant treatment in the absence of cotreatment with an antipsychotic agent in persons with schizophrenia has been associated with exacerbation of psychosis [4,55]. Usual starting doses and maintenance doses for commonly used antidepressants in the treatment of depression are found on the table (table 4).

●For patients treated with clozapine – We are cautious when using SSRIs in individuals who are treated with clozapine. We avoid treating patients on clozapine with fluvoxamine due to its interaction leading to toxic clozapine levels in some [56]. Our preference in individuals on clozapine is treatment with fluoxetine or sertraline; however, we are cautious in treating individuals on clozapine with any SSRI and monitor patients closely for signs of toxicity and with frequent plasma levels.

Efficacy — Adjunctive treatment of an antipsychotic agent with an antidepressant appears to reduce symptoms of depression in individuals with schizophrenia in some trials; however, generalizability of findings are limited due to small numbers of participants, heterogeneity of diagnosis, and use of different antidepressant classes [57-60].

In a meta-analysis including 82 trials and 3608 participants with schizophrenia with depressive symptoms, the efficacy and safety of adding an antidepressant to an antipsychotic regimen was evaluated. Adjunctive treatment with an antidepressant as compared with control (placebo or no treatment), led to reductions in depressive symptoms (standardized mean difference -0.25, 95% CI -0.38 to -0.12) and in negative symptoms (standardized mean difference -0.30, 95% CI -0.44 to -0.16) [58]. Treatment with either antidepressant or control led to similar rate of adverse events such as exacerbation of psychosis, premature discontinuation, and number of individuals with at least one adverse effect.

Monitoring — Increased energy, initiative, and confidence may emerge in response to treatment with antidepressant medication. In some cases, emerging psychotic symptoms may result from the addition of an antidepressant.

We monitor all individuals with schizophrenia and major depression for increase in psychosis, irritability, sleep disturbance, and suicidal ideation.

We use the Calgary Depression scale, a scale developed for use in patients with schizophrenia that highlights the affective and cognitive aspects of depression and focuses away from "negative" and motoric symptoms that could come from other sources in the schizophrenic population (figure 1) [61].

SUBSEQUENT MANAGEMENT — 

Our subsequent choice of pharmacologic management of depression in individuals with schizophrenia is similar to our choice in individuals without schizophrenia:

●Inadequate response – For individuals whose response to antidepressant treatment does not lead to adequate improvement, we assess for and address possible reasons for inadequate response (eg, medication nonadherence, inadequate dose of antidepressant, incorrect diagnosis, inability to work in or low motivation for psychotherapy). (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Patients with incomplete response'.)

After addressing causes of inadequate response to initial SSRI, our subsequent choice of medication is similar to our choice made in individuals with depression without schizophrenia who have inadequate response to initial SSRI. This is discussed elsewhere. (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Subsequent management'.)

●Good response to treatment – For patients who respond favorably to the addition of adjunctive antidepressant medication, we typically continue this combination for several years (eg, two to three years). As there are no published guidelines addressing length of maintenance treatment in these individuals, our decision is based on past history, severity of symptoms (eg, suicidality), and difficulty in reaching response. A small study suggests that continuation of an adjunctive antidepressant may prevent relapse in patients with schizophrenia who had initially responded to the antidepressant [60]. When antidepressant is to be discontinued, we prefer a gradual taper off of the antidepressant over several months. (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Patients with response'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psychotic disorders".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Schizophrenia (The Basics)" and "Patient education: Schizoaffective disorder (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Terminology – Individuals with schizophrenia may develop depression at any time during their illness. Depression may be described as an affect, a symptom, or a syndrome. This topic refers to depression as a symptom or a syndrome of major depressive disorder (table 1). (See 'Terminology' above.)

●Clinical features – Depression appears to be associated with the following unfavorable outcomes (see 'Clinical Features' above):

•Suicide attempts and death by suicide

•Relapse of symptoms, hospitalization

•Poor response to treatment

•Psychosocial impairment

●Evaluation – We monitor for at least two weeks for onset of psychosis. During this period we evaluate for suicidality and other causes of depression.

•Assess for suicidality – We involve family members and caregivers for collateral information. We refer individuals with an increase in suicidality for an urgent safety evaluation in an emergency department. (See 'Assess for suicidality' above.)

•Evaluate and treat medical or substance use disorder – Depression may be secondary to general medical disorders or co-occurring substance use or disorder. We review prior medical history and past history of substance use and address each of these as indicated (table 2). (See 'Assess for and treat co-occurring disorders' above.)

•Consider negative symptoms of schizophrenia – Negative symptoms syndrome of schizophrenia such as anhedonia (lack of pleasure), anergia (lack of energy), alogia (lack of having things to say), blunted affect, social withdrawal, may appear similar to those seen in depression. (See 'Negative symptoms of schizophrenia' above.)

●Diagnosis – The diagnostic possibilities are guided by the patient's clinical state at the end of the monitoring period. (See 'Diagnosis' above.)

•If the depression remits and the patient returns to their prior level of functioning, we consider the depression to be the response to psychosocial stressors, a disappointment reaction, or difficulty coping.

•If symptoms of psychosis emerge, we consider the depression to have been a prodrome to recurrent psychosis and address the psychosis with antipsychotic medication.

•If the depression persists without other clinical changes (ie, psychosis), we address the depressive symptoms.

●Psychosocial intervention for all – We encourage psychosocial intervention in all patients with schizophrenia and depression who are willing to engage in psychotherapy and stand to benefit from the treatment. (See 'Psychosocial intervention for all' above.)

●Pharmacotherapeutic interventions – In individuals with schizophrenia, we are extremely cautious in making changes to antipsychotic regimens for fear of exacerbation of symptoms. We do not make changes to antipsychotic regimen in individuals whose psychosis was difficult to treat or severe, or in those treated with clozapine. (See 'Pharmacotherapeutic considerations' above.)

For those individuals in which adjustment of antipsychotic medication is clinically reasonable, we do the following:

•We address adverse effects of antipsychotic medication. Adverse effects of antipsychotic medications such as dysphoria or extrapyramidal effects may produce symptoms that are similar to those seen in depression (table 3). (See 'Address adverse effects of antipsychotic agents' above and "Schizophrenia in adults: Maintenance therapy and side effect management".)

•Make changes to the antipsychotic regimen (eg, lower medication, change medication) as needed. We do this in small increments and with frequent monitoring. (See 'Change to antipsychotic regimen' above.)

●Treatment of depression – In individuals whose depression persists despite the above measures, we suggest treatment with a selective serotonin reuptake inhibitor rather than other medications (table 4) (Grade 2C). (See 'Treatment of major depression' above.)

During the antidepressant trial, we continue antipsychotic medications because antidepressant treatment in the absence of cotreatment with an antipsychotic agent in persons with schizophrenia has been associated with exacerbation of psychosis. (See 'Treatment of major depression' above.)

●Subsequent management – Our subsequent choice of pharmacologic management of depression in individuals with schizophrenia is similar to the management of those with depression alone. (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Patients with incomplete response'.)