Depressive Episode, Recurrent Depressive Disorder: Clinical Guidelines

List of Abbreviations

AD – antidepressant

SGA – second-generation antipsychotic

FGA – first-generation antipsychotic

ATC – Anatomical Therapeutic Chemical classification

BD – bipolar disorder

WHO – World Health Organization

rTMS – repetitive transcranial magnetic stimulation

DBS – deep brain stimulation

DE – depressive episode

MAOI-A – monoamine oxidase A inhibitor

IPT – interpersonal psychotherapy

CBT – cognitive behavioral therapy

CT – computed tomography

ICD-10 – International Statistical Classification of Diseases and Related Health Problems 10th Revision

MST – magnetic seizure therapy

MRI – magnetic resonance imaging

PSA – psychoactive substances

PDT – psychodynamic psychotherapy

RDD – recurrent depressive disorder

RDFT – reducing diet therapy

RCTs – randomized controlled trials

REG – rheoencephalography

VNS – vagus nerve stimulation

SSRIs – Selective Serotonin Reuptake Inhibitors

SNRI – serotonin-norepinephrine reuptake inhibitor (according to the ATC classification: other antidepressants)

rTMS – Transcranial magnetic stimulation

MBCT – mindfulness-based cognitive therapy

ACT – acceptance and commitment therapy

tDCS – transcranial direct current stimulation

TeCA – tetracyclic antidepressant (according to the ATC classification: other antidepressants)

TSH – thyroid-stimulating hormone

TCA – tricyclic antidepressant (according to the ATC classification: non-selective monoamine reuptake inhibitors)

ECG – electrocardiography

ECG – electrocardiogram recording

ECT – electroconvulsive therapy

Terms and Definitions

Second-generation antipsychotics – a group of drugs that moderately and/or selectively affect dopaminergic receptors, carry a lower risk of extrapyramidal side effects compared to FGAs, and are used in the treatment of DE and RDD to manage psychotic symptoms (in combination with ADs), augment the action of ADs, or manage DE with mixed features. These include: #risperidone**, #quetiapine**, aripiprazole, #cariprazine**, #olanzapine**, #brexpiprazole, #lurasidone**, #ziprasidone, #amisulpride.

First-generation antipsychotics – a group of drugs with pronounced antagonism toward dopaminergic receptors, carrying a high risk of extrapyramidal side effects; in DE and RDD, their use is limited to certain cases for the augmentation of AD effects. These include: #sulpiride**, #flupentixol**.

Recovery – a state of complete remission lasting more than 6 months.

Incomplete remission – a period during which significant improvement is noted, but symptoms not reaching syndromal completeness persist.

Relapse – the recurrence of symptoms to a significant degree of severity during a remission period (prior to recovery).

Recurrent episode – the development of a new episode after recovery from the previous one.

Complete recovery (restoration) – full return of social and occupational functioning without any residual depressive symptoms.

Complete remission – absence of any signs of affective disorder for 6 months.

Psychopharmacotherapy resistance – lack of therapeutic response to two courses of adequate therapy with antidepressants (ADs) from different groups at sufficient dosages and durations.

Remission (symptomatic) – symptom severity on the Hamilton Depression Rating Scale of less than 7 points and/or on the Montgomery–Åsberg Depression Rating Scale of less than 10 points.

Therapeutic effect (response) – a 50% improvement in symptoms according to psychometric depression rating scales.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Depressive episode (DE) – an affective disorder typically characterized by depressed mood, loss of interest and pleasure, and reduced energy, which may lead to increased fatigue and decreased activity. Marked fatigue is observed even with minimal effort. Other symptoms include reduced concentration and attention; lowered self-esteem and self-confidence; ideas of guilt and worthlessness (even in mild episodes); bleak and pessimistic views of the future; ideas or acts of self-harm or suicide; sleep disturbances; and reduced appetite [1].

Recurrent depressive disorder (RDD) – an affective disorder characterized by repeated episodes of depression, as described in F32, without a history of independent episodes of elevated mood and hyperactivity that could meet the criteria for hypomanic, manic, or mixed affective episodes (F30.-) [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology and pathogenesis of DE and RDD remain not fully established. Apparently, the occurrence of depressive disorders is determined by a combination of multiple factors: biological (constitutional-genetic), psychological, and social. Among biological concepts, the monoamine theory of depression is traditional, according to which the main pathogenetic mechanism of its occurrence is the insufficiency of synaptic activity of monoamines (serotonin, dopamine, noradrenaline) in the brain. Other pathophysiological processes are also considered significant: manifestations of psychosocial and biological distress, the chronobiological hypothesis, impaired neuroplasticity processes, dysregulation of the hypothalamic-pituitary-adrenal axis, neurotrophin synthesis, the CREB transcription factor, as well as neuroanatomical features of the hippocampus, amygdala, nucleus accumbens, and other brain regions [2, 3, 4].

1.3 Epidemiology of the Disease or Condition

DE and RDD are among the most common mental disorders. These disorders typically resolve completely during periods of remission, and the degree of patients' social maladaptation is determined by the frequency, duration, and severity of recurring depressive symptoms. Patients with RDD belong to the most functionally preserved group of patients suffering from mental disorders; however, mortality in RDD is only slightly lower than that of cardiovascular diseases, as up to 15% of depressed patients die by suicide. Currently, depression ranks second globally among all medical causes of disability and mortality, and among young individuals (under 45 years of age) it has long held the leading position in this regard [5]. According to World Health Organization (WHO) projections, by 2030 RDD will rank first in these indicators [5, 6, 7]. Epidemiological studies regarding affective disorders have not been conducted in our country. According to Federal State Statistical Observation Form 10, "Information on the number of diseases registered in patients living in the service area of a medical organization", in 2022, 79.3 patients per 100,000 population were registered with unipolar depression. Over the past five years, an increase in this indicator has been noted: in 2018 it was 72.3 per 100,000 population, in 2019 – 73.7, in 2020 – 73.1, in 2021 – 76.9. The high prevalence of RDD (around 6% among men, up to 15% among women), frequent recurrence (repeated episodes in 85% of patients), tendency toward protracted courses and chronification of episodes, worsening of the course and outcomes of somatic and mental comorbid disorders, as well as other numerous problems associated with the damage caused by this disease, determine the high interest of specialists in new opportunities in the field of depression therapy.

1.4 Features of Coding the Disease or Condition

Depressive episode (F32):

F32.0 – Mild depressive episode;

F32.00 – Mild depressive episode without somatic symptoms;

F32.01 – Mild depressive episode with somatic symptoms;

F32.1 – Moderate depressive episode;

F32.10 – Moderate depressive episode without somatic symptoms;

F32.11 – Moderate depressive episode with somatic symptoms;

F32.2 – Severe depressive episode without psychotic symptoms;

F32.3 – Severe depressive episode with psychotic symptoms;

F32.33 – Depressive-delusional state with mood-congruent delusions;

F32.34 – Depressive-delusional state with mood-incongruent delusions;

F32.38 – Other severe depressive episodes with other psychotic symptoms;

F32.8 – Other depressive episodes;

F32.9 – Unspecified depressive episode.

Recurrent depressive disorder (F33):

F33.0 – Recurrent depressive disorder, current episode mild;

F33.00 – Recurrent depressive disorder, current episode mild without somatic symptoms;

F33.01 – Recurrent depressive disorder, current episode mild with somatic symptoms;

F33.1 – Recurrent depressive disorder, current episode moderate;

F33.10 – Recurrent depressive disorder, current episode moderate without somatic symptoms;

F33.11 – Recurrent depressive disorder, current episode moderate with somatic symptoms;

F33.2 – Recurrent depressive disorder, current episode severe without psychotic symptoms;

F33.3 – Recurrent depressive disorder, current episode severe with psychotic symptoms;

F33.33 – Depressive-delusional state, monopolar type with mood-congruent delusions;

F33.34 – Depressive-delusional state, monopolar type with mood-incongruent delusions;

F33.38 – Other recurrent depressive disorder, current episode of severe depression with other psychotic symptoms;

F33.4 – Recurrent depressive disorder, currently in remission;

F33.8 – Other recurrent depressive disorders;

F33.9 – Unspecified recurrent depressive disorder.

1.5 Classification of the disease or condition

The classification of depressions presented in ICD-10 (diagnostic categories F32–F33) is based on a syndromal approach using operational criteria that ensure maximum clinical homogeneity, reproducibility, and comparability of the defined diagnostic categories.

The central place in the classification is occupied by the category "depressive episode". According to the course variants, the following forms of the disorder are distinguished: single depressive episode (DE) and recurrent depressive disorder (RDD). The rationale for this separation is that a significant proportion of patients experience only a single episode [1].

Due to their importance for treatment and management planning, three degrees of severity of a DE are distinguished: mild, moderate, and severe. These three severity levels are designated to encompass the wide range of clinical conditions encountered in psychiatric practice. Patients with mild forms of DE are frequently seen in primary care and general medical settings, whereas inpatient units primarily deal with patients suffering from more severe depression. Differentiation between mild, moderate, and severe degrees is based on a complex clinical assessment that includes the number, type, and severity of the symptoms present. The degree of impairment in normal social and occupational functioning can often assist in determining the severity of a DE [1].

Depending on the severity of somatic manifestations in the clinical picture of mild and moderate depressions, depressive episodes with and without somatic symptoms are distinguished. Symptoms designated as "somatic" could also be called "melancholic," "vital," "biological," or "endogenomorphic." It is assumed that in a severe depressive episode, the somatic syndrome is almost always present [1].

1.6 Clinical presentation of the disease or condition

In typical cases, a patient with a DE suffers from depressed mood, loss of interest and enjoyment, and reduced energy, which can lead to increased fatigability and diminished activity. Marked fatigue is noted even after minimal effort. Other symptoms include: reduced ability to concentrate and pay attention, reduced self-esteem and self-confidence, ideas of guilt and worthlessness (even in mild episodes), a gloomy and pessimistic view of the future, ideas or acts of self-harm or suicide, sleep disturbance, and reduced appetite.

The depressed mood varies little from day to day and often fails to react to environmental circumstances, though characteristic diurnal variations may occur. In some cases, anxiety, despair, and motor agitation may at times be more pronounced than depression, and mood changes may also be masked by additional symptoms: irritability, excessive alcohol consumption, hysterical behavior, exacerbation of pre-existing phobic or obsessive symptoms, or hypochondriacal ideas.

Some of the above symptoms may be pronounced and exhibit characteristic features considered to have special clinical significance. The most typical examples are somatic and psychotic symptoms.

In some cases, subsyndromal manic symptoms are observed within the structure of a depressive episode, regardless of whether they occur within bipolar affective disorder (BAD) or RDD. ICD-10 does not divide mixed states by dominant affect. Unlike ICD-10, DSM-5 introduces the specifier "with mixed features" and distinguishes depressive episodes with mixed features and manic episodes with mixed features.

Diagnostic criteria for depression with mixed features are identical for a depressive episode within the framework of RDD and BAD. The patient must meet the criteria for a depressive episode and exhibit 3 or more manic/hypomanic symptoms:

• elevated or expansive mood;

• inflated self-esteem or grandiosity;

• more talkative than usual or pressure of speech;

• flight of ideas or racing thoughts;

• increased energy or goal-directed activity;

• engaging in risk-taking behavior;

• decreased need for sleep.

Symptoms must be present for the majority of the time during the depressive episode and be noticeable to others, and behavior must represent a change from the usual behavior [8]. Given the substantial body of research confirming the frequent detection of subsyndromal manic symptoms within the structure of depressive episodes—regardless of whether they occur in the context of BAD or RDD—as well as the high proportion of depression with mixed features among all variants of the depressive syndrome [8, 9, 10, 11, 12, 13, 14, 15], it appears appropriate to distinguish this depression subtype in these clinical guidelines.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The initial assessment of the depressive syndrome and diagnosis must be performed by a psychiatrist. The physician's action algorithm flowchart is presented in Appendix B2 (sub-chart "Diagnosis of an adult patient with depressive disorder or recurrent depressive disorder").

Criteria for establishing the disease or condition

Diagnostic criteria according to ICD-10 are provided below.

F32 Depressive episode

General diagnostic guidelines:

A. Most typical symptoms:

1. depressed mood;

2. loss of interest and enjoyment;

3. reduced energy leading to increased fatigability and diminished activity;

B. Other common symptoms:

1. reduced concentration and attention;

2. reduced self-esteem and self-confidence;

3. ideas of guilt and worthlessness;

4. gloomy and pessimistic view of the future;

5. ideas or acts of self-harm or suicide;

6. disturbed sleep;

7. decreased appetite;

C. the depressed mood state shows little variation over the course of a depressive episode, although the mood may exhibit diurnal fluctuations (more pronounced in the morning hours);

D. the categories F32.0, F32.1, and F32.2 are used for a single depressive episode; for two or more depressive episodes, the categories of recurrent depressive disorder (F33) are used;

E. no history of manic or hypomanic symptoms meeting the criteria for a manic episode;

F. the episode cannot be attributed to psychoactive substance use or an organic mental disorder.

ICD-10 also provides for a somatic syndrome of depression if at least four of the following symptoms are present:

1. loss of interest or pleasure in activities normally pleasurable to the patient;

2. lack of emotional reactivity to events or activities normally productive of emotional response;

3. waking in the morning two or more hours earlier than usual;

4. depression worse in the morning;

5. objective evidence of marked psychomotor retardation or agitation (observed or described by others);

6. marked loss of appetite;

7. weight loss (5% or more of body weight in the past month);

8. marked loss of libido.

Differentiating depression by severity (Table 1) is of great importance for assessing the patient's condition, determining the setting and method of treatment, and planning the further pathway of medical care.

Table 1. Diagnostic criteria for different severities of depressive episode

F32.0 Mild depressive episode

A. there must be at least two of the three typical symptoms described in F32;

B. these symptoms must be accompanied by at least two of the other common symptoms described in F32;

C. none of the specified symptoms should be marked or severe;

D. the minimum duration of the episode is two weeks.

F32.00 Mild depressive episode without somatic symptoms

F32.01 Mild depressive episode with somatic symptoms (four or more somatic symptoms or two to three strongly pronounced symptoms).

F32.1 Moderate depressive episode

A. there must be at least two of the three typical symptoms and three (preferably four) of the other common symptoms described in F32;

B. the severity is determined either by the severity of the symptoms or by the abundance of symptomatology;

C. considerable difficulty in continuing occupational and social activities;

D. the minimum duration of the episode is two weeks.

F32.10 Moderate depressive episode without somatic symptoms

F32.11 Moderate depressive episode with somatic symptoms (four or more somatic symptoms or two to three strongly pronounced symptoms).

F32.2 Severe depressive episode without psychotic symptoms

A. manifested by marked tension or agitation, or particularly pronounced retardation;

B. all three typical symptoms of the depressive episode F32 are present, plus four or more other symptoms, some of which should be severe;

C. the patient is practically unable to continue occupational, social, and domestic activities. Such activities may be performed only to a very limited extent;

D. the minimum duration of the episode is two weeks; in the case of particularly severe symptoms, the diagnosis of F32.2 may be made after a period of less than two weeks.

F32.3 Severe depressive episode with psychotic symptoms

A. the disorder meets the criteria for F32.2;

B. the clinical picture is supplemented by delusions, hallucinations, or depressive stupor;

C. delusions and hallucinations are mood-congruent or mood-incongruent.

F32.33 Depressive-delusional state with mood-congruent delusions

F32.34 Depressive-delusional state with mood-incongruent delusions

F32.38 Other severe depressive episode with other psychotic symptoms

F32.8 Other depressive episodes

A. the episode does not meet the criteria for F32.0-F32.3;

B. there are clinical grounds for considering the disorder to be depressive in nature (e.g., a fluctuating mixture of depressive symptoms with non-diagnostic symptoms such as tension, anxiety, or despair; a mixture of somatic depressive symptoms with persistent pain or fatigue not due to organic causes).

F32.9 Depressive episode, unspecified

F33 Recurrent depressive disorder

General diagnostic guidelines:

A. a recurrent depressive episode meeting the diagnostic criteria for F32;

B. at least one depressive episode of any severity in the past, lasting at least two weeks and separated from the current episode by a period of at least 2 months without any significant affective symptoms (otherwise, another recurrent affective disorder F38.1 must be diagnosed);

C. absence in the past of any episodes meeting the criteria for a hypomanic or manic episode (F30), except for brief episodes of mildly elevated mood and hyperactivity that meet the criteria for hypomania and occur immediately after a depressive episode (sometimes they may be provoked by antidepressant treatment).

F33.0 Recurrent depressive disorder, current episode mild

A. the criteria for F33 are met, and the current episode meets the criteria for a mild depressive episode F32.0.

F33.00 Recurrent depressive disorder, current episode mild without somatic symptoms

F33.01 Recurrent depressive disorder, current episode mild with somatic symptoms

F33.1 Recurrent depressive disorder, current episode of moderate severity

A. Criteria for F33 are met, and the current episode meets the criteria for a moderate depressive episode F32.1.

F33.10 Recurrent depressive disorder, current episode of moderate severity without somatic symptoms

F33.11 Recurrent depressive disorder, current episode of moderate severity with somatic symptoms

F33.2 Recurrent depressive disorder, current episode severe without psychotic symptoms

A. Criteria for F33 are met, and the current episode meets the criteria for a severe depressive episode without psychotic symptoms F32.2.

F33.3 Recurrent depressive disorder, current episode severe with psychotic symptoms

A. Criteria for F33 are met, and the current episode meets the criteria for a severe depressive episode with psychotic symptoms F32.3;

B. Delusions and hallucinations are mood-congruent or mood-incongruent.

F33.33 Depressive-delusional state, monopolar type with mood-congruent delusions

F33.34 Depressive-delusional state, monopolar type with mood-incongruent delusions

F33.38 Other recurrent depressive disorder, current episode of severe depression with other psychotic symptoms

F33.4 Recurrent depressive disorder, currently in remission

A. Criteria for F33 were met in past episodes, but the current state does not meet the criteria for a depressive episode of any severity and does not meet the criteria for other disorders in the F30–F39 category.

F33.8 Other recurrent depressive disorders

F33.9 Recurrent depressive disorder, unspecified

2.1 Complaints and Anamnesis

• All patients undergo an initial psychiatric evaluation (examination, consultation) including psychopathological assessment and suicide risk screening for primary diagnosis [16, 17, 18, 19].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• All patients undergo screening to identify symptoms of depression in their mental status for primary diagnosis [1, 16, 17, 18].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: The symptomatology of depressive disorders includes affective, psychomotor, cognitive, psychovegetative, and somatic disturbances. The core symptoms of depression are depressed mood, anhedonia, and loss of energy and activity [1]. Since many patients with depressive disorders do not initially present with complaints of these symptoms, targeted questioning is crucial.

• All patients whose mental status reveals symptoms of depression should undergo the following mandatory steps to refine the diagnosis:

− assess whether the patient's symptoms meet the diagnostic criteria for a depressive episode [1, 16, 17, 18].

− obtain medical history or documentation regarding the presence of prior depressive episodes [1, 16, 17, 18].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: To assess the severity of depressive disorder and therapeutic dynamics, it is advisable to use rating scales: the Hamilton Rating Scale for Depression (see Appendix G1) and the Montgomery-Asberg Depression Rating Scale (see Appendix G2).

• All patients diagnosed with a first-time or recurrent depressive episode should be screened for manic symptoms to identify a depressive episode with mixed features (subsyndromal hypomanic symptoms) [11, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• All patients diagnosed with a first-time or recurrent depressive episode should undergo a targeted clinical interview to rule out bipolar affective disorder by identifying history of manic, hypomanic, and mixed episodes [31, 32, 33, 389, 390].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: Retrospective detection of hypomania is a difficult practical task, and currently there is no effective, objective instrument to achieve it [31]. To identify potential past hypomanic episodes, it is advisable to screen using the validated Russian-language version of the Hypomania Checklist (HCL-33) (see Appendix G3) [34, 35].

• All patients diagnosed with a first-time or recurrent depressive episode should undergo a thorough history-taking to rule out exogenous and somatogenic causes of depressive symptoms

− regarding past trauma, brain infections, or somatic illnesses preceding the onset of depressive symptoms [36];

− regarding the use of psychoactive substances or medications that can cause depressive symptoms immediately before the onset of the depressive episode [37, 38, 39, 40].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• All patients diagnosed with a first-time or recurrent depressive episode who are receiving treatment should have a follow-up psychiatric consultation (examination) to evaluate treatment efficacy [16, 17].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• All patients diagnosed with a first-time or recurrent depressive episode receiving inpatient treatment should be examined daily by a psychiatrist, with observation and nursing care provided by mid-level and junior medical staff in the inpatient ward, including assessment of treatment course efficacy [16, 17].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

2.2 Physical Examination

• In addition to standard physical examination, all patients should undergo skin inspection to check for injection marks in order to rule out the use of psychoactive substances or medications that may cause depressive symptoms [37, 38, 39, 40].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

2.3 Laboratory Diagnostics

There are no specific laboratory diagnostic methods for depressive episodes and recurrent depressive disorder.

• Patients with depressive episodes or recurrent depressive disorder should undergo a complete blood count and routine urinalysis as part of their initial assessment prior to prescribing treatment to evaluate somatic health risks, upon hospital admission, and during inpatient follow-up (at least once a month) to determine disease activity and assess organ and system involvement [41, 42, 43, 44].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

• Patients with depressive episodes or recurrent depressive disorder should undergo a general clinical blood chemistry panel (including blood glucose, creatinine, total protein, total bilirubin, aspartate aminotransferase, and alanine aminotransferase), and a lipid profile as part of their initial evaluation before starting treatment to assess somatic health risks, upon hospital admission, and during inpatient monitoring (at least once a month) to assess renal and hepatic function, rule out inflammation, and evaluate for metabolic syndrome [42, 43, 44, 45, 46, 47, 48, 49, 50, 51].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• Patients with depressive episodes or recurrent depressive disorder should be tested for hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus, antibodies to Treponema pallidum, and HIV-1/HIV-2 IgM and IgG antibodies during initial evaluation, upon hospital admission, and subsequently every 12 months to rule out co-occurring HIV infection, hepatitis, or syphilis [52, 53, 54].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

• Patients with newly diagnosed depressive episodes or recurrent depressive disorder, or when clinical or anamnestic indications are present, should have blood levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) measured to assess thyroid function and rule out thyroid pathology [55, 56, 57, 58, 59].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

2.4 Instrumental Diagnostics

There are no specific instrumental diagnostic methods for depressive episodes and recurrent depressive disorder.

• Patients with depressive episodes or recurrent depressive disorder should undergo additional diagnostic examinations prior to initiating treatment to assess various somatic health risks and perform differential diagnosis [17, 60], which include:

- electrocardiography (ECG) [61, 62];

- electroencephalography (EEG) [63, 64];

- rheoencephalography (REG) [65, 66];

- transcranial Doppler ultrasound of cerebral arteries with monitoring [67, 68];

- magnetic resonance imaging (MRI) of the brain (preferred) [69]/ computed tomography (CT) of the brain [68, 70].

GOR BLOE 3Grade of Recommendation – B (Level of Evidence – 3).

Comments: The listed instrumental diagnostic examinations are recommended when clinical or anamnestic indications are present.

2.5 Other Procedures

• All patients are strongly recommended to undergo a targeted clinical and anamnestic assessment to identify suicide risk factors [19, 71].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: When assessing suicide risk, it is recommended to take into account the following factors: presence of suicidal thoughts, intentions, plans, and behavior; history of past suicide attempts; access to means of suicide and the lethality of these means; presence of severe anxiety, panic, agitation, and/or impulsivity; presence of psychotic symptoms, such as imperative hallucinations, or impaired insight into oneself, one's judgments, actions, and their consequences; alcohol and/or other psychoactive substance use; family history of suicide; absence of deterrent factors (e.g., support from family and friends, having children, pregnancy, religiosity, understanding of family responsibilities, employment, psychological coping skills, a certain degree of life optimism, etc.).

To assess the severity of suicide and suicidal risk, it is advisable to use the Columbia Suicide Severity Rating Scale (see Appendix G4).

• For patients with depressive episode (DE) or recurrent depressive disorder (RDD) with comorbid personality disorders and/or differential diagnostic difficulties, an initial consultation (testing, interview) with a clinical psychologist and a pathopsychological-experimental-psychological (psychodiagnostic) examination are recommended [72].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

• For patients with DE or RDD, prior to initiating therapy, for differential diagnosis with other conditions, to rule out contraindications to certain drugs prescribed for DE, if hospitalization is necessary, and to assess various somatic health risks, a consultation (examination) by a general practitioner, a consultation (examination) by a neurologist, a consultation (examination) by an ophthalmologist, and for women, a consultation (examination) by an obstetrician-gynecologist are recommended; for women of childbearing potential not using reliable methods of contraception, a pregnancy test is recommended; for men presenting with sexual dysfunction, a consultation (examination) by a urologist is recommended [17, 36, 42, 43, 44, 73, 74].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

• Upon re-hospitalization, to rule out contraindications to certain drugs and to assess various somatic health risks, all patients are recommended to undergo a consultation (examination) by a general practitioner, a consultation (examination) by a neurologist, a consultation (examination) by an ophthalmologist, and for women, a consultation (examination) by an obstetrician-gynecologist; for women of childbearing potential not using reliable methods of contraception, a pregnancy test is recommended; for men presenting with sexual dysfunction, a consultation (examination) by a urologist is recommended [17, 36, 42, 43, 44, 73, 74].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Prior to initiating therapy, an individualized treatment plan should be developed, taking into account the continuity of various therapy stages, the efficacy and tolerability of previous therapy, clinical features of the condition (e.g., presence of psychotic symptoms, agitation, anxiety, sleep disturbances, or atypical symptoms), disease severity and suicide risk, patient compliance, psychoactive substance abuse, comorbid conditions and associated pharmacotherapy, the possibility of pregnancy, and other individual factors capable of influencing the efficacy and tolerability of the prescribed antidepressant. If indicated (e.g., in cases of psychotic symptoms and suicidal thoughts), inpatient treatment should be considered. Thymoleptic therapy in the acute phase of disorders also requires at least weekly dynamic monitoring of the patient's mental and somatic status, including periodic review of the diagnosis and assessment of suicide risk, monitoring of treatment response and the development of adverse effects, as well as checking patient compliance and fostering adherence to therapy using various psychoeducational techniques.

Important for understanding the course and therapy of DE and RDD is the dynamic disease model proposed by D.J. Kupfer (1991) (Fig. 1) [75].

Figure 1. Diagram of the course of DE and RDD and stages of therapy

In accordance with this model, in the treatment of DE, it is important to follow all three main therapeutic stages: 1) acute (active) therapy, 2) continuation or stabilization therapy, and 3) long-term recurrence prevention (maintenance) therapy.

3.1 Acute DE therapy at the first stage

The goal of acute therapy is to achieve complete remission [76].

• For patients meeting current diagnostic criteria for DE and RDD (ICD-10), for the alleviation of current depressive symptoms and achievement of remission, thymoleptic pharmacotherapy is recommended: administration of antidepressants in effective doses (depending on medical indications and in the absence of medical contraindications) [77, 78, 79].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments. Antidepressants should be prescribed at the minimum effective doses; in the absence of adverse effects or upon reduction of adverse effects within a few days, dose titration within standard dosage ranges is recommended until symptoms begin to remit. In the absence of dynamics or in case of an insufficient effect (symptom reduction rate from 25% to 50%) after 3–4 weeks, dose escalation to the maximum dose is recommended (Appendix A3, Table 2) [79].

The thymoleptic effect usually occurs within 3–4 weeks of treatment, but in some cases, especially when using selective serotonin reuptake inhibitors (SSRIs), improvement develops more gradually, and a full effect is achieved at weeks 4–6 or even week 8. In the majority of therapy responders, clinical improvement becomes noticeable within the first two weeks of treatment. Usually, such an early response is associated with a more favorable prognosis for the overall efficacy of the administered therapy.

Current criteria for depressive syndrome may include fairly heterogeneous groups of patients with various types of depression ranging from biologically determined conditions (so-called endogenous or melancholic depressions) to variously situationally provoked or personality-related conditions (so-called reactive or neurotic depressions). Unfortunately, most randomized controlled trials (RCTs) of antidepressant drugs have used generalized undifferentiated criteria for DE, and it is not possible to isolate their proven efficacy with respect to individual clinical variants of depression, such as anxious, melancholic (with somatic symptoms), atypical, retarded (with catatonic symptoms), seasonal, or with predominant cognitive impairment.

There is no evidence of greater efficacy or a more rapid onset of action of antidepressants of any single class, although in severe depressions requiring hospitalization, certain tricyclic antidepressants (amitriptyline** and clomipramine**) and venlafaxine prove to be somewhat more effective than selective serotonin reuptake inhibitors (SSRIs) [82, 83]. Regarding second-generation antidepressants, a comparative meta-analysis of 117 RCTs involving 25,928 patients showed that mirtazapine, escitalopram, venlafaxine, and sertraline** were slightly more effective than duloxetine, fluoxetine**, fluvoxamine, and paroxetine** [84]. In a later meta-analysis by the same authors [85] based on 522 RCTs involving 116,477 participants and 21 antidepressants, odds ratios were found to be quite similar across different antidepressants for both efficacy and tolerability, with wide confidence intervals in most comparative analyses. In direct comparisons, agomelatine**, amitriptyline**, escitalopram, mirtazapine, paroxetine**, venlafaxine, and vortioxetine showed higher efficacy than other antidepressants, whereas fluoxetine**, fluvoxamine, and trazodone proved to be less effective. Regarding tolerability, agomelatine**, citalopram, escitalopram, fluoxetine**, sertraline**, and vortioxetine were better tolerated than other antidepressants.

Antidepressants primarily differ in their side-effect profile, drug-interaction potential, and overdose risk (Appendix A3, Table 3) [86]. SSRIs, SNRIs, and other second- and third-generation antidepressants are generally better tolerated than first-generation agents (tricyclic antidepressants, TCAs), which helps reduce the likelihood of patients independently discontinuing treatment. TCAs are most characterized by anticholinergic (dry mouth, constipation, blurred vision, urinary retention, tachycardia), cardiovascular (α-adrenergic blockade, orthostatic hypotension, bradyarrhythmia, tachycardia), antihistaminic (sedation) side effects, weight gain, and neurological symptoms (mild myoclonus, seizure states in overdose, delirium in elderly patients).

Given that SSRIs have a better tolerability profile compared to TCAs and rarely produce the anticholinergic and cardiotoxic effects typical of TCAs, they and other newer-generation antidepressants are the drugs of choice for patients with cardiovascular diseases as well as in outpatient practice. TCAs should not be prescribed to patients with moderate to severe cardiovascular disease, angle-closure glaucoma, prostatic hypertrophy, cognitive impairment, seizure disorders, and delirious states.

The side-effect spectrum of SSRIs includes gastrointestinal effects (nausea, vomiting, diarrhea), activation/anxiety (increased anxiety, agitation, sleep disturbances), sexual dysfunction (erectile dysfunction and delayed ejaculation in men, loss of libido and anorgasmia in women and men), and neurological effects (exacerbation of tension headaches and migraines) [174,388]. SSRIs can affect platelet function, specifically causing thrombocytopenia and increasing the risk of bleeding, especially when combined with other antiplatelet agents. It is also important to remember that high doses of SSRIs (particularly citalopram and escitalopram) can cause QTc interval prolongation.

Side effects of SNRIs (venlafaxine and duloxetine) occur somewhat more frequently than those of SSRIs, leading to a higher rate of treatment discontinuation [85]. When prescribing venlafaxine, it is necessary to consider the potential for arterial hypertension development and monitor blood pressure.

The most characteristic side effects of mirtazapine are weight gain and hypersedation. When using agomelatine**, one should consider the increased risk of liver damage (cases of a 10-fold increase in transaminase levels, hepatic failure, hepatitis, and jaundice have been described). At the start of treatment and when increasing the dosage, regular blood tests for total bilirubin, as well as aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activity, are mandatory.

3.1.1 Acute therapy for mild DE

Mild depressive episodes are usually treated on an outpatient basis within the primary psychiatric care setting [87].

• For patients with mild depressive episodes, in order to relieve depressive symptoms and achieve remission, oral antidepressant therapy is recommended: SSRIs [77, 80, 81, 82, 83, 88] and other newer-generation antidepressants (agomelatine**, vortioxetine) [89, 90, 91].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: in the treatment of patients with mild depressive episodes, psychotherapy, psychoeducation, or social rehabilitation methods can sometimes be sufficient (see Section 3.5, Psychotherapy). Furthermore, for mild depressive episodes, patients who are reluctant to take traditional antidepressants may be recommended herbal preparations (#St. John's wort herb) [92, 93].

3.1.2 Acute therapy for moderate DE

Treatment of patients with moderate depressive episodes is carried out on an outpatient, day-hospital, or inpatient basis, depending on the specifics of the depression and social conditions. Given the high risk of sudden clinical deterioration in solitary patients living apart from relatives, as well as the potential emergence of suicidal ideation, inpatient or day-hospital treatment is preferable, provided the patient gives informed consent.

• For patients with moderate depressive episodes, in order to relieve depressive symptoms and achieve remission, the prescription of oral antidepressants is recommended: SSRIs [77, 80, 82, 83, 88], SNRIs (classified as other antidepressants according to ATC) [94, 95, 96, 97], mirtazapine [98, 99], agomelatine** [89, 90], and vortioxetine [91].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: TCAs are generally considered second-line drugs in the acute treatment of moderate depressive episodes due to a less favorable tolerability profile, as noted above [83, 85]. Trazodone and mianserin can also be classified as second-line drugs. Trazodone is a specific serotonergic antidepressant (classified as other antidepressants according to ATC) and likely has comparable efficacy to SSRIs but a different side-effect profile: sedation and orthostatic hypotension are more common with trazodone, whereas sexual dysfunction (though severe priapism occurs in rare cases), insomnia, exacerbation of anxiety, and nausea are less common compared to SSRIs [100, 101]. Mianserin, like its derivative mirtazapine, belongs pharmacologically to noradrenergic and specific serotonergic antidepressants (classified as other antidepressants according to ATC), has predominantly sedative effects, and has a rather weak evidence base, although several RCT publications from the 1980s reported efficacy similar to amitriptyline [102, 103]. The Russian tricyclic-structure antidepressant pipofezine** (classified as other antidepressants according to ATC) has an even weaker evidence base, supported only by open-label trial data [104]. The efficacy of another Russian drug, pirlindole (classified as other antidepressants according to ATC), has also been studied exclusively in open-label trials [105]; furthermore, as an MAO-A inhibitor by mechanism of action, it may be effective in treating atypical depressions and in treatment-resistant stages [106].

In moderate depressive episodes, psychotherapy combined with pharmacotherapy should be administered whenever possible.

3.1.3 Acute therapy for severe DE without psychotic symptoms

Treatment of patients with severe depressive episodes is preferably carried out in an inpatient setting.

• For patients with severe depressive episodes without psychotic symptoms, in order to relieve depressive symptoms and achieve remission, the prescription of antidepressants with a broad spectrum of neurochemical mechanisms of action is recommended: SNRIs, mirtazapine, TCAs, which have somewhat greater efficacy in treating severe depression compared to SSRIs [82, 83, 107, 108, 109, 110, 111, 112].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: due to better tolerability, preference should be given to SNRIs (venlafaxine, duloxetine) or mirtazapine, followed by TCAs (imipramine**, amitriptyline**, clomipramine**). SSRIs and other newer-generation antidepressants (agomelatine**, vortioxetine), which have slightly better tolerability but lower efficacy, are second-line drugs.

For certain antidepressants (amitriptyline**, clomipramine**), intramuscular and/or intravenous drip administration is permitted.

Psychotherapy in the early stages of severe depression is generally ineffective.

• Treatment of depressive episode patients with high suicide risk, aimed at preventing suicidal acts and relieving depressive symptoms, is recommended to be carried out in an inpatient setting, considering the option of prompt ECT [113, 114, 115, 116, 117].

ROB BLOE 1Recommendation grade – B (evidence level – 1).

Comments. Compared to SSRIs, more severe consequences in the event of antidepressant overdose taken with suicidal intent are observed with TCAs, venlafaxine, and mirtazapine.

3.1.4 Acute therapy for severe DE with psychotic symptoms

Treatment of severe depressive episodes with psychotic symptoms must be carried out in an inpatient setting. Therapeutic tactics are aimed at the rapid achievement of psychotic symptom remission ("break").

• For patients with severe depressive episodes with psychotic symptoms, in order to relieve depressive symptoms and achieve remission, it is recommended to prescribe antidepressants with a broad neurochemical mechanism of action (SNRIs, TCAs, TetrCAs) from the first days in combination with atypical antipsychotics [118, 119, 120, 121].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: if oral administration is difficult due to the patient's mental state, intramuscular antipsychotics may be used. If well tolerated, drug doses are rapidly titrated to maximum levels.

Among SSRIs in the treatment of psychotic depression, evidence for the efficacy of fluvoxamine is the most compelling, which is presumably related to its high affinity for sigma-1 receptors [122, 123, 124, 125, 392].

3.1.5 Acute therapy for DE with mixed features

Antidepressant monotherapy should not be used for depression with mixed features, regardless of the depressive episode diagnosis (MDD, bipolar II disorder, or bipolar I disorder), given their questionable efficacy in treating depression within the framework of bipolar disorder and their ability to provoke or exacerbate manic symptoms and destabilize mood [21, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141].

Currently, there are no approved medications indicated specifically for the treatment of depressive episodes with mixed features. However, most atypical antipsychotics (AAPs), though not all, have proven effective for depression with mixed features and/or depression [142]. Most studies evaluating the efficacy of AAPs in treating depression with mixed features were conducted in patients with bipolar disorder, so their results should be extrapolated to MDD with a certain degree of caution. There is also clinical experience supporting the effective use of typical antipsychotics and benzodiazepine derivatives in treating depression with mixed features. However, typical antipsychotics carry many severe side effects, while benzodiazepine derivatives carry a risk of dependence [29].

• All patients with depressive episodes with mixed features are recommended regular follow-up to monitor the severity of hypomanic symptoms and suicidal ideation [10, 29, 143, 144, 145].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

• For untreated patients with depressive episodes with mixed features, prescribing atypical antipsychotics is recommended to relieve acute symptoms and achieve remission:

− #lurasidone** at a dose of 20–60 mg/day [146, 147, 148],

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

− or #ziprasidone at a dose of 40–160 mg/day [149, 150],

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

– or #cariprazine** at a dose of 1.5–3 mg/day [151, 152].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• Patients with depressive episodes with mixed features who are responding positively to antidepressant monotherapy and show no increase in hypomanic symptom severity are recommended to continue antidepressant therapy to achieve full remission [27, 29, 145, 153].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

• Patients with depressive episodes with mixed features receiving antidepressant monotherapy who exhibit an increase in the severity of hypomanic symptoms are recommended to discontinue antidepressants to prevent affective switch [29, 153].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comment: Tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) carry the highest risk of phase switch, while selective serotonin reuptake inhibitors (SSRIs) carry a lower risk [27, 131, 135, 154, 155, 156, 157, 158, 159].

• Patients with depressive episodes with mixed features who show insufficient response to antidepressant monotherapy are recommended to completely discontinue them to reduce the risk of exacerbating hypomanic/manic symptoms [27, 145, 155, 157, 160, 161, 162, 163, 164, 165].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

Comments: following antidepressant discontinuation, it is advisable to prescribe atypical antipsychotics: #lurasidone** [146, 147, 148], #ziprasidone [149, 150], or #cariprazine** [151, 152], which possess high efficacy in the treatment of depressive episodes with mixed features.

3.2 Acute DE therapy at the second stage

In at least 30–50% of cases, patients with depressive episodes fail to achieve an adequate response to any chosen antidepressant despite properly conducted first-line therapy. In such situations, it is necessary to re-verify the diagnosis, check whether the prescribed dose is sufficient, and assess patient compliance.

In the absence of clinical dynamics or when the clinical effect is insufficient (symptom reduction rate between 25% and 50%) within 3–4 weeks of therapy, or in case of poor tolerability of antidepressant pharmacotherapy, one should proceed to the second course or stage of treatment. Evidence supporting these strategies is quite limited, as large-scale randomized controlled trials have not been conducted. Currently, there is no clear consensus on the preferred strategy for treatment-resistant patients, especially regarding second-choice drugs. Data analysis from the STAR*D project demonstrated that remission rates could be increased from 27% achieved with first-line therapy to a cumulative level of 67% after all four subsequent therapeutic intervention steps. However, the probability of achieving remission after the first two courses of therapy was higher (20–30%) than after the last two (10–20%) [166].

• In the absence of clinical dynamics or when the clinical effect is insufficient (symptom reduction rate between 25% and 50%) within 3–4 weeks of antidepressant therapy, to overcome potential pseudo-resistance, it is recommended to:

− increase the antidepressant dose to the maximum [167, 168].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

− or partially switch to the parenteral route of administration (when using TCAs) [169].

LoR AGoE 3Level of Recommendations – A (Grade of Evidence – 3).

• In cases where dose titration is impractical (e.g., due to poor tolerability), switching to another antidepressant within the same pharmacological class or with a different mechanism of action is recommended to relieve depressive symptoms [170, 171, 172, 173].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: Modern definitions of treatment-resistant depression imply failure (i.e., symptom reduction on the Hamilton rating scale of no more than 50%) of two consecutive courses of adequate monotherapy lasting an average of 3–4 weeks with antidepressants differing in pharmacological structure and neurochemical action [174, 175, 176].

The strategy of switching to monotherapy with non-selective monoamine oxidase inhibitors was widely used in the past, but has been abandoned in recent years due to an unfavorable risk-benefit ratio (particularly the potential for hypertensive crises) and the disappearance of this antidepressant class from clinical practice. Nevertheless, in certain cases, switching to reversible and selective MAO-A inhibitors (pirlindole) may produce a rapid positive effect, as it involves a completely different mechanism of action and stimulates the release of all three monoamine neurotransmitters into the synaptic cleft.

• For patients with depressive episodes with mixed features who did not respond to monotherapy with #lurasidone** [146, 147, 148] or #ziprasidone [149, 150], or #cariprazine** [151, 152], prescribing an unused first-line agent or #olanzapine** at a dose of 5–20 mg/day is recommended to relieve symptoms and achieve remission [129, 177, 178].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• For patients with depressive episodes with mixed features who did not respond to atypical antipsychotic monotherapy, switching to mood stabilizer therapy (lithium salts — classified as antipsychotics per the ATC classification; valproic acid**, #lamotrigine — classified as antiepileptic drugs per the ATC classification) or combination therapy of atypical antipsychotics with a mood stabilizer is recommended to relieve symptoms and achieve remission [29, 179, 180, 181].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

3.3 Acute DE therapy at the third stage

If the clinical effect is insufficient and there are no obvious reasons for this lack of response—including misdiagnosis (e.g., bipolar II disorder), non-compliance, comorbid psychiatric and somatic conditions, or other factors—the patient is considered to exhibit relative resistance, and the treatment should progress to the third stage, i.e., specific anti-resistance measures. Depending on the situation, any treatment regimen lasting 3–4 weeks can be chosen, but preference should be given to agents with proven efficacy and good tolerability, while also considering potential drug interactions, including those arising from competitive hepatic metabolism.

• Patients with resistance to antidepressant monotherapy are recommended combination therapy using antidepressant combinations with complementary mechanisms of action to achieve a synergistic thymoleptic effect: combining a TCA and an SSRI; combining a monoamine reuptake inhibitor (SSRI, SNRI, or TCA) with an antidepressant that blocks alpha-2 adrenergic autoreceptors (e.g., mirtazapine, mianserin, etc.) [182, 183, 184, 185].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: the negative aspects of this strategy include an increased risk of drug-drug interactions, enhanced side effects, and higher economic costs. The most significant risks are antihistaminic side effects (weight gain and excessive sedation) and anticholinergic side effects (impaired concentration and confusion), as well as orthostatic hypotension with a risk of falls and traumatic consequences [186, 187]. Combining MAO-A inhibitors with SSRIs and other serotonergic antidepressants (e.g., clomipramine**, venlafaxine, etc.) should be avoided due to the potential risk of serotonin syndrome [188, 189, 190, 191].

• For patients with resistance to antidepressant monotherapy, augmentation of atypical antipsychotic efficacy is recommended to relieve symptoms and achieve remission: adding to the antidepressant

- quetiapine**, aripiprazole, olanzapine** (in combination with fluoxetine**), #risperidone** at a dose of 0.25–3 mg/day [192, 193, 194, 195, 196, 197, 198],

Level of Recommendation – BLevel of Evidence – 1 Level of recommendation validity is B (level of evidence reliability is 1).

- or #cariprazine** at a dose of 1.5–3 mg/day, #brexpiprazole at a dose of 0.5–3 mg/day, #ziprasidone at a dose of 40–160 mg [196, 198, 199, 200, 201, 202, 203, 204, 205],

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

- or #amisulpride at a dose of 50–200 mg/day [198, 206, 207].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

Comments: adding any atypical antipsychotic increases the total number of side effects, including hyperprolactinemia, metabolic disorders (weight gain, dyslipidemia, carbohydrate metabolism disorders), leukopenia, sedation and somnolence, anticholinergic and extrapyramidal side effects, which requires a careful risk/benefit assessment when used concomitantly with antidepressants [208].

According to studies confirming the efficacy of aripiprazole in antidepressant augmentation for treatment-resistant depression, the recommended starting dose is 5 mg/day with a possible subsequent increase up to a maximum of 15 mg/day [209, 210]. The most frequent adverse events with aripiprazole are extrapyramidal disorders, akathisia, and weight gain. The high augmenting efficacy of quetiapine** has been confirmed in a number of RCTs, according to which the recommended starting dose is 50 mg/day with a possible increase to 100, 150, 300 mg/day. The maximum dose should not exceed 600 mg/day [192, 193]. The potential for sedation and weight gain must be taken into account. When using olanzapine** to augment the effect of fluoxetine**, the recommended dose range is 5–10 mg/day (the 5 mg dose is outside the approved prescribing information for olanzapine**) [211]. The most common side effects are weight gain, sedation, and elevated prolactin. When using #cariprazine**, the dose range varies from 1.5 to 3 mg/day; the starting dose is 1.5 mg/day [199, 200, 201, 202, 391]. The most frequent adverse events with #cariprazine** are extrapyramidal disorders and akathisia. Regarding the use of #risperidone** for antidepressant therapy augmentation, the recommended starting dose is 0.5 mg/day, and the dose range is 0.25–3 mg/day [197]. The potential for hyperprolactinemia and extrapyramidal disorders should be considered. A meta-analysis of 9 RCTs confirmed the efficacy of #brexpiprazole in resistant depression when administered at an initial dose of 0.5–1 mg with a possible increase up to 3 mg (recommended average dose is 2 mg) [203]. Side effects of #brexpiprazole include akathisia, insomnia, anxiety, somnolence, and weight gain. Several RCTs have demonstrated a significant advantage in the efficacy of #ziprasidone augmentation compared to placebo [204, 205]. The recommended initial dose is 20 mg with a possible increase to 40–160 mg/day. Among side effects, akathisia, weight gain, and QTc interval prolongation occur most frequently [212]. Data on the augmenting efficacy of #amisulpride are limited to open-label studies in which the drug was added to baseline antidepressant therapy at an initial dose of 50 mg with a possible weekly increase of 25 mg up to a maximum dose of 200 mg/day [206], or at a fixed dose of 50 mg/day [207]. The most frequent side effect of #amisulpride is hyperprolactinemia.

• For patients with resistance to antidepressant monotherapy, to relieve symptoms and achieve remission, augmentation of antidepressant effects with lithium salts (#lithium carbonate) at a dose of ≥800 mg (or a dose sufficient to achieve a serum lithium concentration of ≥0.5 µmol/L) is recommended. [213, 214].

ROB BLOE 1Recommendation grade – B (evidence level – 1).

Comments: even low doses of lithium salts (serum lithium concentration of 0.5–0.8 mmol/L) over several days can lead to an improvement in the patient's condition. The course of therapy does not exceed 2–4 weeks; however, if efficacy is achieved, therapy should be continued for several months. It is believed that lithium salts can alter the receptor sensitivity of the postsynaptic membrane and enhance the effect of serotonin. It cannot be ruled out that cases of efficacy were associated with misdiagnosis of treatment-resistant depression and failure to detect bipolar II disorder [215] or "hidden bipolarity" [216]. Combining antidepressants with lithium salts must be done with caution, as elevated dosages can lead to neurotoxic reactions (myoclonus, ataxia, agitation, confusion), and combination with the amino acid L-tryptophan (dietary supplement) (the "Newcastle" or "serotonin" cocktail) can cause serotonin syndrome [189]. In addition, adverse events of lithium salt therapy include cardiotoxicity, nephrotoxicity, thyrotoxicity, and weight gain. Due to the narrow therapeutic window, regular monitoring of blood lithium concentration is required.

• In patients with resistance to antidepressant monotherapy, to relieve symptoms and achieve remission in the presence of additional symptomatic indications (e.g., anxiety, phobias, hypochondriacal, and psychotic symptoms), augmentation of the antidepressant effect is recommended, including the addition of:

− sulpiride** [217, 218, 219]

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

− or flupentixol** [220, 221].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

• In patients with resistance to antidepressant monotherapy, to relieve symptoms and achieve remission, augmentation of the antidepressant effect with antiepileptic drugs is recommended: #lamotrigine at an initial dose of 25 mg/day with a gradual increase up to 200 mg/day [222, 223].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

− or #carbamazepine** at a dose of 400-800 mg/day [224, 225].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• In patients with depressive episodes with mixed features, previously naive to antidepressants, in whom monotherapy with antipsychotics, mood stabilizer therapy, or a combination of antipsychotics and mood stabilizer therapy has proven ineffective, to relieve symptoms and achieve remission, combination therapy of antipsychotics with antidepressants, or olanzapine** with fluoxetine**, or mood stabilizer therapy with antidepressants is recommended [29, 129, 150, 179, 180].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comment: the combination of olanzapine** with fluoxetine** should be used with caution in overweight, obese, or metabolic syndrome patients. The combination of olanzapine** or #risperidone** with carbamazepine** is not indicated due to their drug-drug interactions at the level of hepatic enzymes [179].

3.4 Acute DE therapy at the fourth stage

If the aforementioned measures are ineffective, the clinician proceeds to the fourth stage to overcome resistance, which also consists of several options.

• In patients with treatment-resistant depression where therapy of the first, second, and third stages has proven ineffective, to overcome resistance, a course of electroconvulsive therapy as monotherapy or combined with antidepressants, consisting of 8-12 sessions (2-4 weeks, 3 sessions per week every other day), is recommended [116, 226, 227].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: ECT can be used at any stage of treatment-resistant depression, depending on the clinical picture and the need for a rapid therapeutic response. Psychotic depressions with delusion-like experiences, pronounced psychomotor agitation or retardation, high suicide risk, food refusal, or contraindications to pharmacotherapy (e.g., intolerance or pregnancy) are the main indications for early ECT. In addition, ECT should be considered as an earlier option if the method proved effective in previous episodes [113, 114, 115, 116].

The efficacy of the course is 50–80%, exceeding all other strategies. Therefore, in the absence of contraindications, to counteract further prolongation and chronicization of depression, ECT should be preferred over all other methods at this stage. Currently, modified ECT with short intravenous anesthesia, muscle relaxants, and artificial lung ventilation is used as a safety standard, which almost completely eliminates the motor seizure component. ECT demonstrates good safety and tolerability (adverse events occur in 0.4% of cases) and has no absolute contraindications other than elevated intracranial pressure [227]. Caution should be exercised in patients with cerebrovascular insufficiency, cardiovascular diseases (such as a recent myocardial infarction, myocardial ischemia, congestive heart failure, arrhythmia, or a pacemaker), as well as in patients with abdominal aortic aneurysms and severe osteoporosis. Among side effects, the most important are memory impairments during treatment, which are less pronounced with unilateral electrode placement [228].

• For patients with treatment-resistant depressive episode (DE) in whom first-, second-, and third-line therapy has proven ineffective, simultaneous discontinuation of psychopharmacotherapy is recommended to overcome resistance [229].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: The method was developed and widely tested in the 1970s and 1980s and has a low level of evidence. The "saturation" phase with medicinal products during simultaneous discontinuation involves increasing the doses of tricyclic antidepressants (TCAs) and anticholinergic agents (sometimes including an antipsychotic agent in the regimen) to the maximum tolerated levels (i.e., until side effects appear) and lasts for 10-14 days. This is followed by simultaneous discontinuation of therapy. Diuretics, high fluid intake, intravenous saline infusion, or plasmapheresis are used to enhance the withdrawal effect. In half of the patients, a critical reduction of depressive symptoms occurs on the 5th-10th day after the withdrawal phase. To correct pronounced somatovegetative disorders during this period, symptomatic agents and anxiolytics – benzodiazepine derivatives – are prescribed.

In addition to ECT and simultaneous discontinuation, other previously unused augmentation or third-line combination therapy methods may be attempted, especially those with recommendation grades A1-B2, as well as other pharmacological augmentation methods for antidepressants.

• For patients with treatment-resistant DE in whom first-, second-, and third-line therapy has proven ineffective, the combination of an SSRI with an anxiolytic – the azaspirodecanedione derivative buspirone (a partial 5-HT1A receptor agonist) – is recommended to overcome resistance [230, 231, 232].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• For patients with treatment-resistant DE in whom first-, second-, and third-line therapy has proven ineffective, transcranial magnetic stimulation (TMS), either as monotherapy or for antidepressant augmentation, is recommended to overcome resistance [233, 234, 235, 236].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: High-frequency pulsed or rhythmic stimulation (rTMS) (5–20 Hz) usually produces a moderate stimulating effect, whereas low-frequency (1 Hz) stimulation produces a calming, anti-anxiety effect. The most common option in treatment-resistant depression is high-frequency unilateral rTMS applied to the projection of the left dorsolateral prefrontal cortex. Compared to ECT, the procedure is less effective, but significantly better tolerated by patients [114, 237, 238] and better corrects cognitive impairment [239]. Apart from rarely occurring mild headache and discomfort at the stimulation site, no side effects occur after a 2-week course of TMS. In rare cases, TMS-provoked epileptic seizures have been described [240]. Meta-analyses of controlled studies (compared with sham-TMS procedures) consistently show a small positive effect of a 2-week course of TMS. The studies used a combination of TMS with SSRIs [241, 242, 243, 244].

• For patients with treatment-resistant DE in whom first-, second-, and third-line therapy has proven ineffective, magnetic convulsive therapy (MCT), a form of pulsed rTMS with increased power necessary to provoke an epileptiform seizure, is recommended as a brain electrical stimulation method to overcome resistance [245, 246, 247].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

Comments: with comparable efficacy, MCT leads to less pronounced cognitive and mnestic impairments compared to ECT.

• For patients with treatment-resistant DE in whom first-, second-, and third-line therapy has proven ineffective, brain electrical neurostimulation (transcranial direct current stimulation, tDCS) is recommended to overcome resistance [248, 249].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: in case of ineffectiveness of all the listed stages and especially a course of ECT, it is recommended to recognize absolute resistance and proceed to the fifth stage, which includes long-term courses of previously unused antidepressants, new combination therapy options including a combination of non-selective monoamine reuptake inhibitors, SSRIs, or SNRIs with MAOIs-A, or augmentation and other anti-resistance measures, including new brain electrical stimulation methods. Once an effect is achieved, effective therapy must be continued for another 6–9 months, while achieving complete reduction of residual symptoms and achieving stable remission [250].

• For patients with DE with mixed features in whom first-, second-, and third-line therapy has proven ineffective, ECT is recommended to alleviate symptoms and achieve remission [251, 252, 253].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

Comments: in case of ineffectiveness of all listed stages and ECT, alternative methods (TMS, TCAs, first-generation antipsychotics) are recommended to overcome resistance, alleviate symptoms, and achieve remission [251].

3.5 Stabilizing therapy

• For all patients with a single DE or major depressive disorder (MDD), following acute therapy, stabilization therapy using the antidepressant effective during the acute period and maintaining the previous dose for 4–6 months is recommended to stabilize their condition and achieve full recovery [254, 255, 256].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments. The risk of relapse among patients not receiving stabilizing psychopharmacotherapy in the first six months after the cessation of depressive symptoms averages 50%. Pharmacotherapy adequate in duration and dose reduces the risk of depression recurrence to 10% [257].

3.6 Maintenance (preventive) therapy

Currently, the prophylactic effect refers to the ability of certain drugs, with prolonged continuous administration, to suppress the development of relapse or reduce the severity of the next affective phase.

• For all patients with MDD, continuous long-term (at least 3–5 years) psychopharmacotherapy using doses of drugs that proved effective during the period of depressive phase relief and stabilization of the condition is recommended to prevent relapses [255, 256, 258, 259, 260].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

• For patients with MDD, the use of SSRIs and SNRIs is recommended during the maintenance therapy stage to normalize cognitive functioning [261, 262, 263, 263, 264, 265, 266]

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

- or vortioxetine [262, 263, 264, 267, 268, 269].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments. Cognitive dysfunction is one of the frequent residual symptoms of MDD, leading to social maladaptive behavior patterns and difficulties in daily activities [270], as well as a poorer response to antidepressant therapy regardless of the severity of depressive symptoms [271, 273]. Cognitive impairments that may persist after the complete resolution of affective symptoms hinder full social rehabilitation. Therefore, achieving "cognitive remission" is currently defined as an important goal for antidepressant therapy – [274]. The results of a large number of RCTs and meta-analyses specifically investigating the impact of standard thymoleptic therapy methods on cognitive impairment show that prescribing antidepressants from the SSRI, SNRI, and vortioxetine groups in most cases promotes the improvement of cognitive functions, whereas the use of TCAs, which possess anticholinergic activity, negatively affects them, especially with prolonged use [275]. Unfortunately, large-scale studies directly comparing the impact on cognitive parameters of individual antidepressants from the SSRI and SNRI groups have not been conducted. Encouraging results have been obtained in several open-label studies using fluvoxamine [276, 277, 278], whose procognitive effect is associated with its high affinity for sigma-1 receptors [279]. The most convincing data regarding the ability to improve cognitive functions have been demonstrated for vortioxetine, which is explained by its affinity for various subtypes of serotonergic receptors, in particular, significant antagonism at 5-HT3A receptors, many times exceeding its affinity for other receptor subtypes with which it interacts (5-HT1A, 5-HT1D, and 5-HT7) [280], presumably leading to glutamatergic modulation [281].

• For patients with MDD with intolerance to antidepressants and lithium salts, prophylactic therapy with #carbamazepine** at a dose of 200–600 mg/day is recommended to prevent relapses [282, 283, 284].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

Comments. Psychopharmacotherapy has been and remains the only effective method for preventing recurrences of recurrent depressive disorder (RDD). Before the introduction of next-generation antidepressants into clinical practice, mood stabilizers were used to prevent RDD relapses. Despite the proven efficacy of lithium salts in preventing RDD relapses in several randomized controlled trials (RCTs) [285, 286], antidepressants are currently the more studied and recognized agents for RDD prevention. #Carbamazepine** is recommended for use in case of intolerance to antidepressants and lithium salts [17].

Already the earliest studies on the relapse-prevention efficacy of tricyclic antidepressants (TCAs) [256, 286] in RDD demonstrated their superiority over placebo. The ability to reliably reduce the risk of depression relapse was also identified for mianserin, a tetracyclic compound with a different mechanism of action [287]. It has been shown that dose reduction decreases the efficacy of prophylactic therapy [256, 259]. At the same time, an obstacle to the long-term use of heterocyclic antidepressants is the almost inevitable development of adverse effects in patients, which limits the possibility of using adequate doses. TCAs are not recommended for RDD prophylaxis due to cardiotoxicity and the propensity to accumulate in the myocardium with prolonged use. Long-term TCA therapy is permissible only if other antidepressants are ineffective and strictly under the condition of regular monitoring of tolerability and ECG. Unlike TCAs, newer-generation antidepressants possess good tolerability across the entire dosage range, which is an important advantage during long-term therapy.

The rationale for relapse-prevention therapy in RDD at the present stage is supported by the following facts [288]:

• about 50–80% of patients with depressive disorder experience recurrent exacerbations over their lifetime;

• the risk of exacerbations increases with age and is proportional to the number of previous episodes;

• with an increase in the number of episodes, the duration of remissions decreases;

• there is evidence of the efficacy of antidepressants in preventing depressive episodes (DE);

• the therapeutic response to antidepressant therapy may diminish as the number of prior episodes increases;

• with each episode, disability increases and patients' quality of life declines.

Various strategies are employed in continuation and maintenance therapy for RDD [289]:

1) Active therapeutic strategy: continuation of antidepressant pharmacotherapy at full therapeutic dose (recommended for frequent relapses, significant severity of depressive episodes, and relative somatoneurological well-being of patients).

2) Continuation of antidepressant pharmacotherapy at a reduced dose (recommended for a more favorable course of RDD. Obviously, in some cases, the effective therapeutic dose is quite high, which is accompanied by adverse effects. It is known that most TCAs possess cardiotoxic effects with long-term use, and many antidepressants are hepatotoxic; thus, the question of the feasibility of long-term high-dose therapy in certain categories of patients—such as elderly or somatically compromised individuals—is sometimes resolved in favor of reducing the antidepressant dose. This strategy can be used in patients with mild forms of depression (mild depressive episode) or infrequent depressions (2 or fewer depressive episodes over 5 years).

3) Discontinuation of antidepressant pharmacotherapy upon completion of continuation therapy (4–6 months) with early treatment initiation at the first signs of a new phase (can be used in patients with mild forms of depression (mild depressive episode) or infrequent depressions (2 or fewer depressive episodes over 5 years).

• All patients are recommended a gradual dose reduction upon the planned completion of maintenance therapy or forced premature discontinuation (due to poor adherence or somatic reasons) in order to prevent withdrawal symptoms [290, 291, 292].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: The dose-tapering period may take several days, weeks, or even months, depending on the dose, duration of treatment, pharmacological properties of the drug, and the patient's clinical status [293]. The necessity for a gradual dose reduction is due to the potential development of antidepressant discontinuation syndrome (ADS) [384, 385]. These symptoms are usually transient and rapidly resolve upon re-administration of antidepressants. The risk of their development is higher when the anticholinergic properties of the drug are more pronounced, the dosage used is higher, and the treatment period is longer. Among newer-generation antidepressants, ADS is most characteristic of venlafaxine [290] and short-half-life SSRIs (e.g., paroxetine**), and less characteristic of fluoxetine**. Abrupt discontinuation of TCAs can cause a cholinergic rebound phenomenon (flu-like state, myalgia, cramping abdominal pain). To avoid ADS or manage its manifestations if a decision is made to discontinue the antidepressant, the following algorithm for the prevention and management of antidepressant discontinuation syndrome is proposed (see Appendix B5) [384, 386, 387].

Patients receiving long-term maintenance therapy require regular medical follow-up to identify early signs of relapse and promptly arrest them, monitor potential adverse effects of therapy and adherence to the medication regimen, conduct psychotherapeutic interventions aimed at motivating the patient to continue treatment, and provide assistance in the event of psychosocial stressors.

3.7 Other Treatment

Psychotherapy

The optimal approach to managing patients with depression involves a combination of biological and psychological/psychosocial methods of intervention, which aligns with the modern biopsychosocial model of mental disorder development, highly relevant to RDD as well. Certain types of psychotherapy have proven efficacy both as a primary treatment method for depression and as an adjunct to antidepressant pharmacotherapy at any stage of treatment, including for treatment-resistant depression with a tendency toward chronicity and frequent relapses [294, 295, 296, 297, 298]. Cognitive behavioral therapy (CBT) has the strongest evidence base in this regard; it is a family of psychotherapeutic techniques linked by similarities in theoretical views and technical approaches. CBT is based on information-processing models and functions as an educational process that provides the patient with new experiences [299]. Other methods specifically studied in patients with depression include interpersonal psychotherapy (IPT) [300] and psychodynamic psychotherapy (PDT) [301]. These psychotherapeutic methods have demonstrated efficacy comparable to that of antidepressant treatment, at least in mild to moderate depression [302, 303, 304, 305]. At the same time, according to large RCTs and meta-analyses, the greatest efficacy in treating depression is achieved by combining these psychotherapeutic methods with pharmacotherapy [294, 298, 303, 304, 305, 306, 307, 308].

In recent years, special attention in the treatment of depression has been given to novel psychotherapeutic methods that stem from the cognitive behavioral paradigm while integrating techniques and approaches from other orientations. Among them, mindfulness-based cognitive therapy (MBCT) [309] and acceptance and commitment therapy (ACT) [310] have gained the widest recognition. In recent years, a novel approach combining various psychotherapy options with adaptive virtual reality technology has also been actively developing [393, 394, 395, 396].

During psychotherapy, just as with pharmacotherapy, treatment response and patient safety should be monitored regularly, carefully, and systematically. When determining the frequency of psychotherapy sessions for a given patient, the clinician must consider a complex of factors, including the type and goals of psychotherapy, symptom severity, comorbid disorders, adherence, and the availability of social support. The frequency of visits must be sufficient to establish and maintain a therapeutic alliance, deliver all therapeutic interventions, and track their impact on depressive symptoms and suicide risk.

• All patients with depressive episodes or RDD are recommended to undergo various methods of psychotherapy combined with pharmacotherapy to increase treatment efficacy and improve patients' social functioning [298, 303, 304, 305, 306, 307, 308, 311, 312, 313, 314, 315, 316].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments. The combination of a validated psychotherapy method and pharmacotherapy can be used as initial treatment for patients with mild, moderate, and severe depression and has a number of advantages compared to antidepressant monotherapy: improved short-term patient recovery rates, a faster therapeutic response, reduced relapse rates and severity of residual depressive symptoms, improved long-term social functioning, increased compliance, higher patient satisfaction, and reduced long-term healthcare and social service costs [294, 312, 317, 318].

Psychotherapy in patients with depression is particularly advisable in the presence of significant psychosocial stressors, interpersonal and family conflicts, comorbid personality disorders, patient preference, availability of qualified specialists, and a history of a positive response to a specific psychotherapeutic intervention in the past [295]. Comparative evaluation of various psychotherapy methods is difficult due to the considerable variety of their subtypes, variability of results obtained, and in some cases, the bias of publication authors [319, 320]. At the same time, according to some authors, the leading role in achieving a therapeutic effect is played not so much by the specific features of the method as by non-specific psychological factors (for example, the quality of the contact between the patient and the therapist, as well as expectations regarding the effects of therapy on the part of both the patient and the specialist providing the therapy) [321].

Psychotherapy is the preferred treatment method in pregnant and breastfeeding women, as well as those planning pregnancy, in the absence of strict clinical indications for pharmacotherapy [322, 323] (see Section 7. "Recommendations for the management of patients with depression during pregnancy and preparation for it").

• Patients with depressive episode or recurrent depressive disorder are recommended to undergo CBT by correcting cognitive distortions and mastering adaptive thinking and behavior skills in order to increase treatment efficacy [303, 311, 313, 315, 324, 325, 326, 327, 328].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments. Considering that the largest number of RCTs and meta-analyses confirming the efficacy of psychotherapy for depression are dedicated to CBT, this specific approach is generally recommended first-line. CBT aims to identify and track cognitive distortions of various levels, correct them using logic, psychological functional tests and assignments, as well as by identifying constructive alternatives to these distortions and testing them in practice.

• In patients with dysthymia or MDD, IPT aimed at resolving interpersonal issues is recommended to enhance treatment efficacy [298, 304, 307, 313, 328, 329].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments. IPT for depression focuses on maladaptive interpersonal relationships, such as grief (complicated bereavement), interpersonal role conflicts and role transitions, as well as interpersonal deficits (paucity of attachments). Through the reassessment of current life difficulties and relevant training during therapy, the patient is assisted in developing or restoring important social skills, which helps balance their self-esteem and perception of others. In methods close to IPT (e.g., family or group therapy), psychotherapeutic work usually extends beyond current problems. Nevertheless, modifying the patient's interactions with their immediate social environment remains the primary driver for overcoming depression.

• In patients with dysthymia or MDD, PDT involving an in-depth self-understanding by the patient of their psyche and the causes of their behavior is recommended to enhance treatment efficacy [298, 308, 330, 331, 332, 333, 334].

ROB BLOE 1Recommendation grade – B (evidence level – 1).

Comments. Psychodynamic psychotherapy aims at an in-depth self-understanding by the patient of their psyche and the causes of their behavior, leading to self-liberation from symptoms and suffering associated with depression. Insights emerging during the therapy are often accompanied by corrective emotional experiences that can exert a constructive influence on the patient's behavior and response style. The focus of therapy is usually on the relationship between the patient and the therapist, as well as overcoming immature ego defenses that distort the perception and processing of information in depression. The main techniques of psychodynamic psychotherapy are confrontation, clarification, interpretation, and working through. Their essence lies in the client's repetitive return to experiences associated with past or current psychological problems, their reassessment, and the instilling of an analytical attitude toward oneself and life. All of this contributes to the development of the patient's ability to enter into trusting relationships, the formation of more mature defenses, and the expansion of the spectrum of experienced emotions.

• To increase treatment efficacy, patients with depressive episodes or recurrent depressive disorder are recommended to undergo mindfulness-based cognitive therapy by explaining to patients the role of negative thought patterns in the onset of depression and fostering their mindfulness based on meditative practices [298, 313, 335, 336, 337, 338, 339, 340, 341].

ROB BLOE 1Recommendation grade – B (evidence level – 1).

Comments. Essentially, mindfulness-based cognitive therapy is grounded in the active application of meditative practices to view oneself and one's mental processes from an external perspective, transitioning into a metacognitive stance. This stance allows the patient to "decenter" from maladaptive thoughts, feelings, and reactions. This method can be applied more broadly as it is more accessible to many patients with depression who experience difficulties in tracking and challenging their existing dysfunctional cognitions.

• To increase treatment efficacy, patients with depressive episodes or recurrent depressive disorder are recommended to undergo mindfulness- and values-oriented psychotherapy by altering patients' attitudes toward negative thoughts and experiences through the use of mindfulness techniques, acceptance techniques, and values-related techniques [310, 341, 342, 343, 344, 345].

ROB BLOE 1Recommendation grade – B (evidence level – 1).

Comments. Mindfulness- and values-oriented psychotherapy is a novel form of integrative psychotherapy that integrates CBT, mindfulness-based cognitive therapy, as well as elements of gestalt therapy and logotherapy based on the concept of metacognition. This method is currently gaining popularity, and the literature contains numerous data on its efficacy in treating depressive states. The core principle of this method is separating the patient from depression-induced dysfunctional cognitions, accepting unpleasant feelings and experiences by adopting an observer stance, concentrating on the current moment, and establishing contact with the present. An essential feature of mindfulness- and values-oriented psychotherapy is assisting the patient in formulating their own values and attempting to act in accordance with them.

Surgical treatment

In cases of acknowledged absolute resistance in depressive episodes, the feasibility of employing certain surgical treatment methods may be considered.

• For patients with absolute resistance to conservative treatments, in order to overcome resistance and alleviate symptoms, implantation of a programmable system in the vagus nerve region (vagus nerve stimulation, VNS) is recommended, involving indirect brain stimulation via the vagus nerve [346, 347, 348, 349].

LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).

Comments: A small generator is implanted on the left side above the clavicle and connected via an electrode to the left vagus nerve. The generator delivers rhythmic electrical impulses to the nerve for 30 seconds every 5 minutes. Disadvantages of the method include its invasive nature and a number of side effects (hoarseness, stimulation of the cough reflex, etc.).

• For patients with absolute resistance to conservative treatments, in order to overcome resistance and alleviate symptoms, stereotactic implantation of intracerebral electrodes (deep brain stimulation, DBS) is recommended, involving the stereotactic placement of miniature electrodes in specific neuroanatomical regions of the brain under neuroimaging guidance [350, 351, 352].

GOR BLOE 3Grade of Recommendation – B (Level of Evidence – 3).

Comments: the electrodes are connected to a lead wire attached to an implantable pulse generator for deep brain stimulation placed under the skin of the chest. In treatment-resistant depressions, the target areas for bilateral electrode placement are the subgenual cingulate cortex, the lentiform nucleus, and Brodmann area 25 (BA25). Disadvantages of the method include the invasiveness of the surgical procedure, limited availability and high cost of the technique, as well as uncertainty regarding optimal stimulation parameters.

Other non-pharmacological treatments

• Patients with a single depressive episode (DE) or recurrent depressive disorder (RDD), in addition to pharmacotherapy, are recommended to use the following non-pharmacological methods of treatment to enhance or accelerate the therapeutic effect of antidepressants:

- Visible light radiation therapy (phototherapy) [353, 354, 355];

ROB BLOE 1Recommendation grade – B (evidence level – 1).

Comment: The use of phototherapy is advisable primarily for seasonal affective disorder, a subtype of RDD characterized by the dependence of depressive episodes on the time of year, usually occurring in the autumn-winter period.

- Sleep deprivation [356, 357];

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

- Physical exercise [358, 359, 360];

ROB BLOE 1Recommendation grade – B (evidence level – 1).

- Reflexology (electroacupuncture and electroacupuncture in reflexology, extremely high frequency (EHF) acupuncture) [361, 362];

GCR CLoE 1Grade of Recommendation – C (Level of Evidence – 1).

- Prescription of a therapeutic diet for mental health disorders (reducing and dietary therapy, RDT) [363, 364];

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

- Low-level laser therapy (intravenous laser blood irradiation) (ILBI) [365, 366];

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

- Ultraviolet blood irradiation [367];

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

- Hypoxic therapy (normobaric hypoxia) [368].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

- Electroencephalography-based biofeedback training for central nervous system and brain disorders [369].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

- Plasmapheresis [370].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

- Xenon therapy [371].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

Medical nutrition

The organization of therapeutic medical nutrition for patients with a depressive episode during inpatient treatment in medical organizations is carried out in accordance with the Orders of the Russian Ministry of Health No. 330 dated August 5, 2003, "On measures to improve medical nutrition in medical and preventive institutions of the Russian Federation," No. 395n dated June 21, 2013, "On approval of standards for medical nutrition," and No. 1008n dated September 23, 2020, "On approval of the procedure for providing patients with medical nutrition" (Appendix A3).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• All patients with DE or RDD are recommended to undergo various psychotherapy methods (see Subsection 3.7. Other Treatment. Psychotherapy) in order to maintain remission, reduce the intensity of recurrence, and improve the social functioning of patients at the prophylactic stage of treatment [294, 298, 303, 313, 314, 334, 337].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

• All patients, as well as their relatives, in order to increase awareness of the nature of the disease, its course, prognosis, and treatment methods, are recommended to participate in group psychoeducational work with patients suffering from mental and behavioral disorders, as well as group psychoeducational work with relatives of patients with mental and behavioral disorders [240, 372, 373].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: The patient and their relatives are informed about the procedure and rules for taking medications, potential side effects, the need for hospitalization in a psychiatric hospital or outpatient treatment and follow-up by a psychiatrist. Psychoeducational techniques address the following main tasks:

- improving compliance and actively fostering adherence to long-term relapse-preventive pharmacotherapy;

- establishing the necessary alliance between the attending physician, the patient, and their relatives;

- adherence to the treatment regimen and regular monitoring of laboratory tests, including drug blood level determination, and side effects of therapy;

- full restoration of the level of social functioning; recognition of early manifestations of relapses and probable side effects;

- objective assessment of risks associated with the disease and ongoing therapy (suicide, violation of the law, substance abuse, pregnancy, etc.).

5. Prevention and Dispensary Observation

There are no methods for the primary prevention of RDD. The chronic relapsing nature of RDD necessitates secondary prevention of disease relapses. Secondary prevention consists of administering long-term relapse-preventive therapy (see Subsection 3.6. Relapse-Preventive (Prophylactic) Therapy). The main rules of secondary preventive therapy [373]:

- discuss with the patient the advantages and disadvantages of long-term therapy compared to the risk of relapse;

- establish contact with the patient to identify the earliest signs of relapse and promptly treat them; develop a healthy lifestyle program to reduce the risk of relapse;

- assist the patient in planning and implementing rehabilitation measures;

- review the treatment plan in the event of comorbid diseases and psychosocial stressors;

- conduct active dynamic follow-up for the early detection of depressive symptom relapses;

- use psychotherapeutic techniques for relapse prevention;

- administer preventive pharmacotherapy.

In accordance with Order of the Russian Ministry of Health No. 453n dated June 30, 2022, "On approval of the Procedure for dispensary observation of a person suffering from a chronic and protracted mental disorder with severe, persistent, or frequently exacerbating disease manifestations," patients with RDD require dispensary observation in cases of a chronic and protracted course with frequently exacerbating disease manifestations (of the psychotic register and/or suicidal tendencies) that led to hospitalization in a medical organization providing psychiatric care in inpatient settings.

6. Organization of Medical Care

The provision of care to patients with DE or RDD is carried out in accordance with Order of the Russian Ministry of Health No. 668n dated October 14, 2022, "On approval of the Procedure for the provision of medical care for mental and behavioral disorders" (effective July 1, 2023).

Treatment of patients with mild or moderate DE in the absence of suicidal risk (low suicidal risk) should preferably be carried out in outpatient settings of a psychoneurological dispensary (mental health center, dispensary department of a psychiatric hospital).

Indications for inpatient treatment are:

- severe DE without psychotic symptoms or with psychotic symptoms;

- presence of a high suicidal risk regardless of the severity of depression;

- unfavorable micro-social living conditions (e.g., in solitary patients living apart from relatives) regardless of the severity of depression if there is a high risk of sharp clinical deterioration and the appearance of suicidal ideation.

Discharge of patients from a psychiatric hospital should be carried out after the successful completion of the acute treatment phase and the establishment of symptomatic remission. Further treatment (stabilization and maintenance therapy) can be carried out in outpatient settings of a psychoneurological dispensary (mental health center, dispensary department of a psychiatric hospital).

7. Additional Information

Guidelines for the management of patients with depression during pregnancy and preparation for it

Comments: the question of the benefits or harms of antidepressants in the treatment of depression during pregnancy remains open due to a lack of information and comparative studies, as well as the complexity and high responsibility of conducting specialized studies. Modern guidelines do not strictly prohibit the use of antidepressants during pregnancy. Rather, they suggest balancing risks and benefits for both mother and fetus, and applying an individualized approach to each case [382, 383].

Criteria for Evaluating the Quality of Medical Care

Quality evaluation criteria for primary health care provided to adults with a depressive episode and recurrent depressive disorder (ICD-10 codes: F32, F33)

Quality of care criteria for specialized medical care in adults with a depressive episode or recurrent depressive disorder (ICD-10 codes: F32, F33)

References

Appendix A1. Working Group Composition

1. Akhapkin Roman Vitalievich – Doctor of Medical Sciences, Member of the Russian Society of Psychiatrists

2. Bobrov Alexey Evgenyevich – Doctor of Medical Sciences, Professor, Member of the Russian Society of Psychiatrists

3. Vazagaeva Tamara Irodionovna – Candidate of Medical Sciences, Member of the Russian Society of Psychiatrists

4. Kostyukova Elena Grigorievna – Candidate of Medical Sciences, Member of the Russian Society of Psychiatrists

5. Mazo Galina Elevna – Doctor of Medical Sciences, Member of the Russian Society of Psychiatrists

6. Mosolov Sergey Nikolaevich – Doctor of Medical Sciences, Professor, Member of the Executive Committee of the Russian Society of Psychiatrists, Honored Scientist of the Russian Federation

7. Khasanova Aiperi Kylychbekovna – Member of the Russian Society of Psychiatrists.

All authors confirm that there is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Psychiatrists

2. Psychotherapists

3. Medical psychologists

4. General practitioners (family physicians)

1. Scale for evaluating levels of evidentiary validity (LEV) for diagnostic methods (diagnostic interventions)

2. Scale for evaluating levels of evidentiary validity (LEV) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)

3. Scale for evaluating levels of recommendation certainty (LRC) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Clinical guideline update procedure – review once every 3 years and no more than once every 6 months.

Appendix A3. Reference Materials

1. Federal Law No. 323-FZ dated November 21, 2011, "On the Fundamentals of Protecting Citizens' Health in the Russian Federation".

2. Federal Law No. 3185-1 dated July 2, 1992 (as amended on July 3, 2016) "On Psychiatric Care and Guarantees of Citizens' Rights in Its Provision".

3. Order of the Russian Ministry of Health No. 668n dated October 14, 2022, "On Approval of the Procedure for Providing Medical Care for Mental Disorders and Behavioral Disorders" (Registered with the Russian Ministry of Justice on November 14, 2022, No. 70940)

4. Order of the Russian Ministry of Health No. 453n dated June 30, 2022, "On Approval of the Procedure for Dispensary Observation of a Person Suffering from a Chronic and Prolonged Mental Disorder with Severe Persistent or Frequently Exacerbating Disease Manifestations" (Registered with the Russian Ministry of Justice on July 28, 2022, No. 69429)

5. Order of the Ministry of Health of the Russian Federation No. 1219n dated December 20, 2012, "On Approval of the Standard of Primary Health and Social Care for Mild to Moderate Depressions and Mixed Anxiety and Depressive Disorder in Outpatient Settings of a Psychoneurological Dispensary (Dispensary Department, Office)".

6. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care" (Registered with the Russian Ministry of Justice on May 17, 2017, No. 46740)

7. Order of the Russian Ministry of Health No. 342n dated May 20, 2022, "On Approval of the Procedure for Undergoing Mandatory Psychiatric Examination by Employees Performing Certain Types of Activities, Its Frequency, as Well as the Types of Activities for Which Psychiatric Examination is Performed" (Registered with the Russian Ministry of Justice on May 30, 2022, No. 68626)

8. Order of the Russian Ministry of Health No. 451n dated June 30, 2022, "On Approval of the Procedure for Conducting Medical Psychiatric Examinations" (Registered with the Russian Ministry of Justice on July 28, 2022, No. 69435)

9. Order of the Ministry of Health of the Russian Federation No. 1226n dated December 20, 2012, "On Approval of the Standard of Primary Health and Social Care for Depressions (Remissions) in Outpatient Settings of a Psychoneurological Dispensary (Dispensary Department, Office)".

10. Order of the Ministry of Health of the Russian Federation No. 1661n dated December 29, 2012, "On Approval of the Standard of Specialized Medical Care for Depression (Relapse) in Inpatient Settings".

11. Order of the Ministry of Health of the Russian Federation No. 330 dated August 5, 2003, "On Measures to Improve Medical Nutrition in Healthcare Institutions of the Russian Federation".

12. Order of the Ministry of Health of the Russian Federation No. 395n dated June 21, 2013, "On approval of therapeutic nutrition standards".

13. Order of the Ministry of Health of the Russian Federation No. 1008n dated September 23, 2020, "On Approval of the Procedure for Supplying Patients with Clinical Nutrition."

Table 2. Recommended antidepressant doses

Table 3. Side effect profiles of antidepressants ¹ (adapted from the publication by Bauer M., Pfennig A., Severus E. et al., 2013 [86]).

¹ Severity of side effects: +++ (significant), ++ (moderate), + mild, – (very weak or absent)

² Only clinically significant inhibitory effects on cytochrome P450 enzymes are indicated

Appendix B. Physician Action Algorithms

B1. Flowchart "Stages of management of a patient (adults) with depressive episode or recurrent depressive disorder"

B2. Subchart "Diagnostics of a patient (adults) with depressive episode or recurrent depressive disorder"

B3. "Acute therapy for depressive episode without psychotic symptoms"

B4. Subchart "Acute therapy for depressive episode with mixed features"

Appendix B5. Algorithm for the prevention and management of antidepressant discontinuation syndrome (ADS)

Note. AD – antidepressant, SSRI – selective serotonin reuptake inhibitors, SNRI – serotonin-norepinephrine reuptake inhibitors, ADS – antidepressant discontinuation syndrome

If a decision is made to discontinue long-term antidepressant therapy, a gradual dose reduction of the antidepressant is most preferable; when there is a high risk of antidepressant discontinuation syndrome (ADS), the slowest possible dose reduction is desirable, while there are no uniform recommendations on the duration of the tapering period and the minimum dose to which the medicinal product should be reduced before discontinuation. If ADS cannot be avoided, for mild severity, drug therapy is not indicated, and it is sufficient to inform the patient about the temporary nature of the symptoms. For moderate severity of ADS, symptomatic therapy is necessary. For severe symptoms upon antidepressant discontinuation or a significant dose reduction, the following options can be used, which are equivalent to each other, i.e., have no specific order of application: 1) resume the antidepressant at the minimum effective dose or at the dose where there were no withdrawal symptoms, followed by discontinuation with a more fractional and slower titration; 2) when discontinuing an antidepressant from the SSRI or SNRI group, one can switch to fluoxetine, discontinuing the initial antidepressant after several weeks of fluoxetine treatment and gradually tapering the latter subsequently; when discontinuing antidepressants from other groups, one can switch to a pharmacologically similar antidepressant with a longer half-life and subsequently gradually taper both antidepressants as in the case of switching to fluoxetine.

Appendix C. Patient Information

The patient and their relatives should be told in an accessible form about the nature of the disease, its manifestations, the mechanism of action of medications, likely side effects, and the need for their long-term administration.

The patient must be provided with the following information:

- the name of the medicinal product;

- the need for its regular intake for the treatment of the disease or relief of certain symptoms;

- how to determine if the drug is effective and what to do if these signs are absent;

- when and how to take the medicinal product, including its relation to food intake;

- what to do if a dose is missed;

- duration of treatment;

- the most likely side effects and what to do if they occur;

- precautions for use, potential impact on work, driving, interaction with alcohol and other drugs, the possibility of adverse effects on the fetus in case of pregnancy, the need for contraception while taking the drug, etc.;

- alternative therapies and the approximate cost of the treatment course.

It is extremely important to reach an agreement with the patient on strict compliance with the prescribed treatment regimen. At the same time, it must be explained that in case of any discomfort associated with taking the medication, it is necessary to inform the physician, as this is grounds for a dose adjustment or a change of drug. Do not interrupt treatment on your own.

It is necessary to identify individual symptoms that indicate the risk of relapse in a given patient and motivate the patient to consult a doctor when they appear. This will provide a chance for faster relief of the relapse outside the hospital setting.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Hamilton Depression Rating Scale (HDRS)

Russian name: Hamilton Depression Rating Scale

Original name: Hamilton Rating Scale for Depression (HDRS-17)

Source: Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6(4):278–96.

Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 1988; 45(8):742–7.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: quantitative assessment of the condition of patients with depressive disorders before, during, and after treatment (monitoring clinical dynamics)

Content (template):

Instructions:

• Please inform the patient that accurate answers are essential to achieve the purpose of the questionnaire.

• Please review each item sequentially.

• The reference period for evaluation is the week preceding the interview, except for items 8, 9 (during the interview) and 16 (before the episode).

• For each item, select the expression that best characterizes the patient (mark only one answer).

• Please write notes for each item.

Total score:

Key (interpretation): 0–7 — normal

8–13 — mild depressive disorder

14–18 — moderate depressive disorder

19–22 — severe depressive disorder

above 23 — extremely severe depressive disorder

Notes: clinical interview takes approximately 20–25 minutes

Appendix G2. Montgomery–Åsberg Depression Rating Scale (MADRS)

Russian title: Montgomery–Åsberg Depression Rating Scale

Original title: Montgomery-Asberg Depression Rating Scale (MADRS)

Source: Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-9.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: quantitative assessment of the severity of condition in patients with depressive disorders before, during, and after treatment (monitoring clinical dynamics)

Content (template):

Instructions: The assessment should be based on a clinical interview during which questions are initially asked in broader terms, followed by a detailed clarification of the severity of symptoms according to the scale's criteria. The rater must decide whether the severity of symptoms corresponds to the main rating definitions of the scale (0, 2, 4, 6) or their intermediate values (1, 3, 5).

It should be kept in mind that for depressed patients, cases where accurate assessment based on the interview is difficult are extremely rare. If information cannot be obtained through patient questioning, it must be established for the scale rating from other objective sources in accordance with standard clinical practice.

Total score:

Key (interpretation): 0–6 — normal

7–19 — mild depressive disorder

20–34 — moderate depressive disorder

over 34 — severe depressive disorder

Notes: clinical interview takes approximately 20–25 minutes

Appendix G3. HCL-33 Hypomania Checklist

Russian title: HCL-33. Hypomania Checklist

Original title: Hypomania Checklist (HCL-33)

Source (official developer website, publication with validation):

Mosolov S.N., Yaltonskaya P.A., Senko O.V., Kursakov A.A., Alfimov P.V., Angst J. Detecting hypomania in patients with recurrent depression using the new HCL-33 questionnaire // Russian Journal of Psychiatry. 2021. No. 6. P. 59-69 DOI: 10.47877/1560-957X-2021-10607

Mosolov S.N., Yaltonskaya P.A., Senko O.V., Angst J. Validation of the Russian version of the hypomania checklist (HCL-33) for the detection of bipolar disorder in patients with a current diagnosis of recurrent depression // Journal of Affective Disorders Reports, 2021; Vol. 4, p. 1-7 (100086) https://doi.org/10.1016/j.jadr.2021.100086

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: detection of history of hypomania.

Content (template):

At various periods of life, all people experience changes or fluctuations in energy, activity, and mood ("periods of highs" and "periods of lows"). The purpose of this questionnaire is to explore "periods of highs"

1) First of all, please indicate how you feel today compared to your usual condition:

(please select only one statement from the list)

2) How do you usually rate yourself compared to other people?

Regardless of how you feel right now, indicate how you generally perceive yourself compared to other people. Choose the most appropriate formulation from the list below:

Compared to other people, my level of activity, energy, and mood...

(please select only one statement from the list)

3) Try to recall a "high" state

How did you feel back then? Please answer the following statements regardless of your current state

4) The impact of "high periods" on various aspects of your life:

5) How did your loved ones react to your "high periods", and what did they say about them?

6a) How long was the longest "high period" in your life?

(Please check only one option)

6b) As a rule (on average), how long does your "high period" last?

(Please check only one option)

7) Have you had "high periods" over the past 12 months?

8) If yes, try to estimate how many days you spent in a high state over the past 12 months

The last two questions relate to your temperament:

9) Would you say that you are naturally prone to periods of ups and downs?

10) Are you occasionally prone to sudden mood swings?

Appendix G4. Columbia-Suicide Severity Rating Scale (C-SSRS)

Russian title: Columbia-Suicide Severity Rating Scale

Original title: Columbia-Suicide Severity Rating Scale (C-SSRS)

Source: Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: assessment of suicide severity and suicide risk.

Content (template):

Total score:

Key (Interpretation): A score of "3" or higher on the severity of suicidal ideation indicates a serious risk of suicide. A score of "5", as well as any identified suicidal behavior, indicates an extremely high risk and an absolute necessity for urgent therapeutic interventions and hospitalization. The "suicidal intent" section allows for a more accurate assessment of the severity of the condition and prediction of its dynamics.