Bipolar Disorder: Clinical Guidelines

List of Abbreviations

SGA — second-generation antipsychotics

AD — antidepressants

FGA — first-generation antipsychotics

BD — bipolar disorder

BD — bipolar depression

RT — rapid tranquilization

RC — rapid cycling course

DBT — dialectical behavior therapy

DLPFC — dorsolateral prefrontal cortex

DE — depressive episode

IPT — interpersonal psychotherapy

CBT — cognitive behavioral therapy

CT — computed tomography

ICD — International Classification of Diseases

MRI – magnetic resonance imaging

MS — manic states

PSAs — psychoactive substances

MDD — major depressive disorder / Recurrent depressive disorder

RCTs — randomized controlled trials

MD — mixed depression

SSRI — selective serotonin reuptake inhibitor

MM — mixed mania

FT3 — free triiodothyronine

rTMS – Transcranial magnetic stimulation

MBCT — mindfulness-based cognitive therapy

IPSRT — interpersonal and social rhythm therapy

TSH — thyroid-stimulating hormone

TCA — tricyclic antidepressants (non-selective monoamine reuptake inhibitors)

LoE — level of evidence

LeR — level of recommendation validity

ECG – electrocardiography (recording of electrocardiogram)

EPS — extrapyramidal symptoms

ECT — electroconvulsive therapy

EEG — electroencephalography

DSM — Diagnostic and Statistical Manual of Mental Disorder

Terms and Definitions

Recovery from the last affective episode — a state of complete remission lasting more than 6 months.

Cognitive behavioral therapy is a psychosocial intervention (a form of psychotherapy) aimed at correcting cognitive distortions (negative, anxious, intrusive, and other thoughts) through their awareness and processing, followed by changing pathological behavioral patterns.

Crisis/Acute therapy — a set of therapeutic measures aimed at the rapid suppression of symptoms of the current affective episode.

Incomplete remission — a period during which significant improvement is noted, but symptoms (not reaching syndromal unity) persist.

Mood stabilizers (mood-stabilizing drugs, thymoleptics) — a group of drugs capable of exerting a secondary prophylactic effect on affective phases (manic, depressive, mixed states) with prolonged use and maintaining stable mood (euvithymia). These include: Lithium carbonate, Valproic acid**, Carbamazepine**, Lamotrigine, #Oxcarbazepine**, #Topiramate** (According to ATC: antiepileptic drugs, lithium preparations).

Exacerbation — the resurgence of symptoms to a significant degree of severity during remission (prior to recovery).

Recurrent affective episode — the development of a new depressive episode after recovery from the previous one.

Complete remission — the absence of any signs of an affective disorder for 6 months.

Prophylactic therapy — a set of therapeutic measures aimed at preventing a recurrent affective episode.

Psychotherapy — the application of scientifically grounded medical and psychological interventions aimed at changing cognitive-semantic processes, emotional and psycho-autonomic responses, as well as human behavior for the purpose of treatment, prevention, and rehabilitation of mental and somatic disorders.

Psychopharmacotherapy — the use of pharmacological agents in treatment.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Bipolar affective disorder (BD) or bipolar disorder is a chronic relapsing psychiatric disorder of the affective sphere, often leading to impaired behavior and social functioning, the main feature of which is the development of manic, hypomanic, or mixed states. According to modern classifications, bipolar disorders include BD-I (type I) in the presence of syndromal mania, BD-II (type II) in the presence of subsyndromal mania (hypomania), cyclothymia in the presence of chronic subsyndromal affective fluctuations, and residual atypical diagnostic categories; unipolar recurrent manias or hypomanias are significantly less common. Since hyperthymia is the main diagnostic criterion for BD, some authors, depending on the presence, severity, and duration of individual manic symptoms, distinguish BD with short manic/hypomanic episodes, as well as various variants of mixed states (MS), including those developing during antidepressant therapy or in individuals with hyperthymic traits. All these disorders are usually included in the broader concept of the bipolar spectrum. This expanded diagnostic concept is experimental and is not shared by all researchers.

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

The etiology and pathogenesis of BD are not yet fully understood. Concepts of etiology are based primarily on genetic theory [1,91,227]. First-degree relatives show an accumulation of cases of unipolar depression and BD. The results of genetic, biological, neurotransmitter, and neuroendocrine studies, theoretical physiological models, and psychosocial theories suggest that the disease has a complex etiology [397]. Chronobiological disturbances [387,394] and neuroinflammatory changes in the CNS [398-400] appear to play an important role in the pathogenesis of BD. Individual predisposing genetic and biological factors interact with environmental influences and various psychosocial factors. Compared to schizophrenia, the impact of environmental factors (pregnancy and childbirth pathology or living in large cities) on the development of the disease is less certain, but the hereditary load of bipolar spectrum disorders is higher than in other mental disorders. Early onset and delayed diagnosis increase the risk of comorbid psychiatric disorders and worsen the course of BD [1,4,91,227].

1.3 Epidemiology of the Disease or Condition

The disease typically manifests at a young age or in late puberty (under 20 years old), which is significantly earlier compared to the onset of recurrent depression. According to international data, the prevalence of bipolar disorder (BD) ranges from 0.5 to 2% (averaging about 1%) [3–8], the lifetime risk reaches up to 5% [8], and up to 12% when considering sub syndromal forms [9]. No significant geographical or ethnic differences in incidence rates have been established. The disorder is more common in women than in men, with a ratio of approximately 3:2 (compared to 2:1 for recurrent depression). BD is a disease with a high mortality rate, including risks associated with suicide [10,11] and comorbid somatic diseases. The lifetime risk of completed suicide in BD is 20%, which is 20–30 times higher than in the general population and higher than in recurrent depression. Information on the prevalence of BD in Russia is practically non-existent. In the 21st century, no epidemiological studies regarding this disease have been conducted in our country. Isolated studies from the past century indicate a huge gap between the prevalence rates of BD obtained in our country and in foreign studies [272]. For example, in the 1980s, the prevalence of BD-I (manic-depressive psychosis according to the International Classification of Diseases (ICD), 9th revision) was 0.36 cases per 1,000 population (0.036%), and the proportion of BD patients among those registered at psycho-neurological dispensaries was 0.045% [12]. According to Federal State Statistical Observation Form No. 10, "Information on the number of diseases registered in patients living in the service area of a medical organization", 2.24 BD patients per 100,000 population were registered in 2022, of whom 0.12 were newly diagnosed [13]. According to international data, 60–70% of patients with BD are initially misdiagnosed, and a correct diagnosis is subsequently established only an average of 8–10 years later after evaluation by three different physicians [14,15]. In Russia, with careful diagnosis in accordance with modern operational diagnostic criteria of ICD-10 [16], among patients monitored with a diagnosis of "recurrent depressive disorder" (RDD), the proportion of patients with BD is 40.8% [17], and among patients diagnosed with "schizoaffective disorder or episodic schizophrenia", it is 40.3% [18].

1.4 Features of Coding the Disease or Condition

F31 - Bipolar affective disorder

F31.0 - Bipolar affective disorder, current episode hypomanic

F31.1 - Bipolar affective disorder, current episode manic without psychotic symptoms

F31.2 - Bipolar affective disorder, current episode manic with psychotic symptoms

F31.3 - Bipolar affective disorder, current episode moderate or mild depression

F31.4 - Bipolar affective disorder, current episode severe depression without psychotic symptoms

F31.5 - Bipolar affective disorder, current episode severe depression with psychotic symptoms

F31.6 - Bipolar affective disorder, current episode mixed

F31.7 - Bipolar affective disorder, currently in remission

F31.8 - Other bipolar affective disorders

F31.9 - Bipolar affective disorder, unspecified

1.5 Classification of the disease or condition

In accordance with ICD-10, the diagnosis is established if there is at least one manic or mixed episode in the course of the disease.

In foreign literature, BD-I and BD-II types are distinguished. The American classification Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) [19] differentiates BD type I (presence of at least one full-blown manic or mixed episode and one depression) and type II (presence of at least one hypomanic episode and one depressive episode, with no history of full-blown manic states). BD type II is an independent disorder with an extremely low probability of transforming into BD type I. These diagnostic variants of BD are important for selecting differentiated therapy, as there is compelling evidence from randomized controlled trials (RCTs) showing differences in the therapeutic efficacy of medications across different variants of the disease course [274]. In Russia, the diagnosis of BD-II is not made. Although ICD-10 does not provide criteria for diagnosing BD type II, establishing this diagnosis is possible under the category F31.8 "Other bipolar affective disorders". Unipolar mania occurs in 5–10% of BD cases and, in accordance with ICD-10, should be diagnosed as unspecified bipolar affective disorder.

When diagnosing BD, it is necessary to specify the current episode. ICD-10 provides the following diagnostic options within BD:

F31.0 Bipolar affective disorder, current episode hypomanic

A. The current episode meets the criteria for hypomania (F30.0)

B. There has been at least one other affective episode in the past (hypomanic, manic, depressive, or mixed)

F30.0 Hypomania

A. A persistent mild elevation of mood or irritability, which is clearly abnormal for the individual concerned and persists for at least 4 consecutive days.

B. At least three symptoms from the following must be present, interfering with personal functioning in daily life:

a. increased activity or physical restlessness;

b. increased talkativeness;

c. difficulty in concentration or distractibility;

d. decreased need for sleep;

e. increased sexual energy;

f. mild overspending or other types of reckless or irresponsible behavior;

g. increased sociability or overfamiliarity.

B. The disorder does not meet the criteria for mania (F30.1 and F30.2), depressive episode (F32.-), cyclothymia (F34.0), or anorexia nervosa (F50.0).

G. Most commonly used exclusion criteria:

The episode cannot be attributed to psychoactive substance use (F10-F19) or any organic mental disorder meeting the criteria of F00-F09 according to ICD-10.

F31.1 Bipolar affective disorder, current episode mania without psychotic symptoms

A. A current episode meeting the criteria for mania without psychotic symptoms (F30.1).

B. In the past, at least one other affective episode meeting the criteria for a hypomanic or manic episode (F30.-), a depressive episode (F32.-), or a mixed affective episode (F38.00).

F30.1 Mania without psychotic symptoms

A. A predominantly elevated, expansive, irritable, or suspicious mood that is abnormal for the individual. This mood change must be prominent and persist for at least one week (unless severe enough to warrant hospitalization).

B. At least three of the following symptoms must be present (four if the mood is merely irritable), leading to severe disruption of personal functioning in daily life:

a. increased activity or physical restlessness;

b. increased talkativeness ("pressure of speech");

c. flight of ideas or subjective experience of racing thoughts;

d. loss of normal social inhibitions, resulting in behavior that is inappropriate to the circumstances;

e. decreased need for sleep;

f. inflated self-esteem or grandiosity;

g. distractibility or constant changes in activity or plans;

h. reckless or irresponsible behavior, the consequences of which are unrecognized by the patient, such as spending sprees, foolish business ventures, or reckless driving;

i. marked increase in sexual energy or sexual indiscretion.

C. No hallucinations or delusions are present, although perceptual disorders may occur (e.g., subjective hyperacusis, colors perceived as especially vivid).

D. Most commonly used exclusion criteria. The episode cannot be explained by psychoactive substance use (F10-F19) or any organic mental disorder meeting the criteria of F00-F09 according to ICD-10.

F31.2 Bipolar affective disorder, current episode mania with psychotic symptoms

A. A current episode meeting the criterion for mania with psychotic symptoms (F30.2).

B. In the past, at least one other affective episode meeting the criteria for a hypomanic or manic episode (F30.-), a depressive episode (F32.-), or a mixed affective episode (F38.00).

F30.2 Mania with psychotic symptoms

A. The episode meets the criteria for mania without psychotic symptoms (F30.1), except for criterion B.

B. The episode does not simultaneously meet the criteria for schizophrenia (F20.0-F20.3) or schizoaffective disorder, manic type (F25.0).

C. Delusions or hallucinations are present, other than those listed as typical for schizophrenia in criteria F20(a), (b), and (c).

G. Most frequently used exclusion criteria. The episode cannot be attributed to psychoactive substance use (F10-F19) or any organic mental disorder (in the sense of F00-F09).

Delusions and hallucinations can be classified as mood-congruent or mood-incongruent. "Incongruent" includes affectively neutral delusional and hallucinatory disorders, for example: delusions of reference without feelings of guilt or blame, or voices talking to the patient about events that have no emotional significance.

F31.3 Bipolar affective disorder, current episode of mild or moderate depression⁺

⁺Note. Unfortunately, the criteria for a depressive episode in bipolar disorder (BD) and major depressive disorder (MDD) do not differ, although there are obvious clinical features and differences. Compared to MDD-associated depression, BD-associated depression is more commonly characterized by features such as earlier onset (under 25 years) or onset in the postpartum period, acute onset of symptoms (days or hours) and their rapid resolution, atypical depression features with hyperphagia, hypersomnia, inverted circadian rhythm, etc., presence of psychotic symptoms, protracted course, and low sensitivity to antidepressant (AD) therapy.

A. Current episode meeting the criteria for a depressive episode (F32) of either mild (F32.0) or moderate severity (F32.1).

B. At least one affective episode in the past meeting the criteria for a hypomanic or manic episode (F30.-), or a mixed affective episode (F38.00).

F32. Depressive episode

A depressive episode (DE) must last for at least two weeks. The episode cannot be attributed to psychoactive substance use (F10-F19) or any organic mental disorder (F00-F09).

Certain depressive symptoms of particular clinical significance are designated as "somatic" (other classifications use terms such as biological, vital, melancholic, or endogenomorphic for these syndromes).

To establish a somatic syndrome, four of the following symptoms must be present:

a. Loss of interest or pleasure in activities normally pleasurable to the patient;

b. Lack of emotional reactivity to events or activities that normally produce an effect;

c. Waking in the morning two or more hours earlier than usual;

d. Depression worse in the morning;

e. Objective evidence of marked psychomotor retardation or agitation (observed or described by others);

f. Marked loss of appetite;

g. Weight loss (five percent or more of body weight in the past month);

h. Marked loss of libido.

F32.0 Mild depressive episode

A. Meets general criteria for a depressive episode (F32).

B. At least two of the following three symptoms:

a. depressive mood to a degree clearly abnormal for the patient, present for most of the day, almost every day, largely uninfluenced by circumstances, and lasting for at least two weeks;

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

c. reduction in energy and increased fatigability.

C. Additional symptom(s) from the following (to a total of at least four):

a. loss of confidence and self-esteem;

b. unreasonable feelings of self-reproach or excessive and inappropriate guilt;

c. recurrent thoughts of death or suicide, or any suicidal behavior;

d. complaints or evidence of reduced ability to think or concentrate, such as indecisiveness or vacillation;

e. change in psychomotor activity, with agitation or retardation (subjective or objective);

f. sleep disturbance of any type;

g. change in appetite (decrease or increase) with corresponding weight change.

F32.00 without somatic symptoms

F32.01 with somatic symptoms

F32.1 Moderate depressive episode

A. Meets general criteria for a depressive episode (F32).

B. At least two of the three symptoms in criterion B of F32.0.

C. Additional symptoms from criterion C of F32.0, making a total of at least six symptoms.

F32.10 without somatic syndrome

F32.11 with somatic syndrome

F31.4 Bipolar affective disorder, current episode of severe depression without psychotic symptoms

A. Current episode meeting the criteria for a severe depressive episode without psychotic symptoms (F32.2).

F32.2 Severe depressive episode without psychotic symptoms

Note: If prominent symptoms such as agitation or retardation are present, the patient may be unable or unwilling to give a detailed report of many symptoms. In such cases, an overall categorization of the episode as severe may still be justified.

A. Meets general criteria for a depressive episode (F32).

B. All three symptoms in criterion B of F32.0.

C. Additional symptoms from criterion C of F32.0, to a total of at least eight symptoms.

D. Absence of hallucinations, delusions, or depressive stupor.

B. At least one well-documented hypomanic, manic (F30.-), or mixed affective episode (F38.00) in the past.

F31.5 Bipolar affective disorder, current episode of severe depression with psychotic symptoms

A. Current episode meeting the criteria for a severe depressive episode with psychotic symptoms (F32.3).

B. At least one well-documented hypomanic, manic (F30.-), or mixed affective episode (F38.00) in the past.

F32.3 Severe depressive episode with psychotic symptoms

A. Meets general criteria for a depressive episode (F32).

B. Meets criteria for a severe depressive episode without psychotic symptoms (F32.2), except for criterion D.

C. Criteria for schizophrenia (F20.0-F20.3) or schizoaffective disorder, depressive type (F25.1) are not met.

Any of the following must be present:

delusions or hallucinations, other than those listed as typically schizophrenic in criterion G1.1 (b), (c), and (d) for F20.0-F20.3 (i.e., delusions other than those completely implausible in content or culturally inappropriate, and hallucinations that do not discuss the patient in the third person or provide a running commentary); most frequent examples include depressive delusions, delusions of guilt, reference, hypochondriacal, nihilistic, or persecutory content; depressive stupor.

F31.6 Bipolar affective disorder, current episode mixed

A. The current episode is characterized by either mixed or rapidly alternating (over a few hours) hypomanic, manic, and depressive symptoms.

B. Both manic and depressive symptoms must be prominent for the majority of a period lasting at least two weeks.

C. Presence in the past of at least one well-documented hypomanic or manic episode (F30.-), depressive episode (F32.--), or mixed affective episode (F38.00).

F38.00 Mixed affective episode

An affective episode lasting for at least 2 weeks and characterized by either mixed or rapidly alternating (usually over a few hours) hypomanic and depressive symptoms.

F31.7 Bipolar affective disorder, currently in remission

A. The current state does not meet the criteria for depression or mania of any severity, or other mood disorders in F30-F39 (possibly due to therapy aimed at reducing the risk of future episodes).

B. In the past, at least one well-documented hypomanic or manic episode (F30.-) and also at least one other affective episode (hypomania or mania) (F30.-), depressive (F32.-), or mixed (F38.00).

F31.8 Other bipolar affective disorders

F31.9 Bipolar affective disorder, unspecified

Based on the clinical course variants of BD, alternating, continual, and rapid-cycling (RC) types are distinguished (including ultrarapid and ultra-ultrarapid cycling).

1. Alternating course — characterized by the onset of a euthymic period

following the next affective phase. Affective phases typically develop autochthonously and tend to resolve spontaneously. The intermission following the resolution of the phase is characterized by a euthymic mood and the emergence of insight into the past illness episode. Social maladaptation in patients is primarily determined by the frequency of developing relapses, their duration, and severity [1].

2. Continual course — absence of intermissions, continuous alternation of

phases. An alternating course may transition into a continual one due to spontaneous worsening of the disease or incorrect pharmacotherapy [1,28]. Even with such an unfavorable course of the disease, the establishment of fairly long euthymic periods is sometimes possible [22,23].

3. Rapid-cycling course (RC) — one of the most unfavorable variants of the disease course, defined by the development of at least 4 affective phases within one year [24, 25].

4. Ultrarapid cycles — development of 4 or more affective phases within

one month [25].

5. Ultra-ultrarapid cycles, occurring within a single day, which

virtually impossible to distinguish from a persistent, highly unstable mixed affective state [26,299].

These variants, along with the clinically similar alternating variant of a mixed affective state and mixed mania, are fairly typical phase manifestations in a continuous course, indicating an unfavorable disease prognosis; they are difficult to treat. Rapid cycling is more common in women, and its occurrence is associated with early onset of the disease, alcohol abuse, hypothyroidism, the influence of female sex hormones, and antidepressant use [27,299].

1.6 Clinical presentation of the disease or condition

BD is a chronic, relapsing psychiatric disorder of the affective sphere, often leading to impaired behavior and social functioning, the main feature of which is the development of manic or hypomanic states. In addition to polar (manic and depressive) phase periods of pathologically altered mood, motor and ideational activity, and energy tone, the disease can be accompanied by a wide range of psychopathological disorders, including psychotic hallucinatory-delusional symptoms, catatonic symptoms, and cognitive impairments (e.g., impairments of attention and reaction time, auditory and visual memory, executive functions, perception of the passage of time, etc.). Usually, this additional productive symptomatology is congruent with the dominant affect and is limited to the duration of the phase, i.e., it disappears completely with the normalization of mood. However, some residual affective symptoms and especially cognitive impairments can persist in remission, being the main cause of social and occupational maladaptation and disability. Affective phases of different poles, having varying degrees of severity and typology (mania, depression, mixed states, affective-delusional formations) can resolve spontaneously with the formation of intermissions characterized by euthymic mood and full insight into the experienced episode of illness. Along with mood and behavior disorders, disorders of other spheres of mental activity (e.g., cognitive, perception) as well as neurovegetative symptoms (sleep, appetite, circadian rhythm, and energy balance disturbances, etc.) are frequently observed in BD. During different periods of the disease, the presence and severity of these symptoms can vary significantly [28,29,32].

In more than half of BD patients, psychotic symptoms are detected at various stages of the disease. In 65%, comorbid disorders are diagnosed (most commonly substance abuse or anxiety disorders) [26,273]. Panic symptoms in BD are observed more frequently than in recurrent depression and can significantly prolong the phase [9]. The risk of developing alcohol dependence is 6–7 times higher than in the general population [8], with this risk being 3 times higher in men and 7 times higher in women [30].

Comorbidity with somatic diseases is observed no less frequently (most commonly cardiovascular pathology, diabetes, obesity, and thyroid dysfunction). Such patients also often exhibit a lack of volitional effort and motivation to combat somatic risk factors, which ultimately leads to an increase in overall morbidity and mortality in the BD patient population [31,379,380,393].

2. Diagnostics, medical indications and contraindications for diagnostic methods

BD Diagnostic Algorithm (Appendix B)

Diagnostic Criteria

The diagnosis of BD is established solely on the basis of clinical features. BD (F31) is a chronic relapsing disease belonging to the category of affective mental disorders. BD is characterized by repeated (at least two) episodes in which mood and activity levels are significantly disturbed. Throughout the patient's lifespan, BD manifests with various symptom complexes: mania, depression, mixed states, intermissions, comorbid disorders, and psychotic symptoms, which frequently join the primary affective symptoms characteristic of BD. Psychotic symptoms, which, especially during mania, combined with psychomotor agitation, make it difficult to recognize the affective-delusional structure of the syndrome, often lead to a misdiagnosis of "schizophrenia" and inadequate therapy.

Acute episode symptoms generally resolve completely during periods of remission. Patients suffering from repeated episodes of mania are rare. They should be classified as bipolar (F31.8 Other bipolar affective disorders. Recurrent manic episodes).

Factors complicating the diagnostic process include the frequent (65% of cases) comorbidity of BD with other disorders, especially anxiety disorders, concomitant substance use dependence [207], as well as the delayed appearance of manic or hypomanic symptoms in patients with recurrent depressive phases.

Timely diagnosis of BD, which determines correctly prescribed therapy, is especially important, given also that the rate of parasuicides in mixed and depressive episodes reaches 25–50% [268,280]. Misdiagnosis or delayed detection of BD seriously worsens the prognosis of the disease, leads to a heavier course and the development of comorbid disorders, including substance abuse [207,273]. The duration of euthymic periods in BD is inversely related to the number of episodes experienced. The functional capacity of patients progressively worsens as the number of BD episodes increases. In particular, this is associated with a possible intensification of brain neurodegenerative processes as the disease progresses, supported by the presence of cognitive deficits detected in BD patients during euthymia and increasing with the number of experienced disease episodes [261,266,358,359,368]. Early sustained remission provides a higher level of psychosocial activity and a longer euthymic period in the future. Early diagnosis, and therefore early pharmacological intervention, can modify the spontaneous course of the disease.

2.1 Complaints and Anamnesis

Level of Evidence - 4, Grade of Recommendation - C.

- evaluate whether the patient's symptoms meet the diagnostic criteria for depressive, manic, or mixed episodes;

- assess the risk of danger to oneself and/or others;

- obtain anamnestic data or medical documentation regarding the presence of at least two episodes of opposite polarity throughout the course of the illness;

- gather anamnestic data on the presence of trauma, infectious diseases of the brain, and somatic diseases directly preceding the development of affective symptoms;

- conduct a targeted interview with the patient and family members to rule out the use of psychoactive substances or medications that can cause manic or depressive symptoms by the patient immediately prior to the onset of the current affective episode [32, 33].

Level of Evidence - 4, Grade of Recommendation - C.

Level of Evidence - 2, Strength of Recommendation - B.

- conduct a thorough, targeted clinical interview with the patient aimed at identifying a history of hypomania [32-36];

- collect collateral information from the patient's family and close contacts to identify possible past hypomanic states [32 - 37, 305, 310];

Level of evidence - 2, Strength of recommendation - B.

2.2 Physical Examination

- examination of the skin to detect injection marks in order to rule out the use of psychoactive substances or medications that can cause manic or depressive symptoms [32, 34];

- assessment of abnormal involuntary movements and muscle hypertonia to rule out extrapyramidal side effects of antipsychotic therapy [20, 37];

Level of Evidence — 5, Strength of Recommendation — C.

2.3 Laboratory Diagnostics

There are no instrumental diagnostic methods specifically for bipolar disorder.

Level of Evidence - 4, Strength of Recommendation - C.

Level of Evidence - 3, Strength of Recommendation - C.

Comments: Thyroid hormone screening (FT3, TSH) should be performed in treatment-naive patients who have never undergone this test before, in the presence of clinical or anamnestic indications, or when the patient is receiving lithium salts [32, 264, 265].

Level of Evidence - 4, Grade of Recommendation - C.

2.4 Instrumental Diagnostics

There are no instrumental diagnostic methods specifically for bipolar disorder.

- ECG

- EEG

- Brain MRI (preferred) / Brain CT

Level of evidence - 5, Grade of recommendation – C.

Comments: Brain MRI or brain CT and EEG are performed for patients who have never undergone these examinations before, or in the presence of clinical or anamnestic indications.

- measurement of blood pressure on peripheral arteries

- measurement of waist circumference and body mass index calculation.

Level of Evidence - 4, Grade of Recommendation - C.

- ECG

- measurement of blood pressure on peripheral arteries

- measurement of waist circumference and body mass index calculation

Level of Evidence — 5, Strength of Recommendation — C.

Comments: performing brain MRI or brain CT and EEG is advisable for patients who have never undergone these examinations before, or in the presence of clinical or anamnestic indications.

2.5 Other Procedures

Psychometric diagnostics

Level of Evidence - 4, Strength of Recommendation - C.

Level of Evidence — 5, Strength of Recommendation — C.

Level of Evidence — 5, Strength of Recommendation — C.

Level of Evidence — 5, Strength of Recommendation — C.

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

3.1 Tactics and stages of pharmacotherapy for manic states (MS) (Appendix B)

3.1.1 Acute Mania Therapy

First-line therapy

Level of Evidence - 1, Strength of Recommendation - A.

Comment: In the treatment of bipolar disorder, to achieve the most rapid relief of acute psychopathological symptoms and subsequent maintenance of the euthymic period, all patients must complete three mandatory stages: acute therapy, continuation (maintenance) therapy, and prophylactic (relapse-prevention) therapy [1, 32].

The treatment strategy for manic states (MS) in bipolar disorder (BD) is built taking into account the subsequent maintenance phase. Step-by-step resolution of MS should be performed according to severity (mild, moderate, severe) and the type of manic syndrome: cheerful (euphoric) mania, dysphoric mania, mania with psychotic features (manic-delusional state) [1, 32].

The choice of therapy for the management of MS is determined not only by the pharmacodynamic profiles of various drug groups, but also by their tolerability. The therapeutic efficacy can be significantly increased by following specific methodological rules of administration. Adequate dosing, dynamic and timely modification of therapy allow for rapid symptom resolution and prevent the prolongation of the episode. It should also be borne in mind that prescribing a medication for maintenance mood-stabilizing therapy (lithium preparations, antiepileptic drugs, second-generation antipsychotics (SGAs) (except for lurasidone**, which is not approved for medical use in the treatment of MS) should be initiated sufficiently early and "overlapped" with the initial phase of acute treatment, since the prophylactic effect of these drugs develops relatively slowly [1, 32, 43].

The use of SGAs is preferable to first-generation antipsychotics (FGAs) in most cases, primarily due to their better tolerability (less pronounced sedation, lower risk of extrapyramidal symptoms (EPS), lower risk of hyperprolactinemia, lower depressogenic effect, and lower risk of phase inversion). Furthermore, it is known that in patients with affective disorders, EPS develop several times more frequently when using FGAs than in patients with schizophrenia, which necessitates the addition of anticholinergic agents [1, 32].

Treatment goal: achieving remission (for a more precise psychometric definition of remission, the Young Mania Rating Scale (see Appendix G3) can be used, according to which symptom severity should not exceed 10-12 points).

Treatment objectives:

- rapid resolution of manic symptoms as quickly as possible

- rapid control of psychomotor agitation and aggressiveness

- prevention of the development or worsening (in mixed states) of depressive symptoms

- selection of drugs taking into account individual tolerability for subsequent long-term prophylactic administration.

The treatment plan for manic states is formulated based on the analysis of the patient's status, medical history, and the dominant polarity of the course of the disease.

Level of evidence - 1, grade of recommendation – A

− valproic acid**,

− carbamazepine** [37, 41, 42, 56, 57-60]

Level of evidence - 1, grade of recommendation - A

- or SGA [32, 44- 55]

Level of evidence — 2, strength of recommendation — A

Comment. The choice of acute therapy drug should be made taking into account the subsequent maintenance phase of therapy and the patient's individual tolerability of the selected medicinal product during long-term use. Valproic acid** is preferred over lithium carbonate (valproic acid** does not require regular plasma concentration monitoring and has a more favorable side effect profile) [1,2,22,32,37,44,56,381]. Other antiepileptic drugs (carbamazepine**, #oxcarbazepine**, #topiramate**, #gabapentin) and calcium channel blockers can be used for alternative therapy [1,21,32,37,40,44,56,147,148]. Haloperidol** administration at the first stage of manic syndrome management should be avoided, except for cases of pronounced psychomotor agitation and/or severe irritability and aggressiveness [1,32,37,40,44,56].

Dosing regimen for #oxcarbazepine**: the initial dose is 600 mg/day (8 - 10 mg/kg of body weight per day), divided into two doses. The dose is increased by no more than 600 mg/day at intervals of approximately 1 week until the desired therapeutic effect is achieved. The dose range is 600 - 1200 mg/day [1,57].

Dosing regimen for #topiramate**: The minimum effective dose is 200 mg/day. Usually, the total daily dose ranges from 200 mg to 400 mg and is taken in 2 doses. Some patients may require an increase in the daily dose to a maximum of 1600 mg. At the beginning of treatment, a low dose should be used followed by a gradual titration to an effective dose. Dose titration starts with 25-50 mg taken at bedtime for 1 week. Subsequently, at intervals of 1-2 weeks, the dose can be increased by 25-50 mg and taken in 2 doses. When titrating the dose, one should be guided by the clinical effect. In some patients, the effect may be achieved with once-daily administration [1,147,148,284,285].

Dosing regimen for #gabapentin: the effective dose ranges from 900 to 4800 mg/day. Therapy can be initiated according to the following schedule: #Gabapentin is prescribed at a dose of 300 to 900 mg/day, usually twice daily, although a single dose at bedtime is also possible. Subsequently, doses of #gabapentin are increased by 300-900 mg/day every 3-14 days depending on efficacy and tolerability up to a maximum dose of 4800 mg/day. Doses above 1500 mg/day should be divided into two doses per day (morning and evening) [147, 215, 371, 372].

Level of evidence — 5, strength of recommendation — C

Comments: The antimanic effect of treatment with lithium carbonate is higher at a concentration of 0.8–1.0 mmol/l [61], which should be checked once a week during dose titration. Therefore, inefficacy of a course of lithium carbonate can only be concluded once the therapeutic plasma concentration range of the drug has been reached. In addition, it should be kept in mind that the effect of lithium carbonate in manic syndrome is achieved no earlier than 7–10 days of therapy.

Level of evidence — 1, strength of recommendation — A. Comments. During the first few days, the intramuscular (IM) route of administration is preferred [1, 32].

Level of evidence — 5, strength of recommendation — C

Comment. Preference should be given to benzodiazepine derivatives with a short half-life (#lorazepam**, #midazolam**), while taking into account the potential for respiratory depression (especially with diazepam**), the muscle relaxant effect, and the accumulation effect of drugs with a long half-life (bromdihydrochlorophenylbenzodiazepine**, diazepam**) [32].

Dosing schedule for #lorazepam** (for oral administration): initial dose — 2–4 mg/day, divided into 1–3 doses [288,289,290,304,376] until psychomotor agitation is resolved.

Level of evidence — 5, strength of recommendation — C

 Comment.  The recommended dose of #ziprasidone is 40 mg twice daily [52]. If necessary, the daily dose may be increased to the maximum within 3 days. The maximum daily dose is 160 mg (80 mg twice daily) [52, 53].

Level of evidence — 5, strength of recommendation — C

Level of evidence — 5, strength of recommendation — C

Comment. The minimum effective dose of #topiramate** is 200 mg/day. Usually, the total daily dose ranges from 200 mg to 400 mg taken in 2 divided doses. Some patients may require an increase in the daily dose up to a maximum of 1600 mg. Treatment should be initiated with low doses, followed by a gradual titration to an effective dose. Dose titration starts with 25-50 mg taken at night for 1 week. Subsequently, at intervals of 1-2 weeks, the dose can be increased by 25-50 mg and taken in 2 divided doses. Dose titration should be guided by the clinical response. In some patients, the effect may be achieved with a once-daily dosing regimen [32, 147, 148, 284, 285].

#Clozapine should be used only if the white blood cell count and absolute neutrophil count are within normal limits prior to treatment. In addition, during treatment, it is necessary to regularly perform a complete blood count (full blood count) and monitor white blood cells and absolute neutrophil counts. The dose of the drug is determined individually. For oral administration, a single dose is 50-200 mg, and the daily dose is 200-400 mg. Treatment is usually started with a dose of 25-50 mg, then gradually increased by 25-50 mg per day up to 200-300 mg/day over 7-14 days. The daily dose can be administered once at bedtime or 2-3 times a day after meals. When discontinuing treatment, the dose should be tapered gradually over 1-2 weeks [32, 147, 286, 287].

Therapeutic strategies for pharmacotherapy-resistant manic episodes

Level of evidence — 5, strength of recommendation — C

Comment. #Nifedipine** is prescribed orally at an initial dose of 20 mg/day. If necessary, the dose is gradually increased to 20 mg 3 times/day. For oral #verapamil**, the initial dose is 160 mg/day or 80 mg twice daily. If efficacy is insufficient, the dose is increased to 240 mg/day 3 times a day under tolerability monitoring [375].

ECT should be performed 3 times a week until manic symptoms are resolved. Usually, three to six ECT sessions are performed [23, 299, 382, 383]. If the patient was receiving antiepileptic drugs, they should be discontinued for the duration of ECT. When performing plasmapheresis, discontinuation of therapy is not required. A manic episode is considered resistant if symptoms do not resolve after 6-10 ECT sessions [23, 32, 37, 40, etc.]. High-frequency TMS is usually applied to the right dorsolateral prefrontal cortex (DLPFC) concurrently with prescribed drug therapy [312-314]. The doses of calcium channel blockers must be titrated with close monitoring of tolerability and efficacy

3.1.2 Maintenance (outpatient) therapy for manic states

Level of Evidence - 5, Strength of Recommendation - C.

Level of evidence — 5, grade of recommendation — C

Level of evidence — 5, strength of recommendation — C

Level of evidence — 5, strength of recommendation — C

Level of evidence — 5, strength of recommendation — C

3.1.3 Management of patients with manic states presenting with marked psychomotor agitation and aggressiveness

Agitation and aggressive manifestations are quite frequently a separate challenge in the treatment of patients with irritable mania, mixed mania, and mania with psychotic features. Aggression in manic patients is usually directed at random individuals and may be unmotivated or provoked by minor factors: remarks made, restrictions, or unfriendly glances. Conflicts related to refusing to comply with inappropriate demands of a patient with a manic state can also act as a triggering factor. At the same time, aggression in psychotic mania develops within the context of disorganized behavior and may be driven by perceptual disturbances or delusional symptoms. Unlike patients with schizophrenia, manic patients retain a high risk of aggression in the inpatient setting after hospitalization.

Level of Evidence — 5, Strength of Recommendation — C.

Comments: De-escalation techniques comprise multiple components simultaneously. First and foremost, they involve continuous risk assessment and situational control with the creation of a safe environment around the patient. Essential conditions include maintaining a safe distance for both the patient and staff, avoiding provocations and coercion, showing a respectful attitude and empathy, and identifying the patient's needs. Attempts to distract the patient, reframe the situation, establish verbal contact, negotiate, and persuade are also necessary [62 - 64].

Level of Evidence - 2, Strength of Recommendation - B.

Level of Evidence — 5, Strength of Recommendation — C.

Comments: In mild agitation and with patient compliance, oral formulations of medications with a sedative component may be preferred. In this case, benzodiazepine derivatives (primarily #lorazepam**), #promethazine, and antipsychotics demonstrate comparable efficacy in the treatment of agitation and aggression [69, 70]. At this stage of therapy, the patient requires hourly observation [69, 70, 71].

Regimen for #lorazepam** (oral): initial dose 1-2 mg/day, divided into 1-3 doses. The dose may be gradually increased up to a maximum of 10 mg/day [288, 376, 392]. Regimen for #promethazine: when administered intramuscularly, care should be taken to avoid accidental subcutaneous injection, which may cause tissue necrosis at the injection site. The usual recommended dose is 25-50 mg deep intramuscularly [275, 276, 294, 306, 391].

Level of evidence — 5, Grade of recommendation — C. Comment:   Parenteral formulations of AVP are not inferior in efficacy to the intramuscular formulation of haloperidol**, but cause fewer neurological side effects [76-81,276].

Therapeutic approaches for agitation and aggression must be differentiated. Manifestations of aggression, as well as conditions with a high risk of its development, require urgent therapeutic measures. These include rapid tranquilization (RT), and if necessary, physical restraint or isolation [62,81,82,83]. Along with this, behavioral therapy techniques should be used. In cases of mild aggression (verbal aggression, etc.), RT may not be advisable. Performing RT requires skills in assessing the risks associated with the potential achievement of deep sedation (development of arterial hypotension and respiratory depression) [62,83]. It is also advisable to have technical equipment necessary for emergency care in case of side effects, including the availability of flumazenil (an antidote, acting as a benzodiazepine receptor antagonist) [83].

At the beginning of therapy, drugs should be prescribed at the lowest effective doses, which can be gradually increased if necessary. More severe forms of agitation require parenteral therapy (Appendix B) [62,81]. When arresting agitation, it is desirable to achieve a therapeutic effect at the level of calming or mild sedation. If necessary, in cases of severe refractory agitation with manifestations of aggression, achieving deep sedation or even anesthesia is permitted [62,84,85]. The use of RT to control agitation is considered a last-line measure [62,83,85]. However, in extremely severe agitation associated with risks of aggression, it should be used immediately.

Level of evidence - 2, Strength of recommendation - B.

Comment: When using this combination, the increased risk of side effects must be taken into account, requiring continuous patient monitoring. Combinations of haloperidol** with benzodiazepine derivatives are usually used — primarily #lorazepam** (orally 2–4 mg/day) or #promethazine [75,83,276,289,290,294,306,376].

Administration schedule for #promethazine: caution should be exercised with intramuscular administration to avoid accidental subcutaneous injection, which can cause tissue necrosis at the injection site. The usual recommended dose is 25–50 mg deep intramuscularly [276,278,294,306].

Combined use of intramuscular benzodiazepine derivatives with #clozapine should be avoided [86] due to the risk of respiratory failure.

Combined use of intramuscular olanzapine** and benzodiazepine derivatives [77,78] should be avoided due to the increased risk of sudden death.

Level of evidence - 2, Strength of recommendation - B.

Comment: Among benzodiazepine derivatives, diazepam** and bromdihydrochlorphenylbenzodiazepine** are used for intravenous administration, and among antipsychotics — haloperidol**, chlorpromazine**, and #droperidol**.  When using intravenous #droperidol** (2.5–10 mg/day) and some other antipsychotics, ECG monitoring is strictly mandatory due to the risk of QT interval prolongation [84,87,88,270,279,281]. When using the intravenous route, the drip method is preferred. Intravenous administration requires continuous bedside staff supervision, ECG, blood pressure measurement on peripheral arteries, and pulse oximetry [84,85,307]. These requirements are feasible in an intensive care unit setting.

Level of Evidence — 5, Strength of Recommendation — C.

Comment: In this case, further management of the patient is carried out in a psycho-intensive care unit. Additional examination of the patient is advisable to potentially clarify the diagnosis. One of the main therapeutic options is the use of ECT, especially in the presence of affective symptoms, catatonic symptoms, and a history of a good response to it in the past [86]. As alternative therapeutic options, the possibility of using dexmedetomidine and #ketamine** should be considered [89,90].

Comment. #Ketamine is administered as a single intramuscular injection at a dose of 4 mg/kg of calculated body weight intramuscularly to calm aggressive and agitated patients [89].

3.2 Tactics and stages of pharmacotherapy for bipolar depression (BD) (Appendix B)

First-line therapy

 Level of evidence — 2, Grade of recommendation — C.

 Comment:     The goal of therapy is to achieve remission (for a more precise psychometric definition of remission, the Hamilton Depression Rating Scale (Appendix G3) can be used, according to which symptom severity should not exceed 7 points, or the Montgomery-Åsberg Depression Rating Scale (Appendix G5), according to which remission is defined as a symptom score below 10).

Tasks of therapy:

- rapid relief of depressive symptoms

- prevention of suicide attempts

- prevention of phase inversion (development of manic symptoms)

The BD therapy plan is based on the analysis of the patient's clinical status, medical history, and the dominant polarity of the disease course.

When deciding on inpatient or outpatient treatment, it is important to consider:

- severity of condition

- suicidal risk

- presence or absence of psychotic symptoms

- anamnestic data

- microsocial environment conditions and the degree of involvement of close relatives in the therapeutic process.

Hospitalization is mandatory in the presence of suicidal risk and/or psychotic symptoms.

Therapeutic tactics for depressive phases in bipolar I and bipolar II disorder do not differ significantly, however, the choice of drug is made taking into account:

- predominant polarity of affect in the course of the disease

- severity of the condition and clinical variant of depression

- presence/absence of mixed features

- efficacy of a particular drug in relieving previous depressions, as well as the risk of phase inversion

In all cases of MD treatment, it is advisable to avoid prescribing TCAs and classical neuroleptics (antipsychotics) [100–102,386,388].

When combining anticonvulsants (antiepileptic drugs), drug interactions at the level of liver enzymes must be considered. Thus, valproic acid** increases the serum concentration of lamotrigine, therefore it is necessary to adjust the dosage of the latter and use a slower titration. #Carbamazepine** accelerates clearance, decreases the concentration of valproic acid* in the blood, and potentiates hepatotoxicity, making this combination undesirable [1,32,316].

Level of evidence - 3, strength of recommendation - C

Comments. In mild depressions, such therapy adjustment is often sufficient to achieve an effect. The most important factor for success in managing patients with mild and moderate depression is also the rapid normalization of sleep disturbances and correction of chronobiological disorders [387].

3.2.1 Treatment strategy for bipolar depression type 1 without psychotic symptoms

First-line therapy for bipolar depression type 1 without psychotic symptoms

- quetiapine** [95,101,108,109]

Level of evidence - 1, strength of recommendation - A

- cariprazine** [118 - 120, 354, 360-363,396]

Level of evidence - 2, strength of recommendation - A

- lurasidone** [115,116]

Level of evidence - 3, strength of recommendation - B

- combination of lurasidone** with #lithium carbonate or valproic acid** [115].

Level of evidence - 2, strength of recommendation - B

Comment. If the patient is already receiving mood-stabilizing therapy for prophylactic purposes, the depression is managed against the background of this ongoing mood-stabilizing therapy. #Lithium carbonate dosing regimen: the dose is determined by the plasma concentration of lithium. The therapeutic plasma concentration of lithium is 0.6–1.0 mmol/L. Administered orally; for adults, the dose is 300–600 mg 3 times a day. The plasma lithium concentration should not exceed 1.2 mmol/L [291,296].

Therapy strategies for bipolar I disorder without psychotic symptoms when first-line therapy is ineffective

Level of evidence - 1, strength of recommendation - A

Level of evidence - 2, strength of recommendation - C

Comment: Among mood-stabilizing agents, taking into account the subsequent prophylactic phase of therapy, preference should be given to valproic acid** if manic phases predominate in the disease course, and to lamotrigine if depressive phases predominate [113,121-124]. The evidence base for #carbamazepine** is weaker [1, 125-127], and its use in bipolar disorder is justified only if the patient is already taking this drug as prophylactic therapy [37,127]. #Carbamazepine** dosing regimen: treatment initiation at 200 mg/day with a subsequent increase in dose based on efficacy and tolerability up to 600–1200 mg/day [127,243].

- valproic acid** [117,122,123]

Level of evidence - 1, strength of recommendation - A

- #lithium carbonate [95,296]

Level of evidence - 2, strength of recommendation - B

Comment: #lithium carbonate dosing regimen: the dose is determined by the plasma concentration of lithium. The therapeutic plasma concentration of lithium is 0.6–1.0 mmol/L. Administered orally; for adults, the dose is 300–600 mg 3 times a day. The plasma lithium concentration should not exceed 1.2 mmol/L [1,296].

- lamotrigine [95,113,114,124]

Level of evidence - 1, strength of recommendation - B

Comment: The starting dose of lamotrigine is 25 mg/day. The dose is increased weekly by 25 mg until reaching 200 mg/day.

- combination of valproic acid** with an antidepressant from the SSRI group [128]

Level of evidence - 1, strength of recommendation - B

- combination of #lithium carbonate with an antidepressant from the SSRI group [128]

Level of evidence - 1, strength of recommendation - B

- combination of an atypical antipsychotic with an antidepressant from the SSRI group [128]

Level of evidence - 1, strength of recommendation - B

- combination of #olanzapine** with fluoxetine** [129,130,297]

Level of evidence - 2, strength of recommendation - B

Comment: Dosing regimen for the combination of #olanzapine** and fluoxetine**: the starting dose is 5 mg of #olanzapine** and 20 mg of fluoxetine** per day [130,297]. Lower starting doses should be used in patients prone to hypotension or with a potentially slow metabolism. Dosage increases are made depending on efficacy and tolerability. The safety of doses higher than 18 mg of #olanzapine** in combination with 75 mg of fluoxetine** has not been studied [297].

ECT [131].

Level of evidence - 2, strength of recommendation - A

Comment: Data confirm the efficacy of brief pulse right unilateral placement, although data are insufficient to decide on unilateral or bilateral electrode placement for ECT in bipolar depression [131].

- #aripiprazole [132, 133]

Level of evidence - 4, strength of recommendations - C

Comment: The starting dose of #aripiprazole is 5-10 mg/day, usually at bedtime, and over the course of a week, depending on response and tolerability, the dose is gradually increased by 5-10 mg/day to a maximum dose of 30 mg/day.

- #carbamazepine** at doses of 400-1000 mg/day [1,2,57,125,127,186,367]

Level of evidence — 5, strength of recommendation — C

- eicosapentaenoic acid (dietary supplement) [134-136,377,378]

Level of evidence - 1, strength of recommendations - A

Comment: Eicosapentaenoic acid is one of several omega-3 polyunsaturated fatty acids (omega-3 triglycerides); doses range from 2 to 6 g/day. It is important that the prescribed dietary supplement is included in the unified register of specialized food products (Decision of the Customs Union Commission dated 09.12.2011 No. 880 (as amended on 22.04.2024) "On the adoption of the technical regulation of the Customs Union 'On food safety'" (together with "TR CU 021/2011. Technical regulation of the Customs Union. On food safety"))

- phototherapy [139]

Level of evidence - 2, strength of recommendations - B

- #levothyroxine sodium** [140]

Comment: dosing regimen – 100 mcg per day 20-30 minutes before meals during the first week of therapy, 200 mcg per day during the second week, 300 mcg once daily from the third to the sixth week of therapy.

Level of evidence - 2, strength of recommendations - B

- #acetylcysteine** [141]

Comment: dosing regimen — 1 g twice a day (2 g/day) in addition to ongoing treatment for 8 weeks

Level of evidence - 2, strength of recommendations - A

- #olanzapine** [2,95,128-129]

Comment: dosing - 5-20 mg/day for 6-10 weeks. If there is a positive effect, therapy can be continued until remission is achieved.

Level of evidence - 1, strength of recommendations - B

- Transcranial magnetic stimulation targeting the left or right dorsolateral prefrontal cortex (DLPFC) [142, 312-314]

Level of evidence - 1, strength of recommendations - B

- SSRIs or monoamine oxidase inhibitors type A (MAOIs-A) [143-146,162,282]

Level of evidence - 2, strength of recommendations - A

Comment: When choosing an antidepressant, preference should be given to selective serotonin reuptake inhibitors (SSRIs) [143,146]. Adding an antidepressant to mood-stabilizing therapy may be justified for depression within the framework of BD I and BD II in patients with a history of a positive response to antidepressant therapy. If the structure of depression contains mixed features (2 or more manic symptoms) or if the patient has a history of phase inversions with the use of antidepressants, their addition is contraindicated. Antidepressant monotherapy should be avoided due to the high risk of phase inversion, increased cycle acceleration, and worsening of the overall disease course [100-102,146]. If antidepressants are prescribed, the appearance of signs of hypomania/mania or psychomotor agitation must be carefully monitored; if they appear, the antidepressant must be discontinued.

In patients with bipolar depression who have no history of rapid cycling or a manic episode directly preceding the current depression, antidepressant therapy combined with mood stabilizer therapy may be continued for up to 6–12 weeks after the resolution of depressive symptoms to treat residual symptoms and achieve stable remission. If the patient has a history of rapid cycling or if the current depressive episode was directly preceded by a manic state, antidepressants should be discontinued as early as possible after the resolution of depressive symptoms, starting as early as the second week after achieving clinical remission. In all circumstances, it is advisable to taper the dose gradually (25–33% every 2–4 days). In the event of a depressive relapse during the dose reduction period or immediately after discontinuation of antidepressants, resumption of the acute treatment regimen is required [1, 2, 37, 125, 126, 146].

Despite the need to limit the duration of antidepressant use, approximately 20% of patients with bipolar disorder require maintenance antidepressant therapy [14]. For patients with frequent depressive relapses caused by antidepressant discontinuation, antidepressants may be prescribed for a prolonged period as part of a prophylactic treatment program. When used long-term, SSRIs may cause a number of side effects, the most frequent of which are nausea and sexual dysfunction [271]. In addition, withdrawal syndrome may develop upon discontinuation of certain medications, so they must be discontinued very gradually [272].

3.2.2 First-line treatment strategies for severe bipolar depression type 1 with psychotic features

Level of evidence — 5, strength of recommendation — C

Comment: The starting dose of #olanzapine** is 10 mg/day at bedtime. If necessary, the dose may be increased up to a maximum of 20 mg/day as a single dose, subject to tolerability [1,32,37].

- For #aripiprazole, the recommended starting dose ranges from 10 mg to 15 mg once daily, with the possibility of a subsequent dose increase up to 30 mg per day depending on efficacy and subject to tolerability [32].

- #Paliperidone** is prescribed at a dose of 6 mg/day. If efficacy is insufficient, the dose may be gradually increased (by 3 mg/day every 5 days) up to 12 mg/day, subject to tolerability [32].

- For #amisulpride, doses ranging from 400 to 800 mg are most commonly used. The maximum dose should never exceed 1200 mg per day. If the daily dose does not exceed 400 mg, it may be taken once daily. If the daily dose exceeds 400 mg, it must be divided into two doses [32].

- #Clozapine should only be used if the leukocyte count and absolute neutrophil count are within normal limits prior to treatment initiation, i.e., leukocyte count ≥ 3500/mm3 (3.5 × 10^9/L) and absolute neutrophil count ≥ 2000/mm3 (2.0 × 10^9/L). Furthermore, during treatment, it is necessary to have the capability for regular monitoring of the leukocyte count and absolute neutrophil count: weekly for the first 18 weeks, and thereafter at least once every 4 weeks throughout the entire course of treatment, as well as 4 weeks after treatment discontinuation. The dose of the drug should be adjusted individually. The minimum effective dose should be used for each patient. To minimize the risk of hypotension, seizures, and sedation, the dose should be titrated cautiously, dividing the daily dose into multiple administrations. The starting dose of #clozapine must not exceed 12.5 mg (1/2 of a 25 mg tablet) and should be taken in the evening. Subsequently, the dose may be increased by 12.5 mg no more than twice a week up to a maximum of 50 mg. A dose of 50 mg should not be used earlier than the end of the second week after treatment initiation. The entire daily dose is preferably taken as a single evening dose. The mean effective dose is 25–37.5 mg per day. If treatment with a daily dose of 50 mg for at least 1 week does not provide a satisfactory therapeutic effect, a further cautious dose increase by no more than 12.5 mg per week is possible. The dose of 50 mg per day may be exceeded only in exceptional cases. The dose of 100 mg per day must not be exceeded [1,32].

Treatment strategies for severe bipolar depression type 1 with psychotic symptoms in case of ineffectiveness of first-line agents

Level of evidence — 5, strength of recommendation — C

Comment: In certain clinical cases, the prescription of FGA is possible; however, due to the predisposition of patients with bipolar disorder—especially during a depressive episode—to develop neurological side effects, preference should be given to SGA.

Therapeutic strategies in case of pharmacotherapy failure in bipolar I disorder with psychotic symptoms

Level of evidence — 5, strength of recommendation — C

- #aripiprazole (5-30 mg/day) [132, 133]

Level of evidence — 4, grade of recommendation — C

Comment: #aripiprazole is prescribed at a dose of 5-10 mg/day at bedtime and may be increased by 5-10 mg/day every 7 days depending on efficacy and tolerability. The maximum dose of #aripiprazole is 30 mg/day.

- #carbamazepine** (400-1000 mg/day) [95, 125, 127, 186, 367]

Level of evidence — 4, grade of recommendation — C

- eicosapentaenoic acid (dietary supplement) [134,135,136, 377,378]

Level of evidence — 1, grade of recommendation — A

Comment: Eicosapentaenoic acid is one of several omega-3 polyunsaturated fatty acids (omega-3 triglycerides); doses range from 2 to 6 g/day [377,378]. It is important that the prescribed dietary supplement is included in the Unified Register of Specialized Food Products (Decision of the Customs Union Commission No. 880 dated December 9, 2011 (as amended on April 22, 2024) "On the Adoption of the Technical Regulation of the Customs Union 'On Food Safety'" (along with "TR CU 021/2011. Technical Regulation of the Customs Union 'On Food Safety'")).

- light therapy [139]

Level of Evidence — 2, Grade of Recommendation — B

- #levothyroxine sodium** (300 mcg/day) [140]

Level of Evidence — 2, Grade of Recommendation — B

Comment: dosing regimen – 100 mcg per day 20-30 minutes before meals during the first week of therapy, 200 mcg per day during the second week, 300 mcg once daily from the third to the sixth week of therapy.

- #acetylcysteine** (2 g/day) [141,303]

Comment: dosing regimen — 1 g twice a day (2 g/day) in addition to ongoing treatment for 8 weeks

Level of Evidence — 2, Grade of Recommendation — A

- #olanzapine** (5–20 mg/day) [95]

Level of Evidence — 1, Grade of Recommendation — B

Comment: dosing - 5-20 mg/day for 6-10 weeks. If there is a positive effect, therapy can be continued until remission is achieved.

- Transcranial magnetic stimulation targeting the left or right dorsolateral prefrontal cortex [142, 312-314]

Level of Evidence — 1, Grade of Recommendation — B

- SSRIs or monoamine oxidase inhibitors type A (MAOI-A) [144-146]

Level of evidence - 2, strength of recommendations - A

3.2.3 Treatment strategy for bipolar disorder type 2 without psychotic symptoms

First-line therapy for bipolar disorder type 2 without psychotic symptoms

Level of evidence - 2, strength of recommendations - B

Treatment strategies for bipolar disorder type 2 without psychotic symptoms when first-line options are ineffective

- #lithium carbonate [156-160]

- lamotrigine [155,157,161,165]

- ECT [131]

- sertraline** [162]

- venlafaxine [163,164]

Level of Evidence - 2, Strength of Recommendation - B.

Comment: #lithium carbonate dosing regimen: the dose is determined by the plasma concentration of lithium. The therapeutic plasma concentration of lithium is 0.6–1.0 mmol/L. Administered orally; for adults, the dose is 300–600 mg 3 times a day. The plasma lithium concentration should not exceed 1.2 mmol/L [1,296].

Treatment strategies for bipolar disorder type 2 without psychotic symptoms when first- and second-line options are ineffective

- valproic acid** [117, 122, 166-171]

Level of Evidence - 1, Strength of Recommendation - B.

Comment. The initial daily dose is 300–500 mg/day, after which it can be increased to 1000–2000 mg/day under the control of tolerability and efficacy. The daily dose is usually divided into 1–2 intakes [117, 122, 168, 169, 171].

- fluoxetine** [172-174]

Level of Evidence - 2, Strength of Recommendation - B

- augmentation with agomelatine** (25-50 mg/day) [175]

Level of Evidence - 3, Strength of Recommendation - C.

- **acetylcysteine** (2 g/day) [176,303]

Level of Evidence - 2, Strength of Recommendation - A.

Comment: dosage regimen: 1 g twice a day (2 g/day) in addition to ongoing treatment for 8 weeks.

- #pramipexole** (0.375-4.5 mg/day) [177]

Level of Evidence - 2, Strength of Recommendation - A.

Comment. Dosage regimen: during the first 5-7 days - 125 mg three times a day. Every 5-7 days, the dose may be increased depending on efficacy and tolerability by 125 mg three times a day to reach the target range of 1.0 to 3.0 mg per day. The maximum allowable dose was 4.5 mg per day.

- thyroid hormones (#levothyroxine sodium** - 300 mcg/day) [178]

Level of Evidence - 2, Strength of Recommendation - A.

Comment: dosage regimen - 100 mcg per day 20-30 minutes before meals during the first week of therapy, 200 mcg per day during the second week, 300 mcg once daily from the third to the sixth week of therapy.

3.2.4 Treatment strategies for severe bipolar II disorder with psychotic features

First-line treatment strategies for severe bipolar II disorder with psychotic features

Level of evidence — 5, strength of recommendation — C

Treatment strategies for severe bipolar II disorder with psychotic symptoms in case of ineffectiveness of first-line prescriptions

Level of evidence — 5, strength of recommendation — C

Comment: In certain clinical cases, the prescription of FGA is possible; however, due to the predisposition of patients with bipolar disorder—especially during a depressive episode—to develop neurological side effects, preference should be given to SGA.

Level of evidence — 5, strength of recommendation — C

Level of evidence — 5, strength of recommendation — C

3.3 Therapy of mixed affective episode or mixed state (MS)

Tactics and stages of pharmacotherapy for mixed states (Appendix B)

Comments: ICD-10 does not divide mixed states by dominant affect. Unlike ICD-10, DSM-5 introduces the refining specifier "with mixed features" and distinguishes depressive episode with mixed features and manic episode with mixed features. Diagnostic criteria for depression with mixed features are identical for a depressive episode within recurrent depressive disorder and bipolar disorder: the patient must meet the criteria for a depressive episode and have 3 or more mania/hypomania symptoms: (1) elevated or expansive mood, (2) inflated self-esteem or grandiosity, (3) talkativeness or pressure of speech, (4) flight of ideas or racing thoughts, (5) increased energy or goal-directed activity, (6) risky behavior, (7) decreased need for sleep. Symptoms must be present most of the time during a depressive episode, and behavior must be different from usual and noticeable to others.

To establish a diagnosis according to DSM-5 for a manic or hypomanic episode with mixed features, the criteria for a manic or hypomanic episode must be met, and at least 3 of the following 6 depressive symptoms must be present: (1) marked dysphoria or depressed mood, (2) psychomotor retardation, (3) feelings of worthlessness or excessive guilt, (4) diminished interest or pleasure in almost all activities, (5) fatigue or loss of energy, or (6) recurrent thoughts of death. Symptoms must be present most of the time during the current or most recent manic/hypomanic episode. Behavior must be different from usual, and this must be noticeable to others [19].

Considering that most RCTs used the aforementioned DSM-5 diagnostic criteria for mixed states, these clinical guidelines divide mixed states based on the predominant affect into mixed depression (MD) and mixed mania (MM).

At all stages of mixed state therapy, the selection of the optimal therapeutic dose (Appendix A3) is carried out taking into account the patient's individual sensitivity to the drug. If it is impossible to use adequate dosages due to the development of side effects, one should switch to another drug from among those listed for this stage of therapy.

The duration of therapy with first-line drugs is at least 2-4 weeks. If the patient shows a partial effect, treatment can be continued for another 4 weeks, or second-line drugs can be prescribed. If there is no effect after 4 weeks of first-line therapy, one should proceed to the second stage of therapy.

3.3.1. Treatment strategy for mixed states with predominant depressive symptoms (mixed depression (MD))

First-line therapy for mixed states with predominant depressive symptoms (mixed depression (MD))

Level of evidence - 2, strength of recommendation - A

Comment. Ziprasidone has been studied only in mixed states within bipolar II disorder. The question of whether these data can be unconditionally extrapolated to bipolar I disorder remains controversial. However, at present, no more evidence-based studies with positive results in mixed depression have been conducted for other drugs.

If the patient is already receiving mood stabilizer therapy for prophylactic purposes, acute treatment of mixed depression and the prescription of ziprasidone should be carried out against this background.

Treatment strategies for mixed depression in case of ineffectiveness of first-line therapy

- **olanzapine as monotherapy or in combination with fluoxetine** [182-185],

Level of Evidence - 2, Strength of Recommendation - B

Comment. #Olanzapine** and fluoxetine** should be used in the dosage regimen specified in the product labeling. It should be borne in mind that fluoxetine** should be used with caution, under careful monitoring of the severity of hypomanic symptoms, given the risk of phase inversion and aggravation of manic symptoms.

- or #carbamazepine** [186],

Level of Evidence - 4, Strength of Recommendation - C

Comment. Dosage regimen for #carbamazepine**: initiation of therapy - 200 mg/day with a subsequent increase in dose under the control of efficacy and tolerability up to 600-1200 mg/day [127, 243].

- or lurasidone** [187]

Level of evidence - 2, strength of recommendations - B

Comment. Lurasidone** should be used in the dosage regimen specified in the product labeling. Dosages should be adjusted depending on efficacy and tolerability.

- or ECT [188-190, 299]

Level of Evidence - 4, Strength of Recommendation - C

Comment: in case of ineffectiveness of the prescribed drug, it is necessary to switch to prescribing an unused option. In cases where the patient is already receiving mood stabilizer therapy for prophylactic purposes, acute treatment of mixed depression should be carried out against the background of the ongoing mood stabilizer.

3.3.2. Treatment strategy for mixed states with predominant manic symptoms (mixed mania (MM))

First-line therapy for mixed states with predominant manic symptoms (mixed mania (MM))

Level of Evidence - 2, Strength of Recommendation - B

Level of Evidence - 2, Strength of Recommendation - B

Treatment strategies for SAD in case of inefficacy of first-line therapy

Level of Evidence - 2, Strength of Recommendation - B

Comment: if the prescribed drug is ineffective, one should switch to an unused option. In cases where the patient is already receiving mood stabilizer therapy for prophylactic purposes, acute treatment of SAD should be carried out against the background of the ongoing mood stabilizer therapy.

Treatment strategies for SAD in case of inefficacy of second-line therapy

- #clozapine at doses of 200-900 mg/day [212,213]

Level of evidence - 4, strength of recommendations - C

- #gabapentin at doses of 300-900 mg/day (maximum studied dose - 4800 mg/day) + mood stabilizer therapy [214, 215]

Level of Evidence - 4, Strength of Recommendation - C

- #oxcarbazepine** (mean doses 900-1800) + lithium carbonate [216, 269]

Level of Evidence - 4, Strength of Recommendation - C

Comment. Doses of #oxcarbazepine** can range from 300 to 2400 mg/day. Their selection is carried out taking into account tolerability and therapeutic effect.

- risperidone** (1-6 mg/day) [217]

Level of Evidence - 2, Strength of Recommendation - B

- AAP [218,269]

Level of Evidence - 2, Strength of Recommendation - B

- ECT [219-223,269,299]

Level of Evidence - 3, Strength of Recommendation - C Comment: if the prescribed drug is ineffective, one should switch to an unused option. In cases where the patient is already receiving mood stabilizer therapy for prophylactic purposes, acute treatment of SAD should be carried out against the background of the ongoing mood stabilizer therapy.

Treatment strategies for SAD in case of inefficacy of third-line therapy

Level of Evidence - 4, Strength of Recommendation - C

Comment: if the prescribed drug is ineffective, one should switch to an unused option. In cases where the patient is already receiving mood stabilizer therapy for prophylactic purposes, acute treatment of SAD should be carried out against the background of the ongoing mood stabilizer therapy.

3.4 Long-term relapse-prevention therapy for bipolar disorder

Level of evidence — 5, grade of recommendation — C

Comment:

Objectives of mood stabilizer therapy:

- prescription of mood stabilizer therapy and selection of an adequate dose

- assessment of tolerability and efficacy of therapy

- maintenance of the euthymic period and symptomatic correction of mild new or residual affective and other mental disorders

- monitoring of the patient's somatoneurological status

- preservation of the premorbid level of social adaptation and quality of life. Setting: outpatient

The choice of drug for prophylactic therapy should be made taking into account the course of the disease, the predominant affect polarity (Appendix G2, Table 1), the patient's somatoneurological status, likely side effects of the drugs, contraindications to their prescription (Appendix A3, Table 2, Table 3), as well as the prior efficacy of a given drug in the acute stage of the disease in the specific patient [1,32,40,365]. It is important to avoid prescribing a drug to which the patient has relative contraindications if the therapeutic options for choosing other drugs have not been exhausted [1,32,37,40]. Dose selection is carried out taking into individual tolerability, the recommended therapeutic dose range, pharmacokinetic parameters (Appendix A3, Table 4), concomitant therapy, and in accordance with the schedule in the approved product labeling [1,32,37].

During the period of selecting prophylactic therapy, follow-up psychiatric examination (consultation) should be performed monthly to monitor therapy tolerability and identify prodromal disorders.

Prophylactic therapy tactics have certain differences in alternating course vs. rapid-cycling or continuous course of BPAD. Given the wide individual variety of disease courses and clinical situations arising during long-term prophylactic therapy, the treatment algorithm can only be presented in a general form indicating the main stages and sequence of actions (Appendix B 5).

3.4.1. First stage of prophylactic therapy

Level of evidence — 5, strength of recommendation — C

Level of evidence — 5, strength of recommendation — C

Level of evidence — 5, strength of recommendation — C

Comments: Dose adjustment should be carried out taking into account potential drug interactions [316]. If the mood stabilizer dose selected at the first stage of therapy proves effective, but side effects are observed, an attempt can be made to reduce the dose to a tolerable one. If the therapeutic effect is completely lost in such a situation, the primary drug should be replaced with another mood stabilizer (in case of a partial effect, combined mood stabilizer therapy or the addition of an antipsychotic is possible) [43,229,230,231]. If complications or comorbid conditions develop that preclude therapy with the prescribed drug, it is necessary to change the mood stabilizer and make a new attempt to establish prophylactic therapy.

3.4.2. Second stage of prophylactic therapy

Level of evidence — 5, grade of recommendation — C

Comment: An attempt to discontinue therapy is possible no earlier than 5 years of stable remission and only at the patient's initiative, upon their persistent request, or in the case of planned pregnancy in women if the potential risk to the fetus outweighs the benefit of continuing therapy. The patient should be warned about the high risk of relapse and persuaded of the need to continue therapy indefinitely.

It should be noted that at this stage of therapy, even after several years of sustained remission, loss of efficacy of the initially prescribed therapy or the development of late adverse effects, complications, or comorbid conditions that contraindicate the continuation of treatment in the previous regimen is possible. In this case, therapy adjustment is carried out in accordance with the approaches of the first stage. After achieving a sustained remission lasting 2 years, the patient's visits to the physician should be scheduled at 3-month intervals. During the visit, it is necessary to identify and evaluate all details of potential changes in the patient's mental status over the past period and the tolerability of the prescribed medications, as well as to outline and discuss the further therapy plan with the patient. Standardized patient self-report forms, which are given to the patient to fill out at home between visits and immediately prior to the doctor's visit (Appendix G2), can serve to effectively utilize the time allotted for contact with the physician. Such a state assessment, regularly recorded independently by the patient, contributes to the development of their ability to monitor their own condition. In addition, during periods of exacerbations, when, for example, in depression the patient loses faith in the possibility of achieving remission, or conversely, during mania claims to never experience problems, the charts filled out earlier by the patient's own hand can serve as a convincing argument for the necessity of treatment.

3.5. Specifics of Therapy in Patients with Continuous and Rapid-Cycling Bipolar Affective Disorder

Level of evidence — 5, strength of recommendation — C

Comments: When treating patients with BD and an RC course, the general principles of prophylactic therapy for BD should be observed. However, certain specific features of treating these most refractory patients with BD should be taken into account [21,22,233]. Factors contributing to the development and maintenance of affective instability with increased frequency of phase transitions include alcohol and psychoactive substance abuse, comorbid somatic (e.g., thyroid dysfunction) and mental disorders, and the intake of certain medications, primarily antidepressants (ADs). Considering that all ADs and tricyclic antidepressants (TCAs) can induce a phase inversion, attempting to discontinue them should be the first step in managing patients with RC [32,40,234,235,315].

Level of evidence - 4, strength of recommendations - C

Level of Evidence - 4, Strength of Recommendation - C

Comment. In severe disease courses with fully developed affective phases, short euthymic periods, or a continuous course, performing ECT is advisable already at early stages of therapy [23,299]. Maintenance ECT is possible in patients with previously demonstrated efficacy of a termination course of ECT and inefficacy of combined mood-stabilizing regimens [237,299-301].

Therapy for the RC course of BD requires systematic (at least once a month) careful monitoring of the patient's condition. To evaluate the efficacy of the therapy prescribed to prevent recurrences, the dynamics of phase transitions are assessed. The fact of resolving the current episode in itself cannot be regarded as a manifestation of a positive therapeutic effect, just as a single exacerbation should not be the basis for changing mood-stabilizing therapy due to its inefficacy. A daily self-assessment chart filled out by the patient (see Appendix G4 - Mood Fluctuation Self-Registration Chart) can serve as a good aid in evaluating the efficacy of therapy and making decisions on further therapeutic tactics. This is especially important for psychoeducational purposes, as the chart clearly shows a gradual decrease in frequency, shortening, or reduction in the severity of episodes. Even in the case of persisting recurrences of severe depression or mania, any evidence of reduced intensity of phase transitions during the first three months of evaluating the applied therapeutic strategy may be precursors of future improvement. The effects of newly prescribed mood-stabilizing therapy or AD discontinuation may not appear for several months. Therefore, the results of therapeutic tactics recorded over a period shorter than the duration of three cycles or four months are only indicative, but not conclusive. In most situations, evaluating the efficacy of newly prescribed therapy requires six months or more. Despite the fact that clinical necessity sometimes dictates the impossibility of postponing the intensification of therapy for more than four months, it is important to do everything possible to maintain a wait-and-see strategy taking into account the known timelines for the onset of any mood stabilizer's effect. Only such a tactic provides an opportunity to obtain a realistic picture of the efficacy of a particular drug. During this period, it is necessary to use the maximum tolerated doses of medications ensuring optimal efficacy [1,21,32,37,40,381].

Increasing the dose of mood-stabilizing therapy can contribute both to reducing phase transitions and to resolving manic or depressive symptoms during a recurrence. Such a tactic, along with the use of 'coverage therapy,' in some cases helps avoid the prescription of atypical antipsychotic drugs (APDs) during periods of mania or ADs during periods of depression, thereby reducing the risk of provoking increased cyclicity. The use of benzodiazepine derivatives, which are available in injectable formulations, makes it possible in most cases to control psychomotor agitation in mania or pronounced anxiety in depression in an inpatient setting. If antipsychotics are required, preference should be given to second-generation (atypical) antipsychotics (SGAs).

In severe depressions, especially with suicidal tendencies, avoiding the prescription of ADs is not possible. In these cases, the tactic of combination treatment is applied, and after symptom resolution, the methods aimed at halting the RC course are resumed. At the same time, treatment of the acute episode is carried out without discontinuing the preceding mood-stabilizing therapy [1,21,32,37,40].

Level of evidence 4, grade of recommendation C.

Comment: Prophylactic therapy in the RC treatment regimen is in most cases carried out even when the disease course no longer meets these criteria. For patients with 1-3 episodes per year, main efforts should be directed towards achieving a longer remission in order to maximally improve their quality of life [1,21,32,37,40].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Level of Evidence - 2, Strength of Recommendation - B

Comment: Certain psychosocial techniques developed specifically for BD are capable of reducing interpersonal conflicts, leveling potential trigger mechanisms of phase development, and/or smoothing out circadian rhythms.

Psychotherapy is an important complementary method of psychosocial intervention and rehabilitation for patients with BD, the potential of which remains largely unrealized in practice. To a certain extent, this is due to the insufficient study of the mechanisms of psychotherapy and, consequently, the small number of evidence-based studies [40,317-323]

The rationale for using psychotherapy in bipolar disorder (BD) is based on data regarding the increased stress load experienced by these patients and their psychological vulnerability. Patients with BD frequently exhibit cognitive process anomalies, which are associated with poor treatment adherence, difficulties in family relationships, as well as deficits in communication skills and self-organization [40,105,106,317,319,322,324,358].

The greatest efficacy of psychosocial interventions in BD is observed in the early stages of the disease [321,325]. This circumstance complicates psychotherapy at advanced and late stages of this disorder. Difficulties in conducting psychotherapy for this type of patients are also due to the high comorbidity of this disorder, in particular with personality disorders, chemical and behavioral addictions, and anxiety disorders, as well as due to the need to adjust therapy when BD phases change.

The main methodological approaches to psychotherapy for patients with BD include group therapy with psychoeducation, interpersonal therapy, and psychotherapy associated with the cognitive-behavioral approach. Interpersonal therapy category includes proper interpersonal therapy (IPT), family-focused therapy [326], couples therapy, as well as interpersonal and social rhythm therapy (IPSRT) [327]. Due to the high frequency of comorbid personality disorders and emotional instability in the interictal period in patients with BD, so-called transdiagnostic forms of psychotherapy are increasingly used. These forms, which rely on certain tenets of the so-called "third wave" of CBT, actually represent its integration with methods borrowed from other psychotherapeutic approaches. This primarily includes mindfulness-based therapy (MBT) [328-330], dialectical behavior therapy (DBT), as well as acceptance and commitment therapy.

Level of Evidence - 2, Strength of Recommendation - B

Level of evidence — 3, grade of recommendation — B.

Comment. Psychoeducation is a key element of any therapeutic intervention in BD [225,331-336]. The most effective forms of psychoeducation are those integrated with group psychotherapy [333-336]. They are structured as training programs covering the main medical and socio-psychological problems faced by patients and include relevant psychological training. Such psychological interventions in BD can help reduce the frequency of relapses and hospitalizations and improve treatment adherence. Psychoeducational programs are particularly promising for patients with frequent phases and comorbid personality disorders [21,336,337].

At the same time, the following main tasks are addressed: improving compliance and actively fostering adherence to long-term relapse-preventive mood stabilizer therapy; establishing the necessary alliance between the attending physician, the patient, and their relatives; compliance with the treatment regimen and regular laboratory monitoring, including drug level determination in the blood, and monitoring of therapy side effects; 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, violations of the law, substance abuse, pregnancy, etc.). Similar tasks are set when using the psychoeducational approach in working with the families of these patients, including coping with stress due to the onset of illness in a family member and establishing intra-family relationships.

The patient and relatives are explained the order and rules of taking medications, the need for hospitalization in a psychiatric hospital or outpatient treatment, and psychiatrist consultations. Table 1 presents some of the most important points of information that are important to cover during psychoeducational seminars for patients receiving mood stabilizer therapy.

Table 1.

Unfortunately, there are few randomized trials on the effectiveness of psychoeducation in BD, although most authors have no doubt about the usefulness of this work.

Level of evidence — 5, grade of recommendation — C.

Comment. In the initial stages of treatment, the goal of psychoeducation is to improve treatment adherence; at later stages, as well as in remission, the goal of individual psychoeducational and psychotherapeutic measures is to improve adherence to pharmacotherapy, reduce symptom severity, decrease relapse frequency, and correct social functioning impairments.

The main targets of psychoeducation in BD are increasing patient compliance, teaching them early recognition of relapses, and identifying comorbid disorders [225,331,335,337]. Psychoeducation is necessary for the patients' relatives and caregivers [17,226,228,332]. Psychoeducation aims to provide patients with theoretical and practical knowledge to overcome the consequences of the disease, including the complexity of relationships between symptoms, personality, interpersonal connections, psychopharmacological drugs, their side effects, and social responsibility [228,335,337,338].

Level of evidence: 5, grade of recommendation: C.

Comment. IPT proves effective in bipolar affective disorder (BD), primarily during the depressive phase. It is believed that one of the most critical factors negatively affecting the emotional state of such patients and provoking relapse is family stress, which can, among other things, be generated by the patient's own behavior. Therefore, stabilizing family relationships exerts a significant therapeutic and protective effect. IPT 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 corresponding training during therapy, the patient is assisted in forming 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. Such an approach is implemented in family-focused therapy [326, 340]. At the same time, modifying the patient's relationships with the surrounding microsocial environment remains the main driver for overcoming depression. There is evidence of sufficient efficacy of IPT utilizing virtual reality technology [103, 104].

Level of evidence: 5, grade of recommendation: C.

Comment. Classical CBT has a positive effect in patients with BD. In particular, when combined with psychopharmacotherapy, CBT can be useful for improving treatment adherence, controlling symptoms, enhancing psychosocial functioning, and possibly reducing the risk of relapse [343-344]. However, studies conducted in this area to date have a number of methodological limitations [345-346]. Moreover, the effects obtained with conventional CBT do not significantly exceed conventional maintenance therapy and, apparently, are associated with non-specific components of the psychological interaction between the therapist and the patient.

Social rhythm therapy (SRT), developed on the basis of IPT, is based on previously obtained data indicating that the positive effects of therapy are largely mediated by improving the regularity of social rhythms, which, in turn, are interrelated with natural biological rhythms, the disruption of which plays a major role in the genesis of BD [341, 387]. Psychosocial stressors to which individuals in this category are exposed have a destabilizing effect on the rhythms of sleep-wake cycles, energy, alertness, and appetite. Therefore, organizing them through the stabilization of life stereotypes, improving the quality of interpersonal relationships, and fulfilling key social roles can help increase the inter-episode interval in BD, as well as provide these patients with the skills necessary to protect against new affective episodes [327]. In patients with low levels of cognitive functioning against the background of SRT, an increase in it may be observed [325, 341-343].

Level of evidence — 5, strength of recommendation — C

Comment. To increase the effectiveness of CBT, a number of new types of integrative psychotherapy have been proposed on its basis. These include, in particular, mindfulness-based interventions.

Mindfulness-based therapy promotes the development of metacognitive skills in patients with BD, which helps reduce the severity of depressive and anxiety symptoms. Nevertheless, the efficacy of this method regarding BD as a whole remains not entirely clear due to an insufficient number of studies, as well as methodological flaws present in such works [328, 347].

The method is based on the application of meditative practices to develop the patient's ability to perceive and evaluate their mental processes from the outside, from a metacognitive stance. Such a stance allows the patient to detach from maladaptive thoughts, feelings, and reactions influencing their state. This method has proven effective in the depressive phase of BD and, in principle, can also be used in a wide range of manic states where patients exhibit so-called "hyper-positive thinking" [322].

Level of evidence — 5, strength of recommendation — C

Comment. The literature also indicates positive effects of using other transdiagnostic psychotherapeutic methods. Thus, dialectical behavior therapy (DBT) has a positive effect. This method of integrative psychotherapy positively influences emotional regulation, improves executive functions, and enhances mindfulness [348-351]. In addition, there is evidence of DBT's efficacy in suicide prevention in patients with BD [352]. Largely similar effects are expected from acceptance and commitment therapy, which aims to overcome the tendency characteristic of these patients to avoid experiences, as well as to increase their psychological flexibility and mindfulness. These measures can help alleviate suicidal thoughts associated with depressive symptoms. However, convincing data on the efficacy of this type of therapy have not yet been published.

5. Prevention and Dispensary Observation

Primary prevention of BD does not exist. Secondary prevention consists of long-term relapse-prevention therapy.

6. Organization of Medical Care

Deciding on inpatient or outpatient treatment:

Moderate or severe mania is an indication for hospitalization of the patient

In case of hypomania, the issue of hospitalization is decided depending on the following factors:

• severity of behavioral disorders and social maladaptation

• suicide risk (in the presence of mixed states)

• anamnestic data (risk of developing mania and the speed of development of previous manic episodes)

• level of the patient's insight into their existing symptoms

• conditions of the microsocial environment and the degree of involvement of close relatives in the therapeutic process

Outpatient therapy for hypomania is possible under the following conditions:

• the patient maintains relative insight into their condition

• the patient is able to follow the physician's prescriptions

• the patient has relatives capable of providing assistance in monitoring compliance with prescriptions and the patient's condition

In mild or moderate depression, the decision is made taking into account the following factors: severity of social maladaptation

• suicide risk

• anamnestic data (risk of phase inversion, worsening of symptoms with the formation of suicidal tendencies, severity of anxiety symptoms)

• level of the patient's insight into their existing symptoms

• conditions of the microsocial environment and the degree of involvement of close relatives in the therapeutic process

In depression with suicidal tendencies (see section 7.2 management of a patient with suicidal tendencies).

7. Additional Information

7.1 Management of patients during pregnancy

BD is not an absolute contraindication for pregnancy and childbirth. The risk of relapse increases significantly if pharmacotherapy is discontinued during pregnancy, especially if drug discontinuation was rapid. From the perspective of relapse recurrence, the postpartum period is the most dangerous.

When choosing therapeutic tactics for the pregnancy period in women suffering from bipolar affective disorder (BD) with stable remission, it is necessary to consider the frequency of previous episodes, age, family situation, i.e., the ability to provide care for the newborn in the event of a relapse in the mother. The issue of using psychotropic medications during gestation should be decided individually in each specific case after carefully weighing the benefit/risk ratio of the drugs versus no pharmacotherapy. At a younger age and with a less severe course of BD, complete or partial discontinuation of therapy for at least the first trimester of pregnancy and the use of psychotherapeutic treatment methods is advisable; however, in most women with moderate to severe forms of mental illness, the benefit of pharmacotherapy generally outweighs its risk. For older women and those with a previously severe course of BD, continuing therapy during pregnancy with regular fetal ultrasound or amniocentesis to detect potential teratogenic effects may be an option.

All issues of planning and managing pregnancy in women with BD should be resolved collegially, taking into account the opinion of a psychiatrist, obstetrician-gynecologist, and pediatrician, based on considerations of the risk-benefit ratio for the mother and the unborn child.

When choosing a therapeutic strategy during pregnancy, it is necessary to consider the potential teratogenic effect of prophylactic drugs prescribed and the risk of relapse during pregnancy and childbirth. The most commonly used drugs during pregnancy include mood stabilizers - antiepileptic drugs (valproic acid**, carbamazepine**, lamotrigine). As is well known, studies on the teratogenic effects of drugs in pregnant women are not conducted for ethical reasons. At the same time, many years of clinical experience with lithium carbonate, valproic acid**, carbamazepine**, and lamotrigine has shown an increased risk of teratogenic effects in women who received these drugs in the first trimester of pregnancy.

Lithium carbonate is believed to increase the risk of congenital cardiovascular defects, especially Ebstein's anomaly [238, 239]. The absolute risk of developing congenital heart anomalies with lithium carbonate use during pregnancy is quite low. Furthermore, Ebstein's anomalies develop only when the exposure of the fetus to lithium carbonate coincides in timing with the period of heart formation during organogenesis (predominantly weeks 3-6 of gestation).

Lithium preparations should, whenever possible, be discontinued in a woman planning a pregnancy, at least for the duration of the first trimester. If pregnancy occurs during lithium carbonate treatment, it is advisable to discuss in detail with the woman the benefits and risks associated with continuing treatment, and instead of discontinuing the drug, offer her careful monitoring of blood lithium concentrations and fetal condition. This is because gradual discontinuation of lithium carbonate over 2-4 weeks after pregnancy has occurred does not reduce the risk of teratogenic action, while abrupt discontinuation is associated with a high risk of relapse. If mood-stabilizing therapy is necessary during pregnancy, including the first trimester, lithium carbonate is considered the drug of choice due to its low absolute teratogenicity risk and relatively well-studied profile [240].

Lithium carbonate has a narrow therapeutic index. The range of its therapeutic concentrations is 0.6-0.8 mmol/L when used as maintenance therapy and 0.8-1.2 mmol/L in the treatment of a manic syndrome. Despite the narrow therapeutic index, there is a correlation between lithium carbonate doses, its blood concentrations, and toxic effects, so monitoring blood concentrations can significantly increase the safety of therapy. In addition, during treatment, it is necessary to monitor serum electrolyte levels, as well as renal and thyroid function [241], since lithium carbonate can cause renal failure, hypothyroidism, and in rare cases, hyperthyroidism in the mother [240].

Lithium doses are selected individually based on blood concentration monitoring data. High serum drug concentrations and the need for dose adjustment may be indicated by symptoms such as tremor, sedation, and forgetfulness.

Renal excretion of lithium increases as pregnancy progresses [242], which usually necessitates increasing its doses. During childbirth, the renal clearance of lithium drops sharply. To prevent toxic effects, it is advisable to discontinue lithium preparations or reduce the dose 7-10 days before delivery, followed by resumption of intake after delivery [242]. Discontinuing lithium carbonate on the day of delivery is inadvisable, as it is associated with a high risk of developing an affective episode in the postpartum period. Women receiving lithium carbonate must be under close medical supervision during labor. Adequate hydration should be maintained, and intravenous fluid administration should be provided for prolonged labor. The pharmacokinetic characteristics of lithium carbonate and recommendations for its monitoring during gestation are summarized in Table 2.

Table 2. Pharmacokinetic characteristics of lithium carbonate and recommendations for use and monitoring during pregnancy

Toxic effects of lithium carbonate in the newborn typically manifest as lethargy and floppy baby syndrome, which is characterized by respiratory distress, cyanosis, and decreased muscle tone. These symptoms are dose-dependent and develop against the background of high blood lithium levels in late pregnancy [240, 245, 246]. They are usually mild and transient in nature. The effect of lithium carbonate on long-term developmental outcomes in children remains unknown.

The use of anticonvulsants (antiepileptic drugs) in early gestation can lead to heart defects, neural tube defects, limb defects, genital defects, characteristic craniofacial anomalies, microcephaly, cleft lip and palate, as well as intrauterine growth restriction. The maximum risk in monotherapy with drugs from this group is associated with the use of high doses of valproic acid**.

Intutero exposure to valproic acid** is associated with an increased risk of cognitive and behavioral problems in children. A particularly high risk of neurobehavioral disorders is observed when valproic acid** is used in combination with other psychotropic agents. At 3 years of age, children exposed to valproic acid** in utero showed an IQ score lag averaging 9 and 6 points lower than their peers whose mothers received lamotrigine and carbamazepine**, respectively, during pregnancy [247-250].

Carbamazepine** can cause vitamin K deficiency in the fetus, leading to bleeding in the newborn and impaired facial morphology [251]. In addition, cases of transient hyperbilirubinemia in newborns have been described. A negative dose-dependent effect of carbamazepine** on the verbal functions of 2-3-year-old children exposed to it in the prenatal period is also possible [250]. The limited and contradictory data do not allow for a definitive conclusion regarding the teratogenic potential of lamotrigine, but it appears to be a safer drug for pregnant women than valproic acid** and carbamazepine**. In newborns exposed to lamotrigine in utero, toxic effects, including skin rash, are potentially possible [251, 253].

The risk of teratogenic effects is highest with the combined use of antiepileptic drugs [254, 255]. The combination of valproic acid** with carbamazepine** is considered the most dangerous in terms of the development of major congenital defects. To date, there are indications of major congenital anomalies developing in children whose mothers took the combination of valproic acid** and lamotrigine, and a complete absence of them in children exposed to the combination of carbamazepine** and lamotrigine.

Folic acid** as monotherapy or in combination with other vitamins and minerals prevents neural tube defects, but does not have a protective effect against other congenital anomalies [256, 257].

The concentrations of most anticonvulsants (antiepileptic drugs) decrease throughout pregnancy, so monitoring is required. For example, blood concentrations of valproic acid** decrease by 50% in the third trimester; however, the levels of the active protein-unbound fraction of the drug do not change significantly. Plasma concentrations of lamotrigine at the end of pregnancy are 3.6 times lower than before conception, and 5.8 times lower during delivery. Because blood concentrations of antiepileptic drugs in pregnant women are subject to significant interindividual variations, the concentration level determined in the woman during the pre-gravid period should be used as a control value. Recommendations for the use and therapeutic monitoring of antiepileptic drugs in pregnant women are presented in Table 3.

Table 3. Pharmacokinetic characteristics of anticonvulsants (antiepileptic drugs) and recommendations for their use and monitoring during pregnancy [258].

If a decision is made to discontinue therapy during the planning stage of pregnancy or upon the occurrence of an unplanned pregnancy, withdrawal should be gradual (over at least 2 weeks) due to the increased risk of relapse with abrupt drug discontinuation.

If pharmacotherapy cannot be discontinued, the response to monotherapy at the minimum effective dose should be evaluated in the pre-gravid period. For this purpose, the drug dose is gradually reduced. The recurrence of disease symptoms against the background of dose reduction or treatment discontinuation generally indicates the need to continue pharmacotherapy during pregnancy.

Where possible, it is advisable to limit the use of valproic acid** during pregnancy to the minimum effective dose in a sustained-release dosage form; the maximum daily dose should not exceed 1000 mg (divided into multiple doses). If necessary, it can be combined with another mood-stabilizing drug (but not with carbamazepine**). The woman must be informed about the increased risk of adverse outcomes for the newborn, including developmental delay in the child [298].

Preference should be given to medicinal products with the least pronounced teratogenic potential, and combination therapy should be avoided whenever possible. However, the most important factor in choosing drug therapy for a pregnant woman is the historical efficacy of the drug. In some cases, proven efficacy may justify the use of drugs with a relatively high teratogenic potential.

To prevent unplanned pregnancies, reliable contraception must be provided to women with bipolar disorder (BD). It should be borne in mind that carbamazepine** in doses exceeding 1200 mg/day enhances the metabolism of systemic hormonal contraceptives; therefore, other methods of contraception should be prescribed when treating with this drug. Patients receiving antiepileptic drugs that induce cytochrome P450 isoenzymes (including carbamazepine**) may also experience decreased efficacy of injectable and implantable dosage forms of systemic hormonal contraceptives. Clinically significant interactions have been identified between lamotrigine and oral systemic hormonal contraceptives. Systemic hormonal contraceptives can reduce lamotrigine concentrations by 49%, and lamotrigine, in turn, can reduce contraceptive efficacy. Other medicinal products used for the treatment of BD are compatible with the use of systemic hormonal contraceptives, although intrauterine contraception is considered the most reliable method for women with BD.

7.2 Management of patients with suicidal behavior

The clinical assessment of patients with suicidal ideation and behavior requires a very precise qualification of mental status and existing risks, as well as the typology of suicide [259]. The highest suicide risk in BD is associated with depressive phases with mixed features [39, 269, 389, 390]. These include the following variants:

True suicide attempt: an act potentially directed against oneself and committed with at least some desire to die as a result of the act. Actual physical injury resulting from the suicide attempt is not required; the potential for such injury is sufficient. An example where there is no injury is a misfire when discharging a firearm.

Interrupted suicide attempt: classified as cases where a person fails to initiate an action (they are interrupted or there are other external circumstances) potentially directed against themselves.

Aborted suicide attempt: the patient initiates actions to carry out a suicide attempt, but stops themselves before the actual commencement of self-destructive actions.

Non-suicidal self-injury: established in cases where self-harm is inflicted not with the intent to die, but for other reasons. The cause may be an internal state (to relieve pain, improve well-being, etc.) or external circumstances (the desire to attract attention, sympathy, or in some cases to anger oneself, etc.). The fundamental point is that the desire to die must be clearly and absolutely absent.

Preparatory acts: these include not only actions preparing a suicide attempt (acquiring pills, etc.) but also any preparations for one's own death resulting from suicide.

When assessing mental status, it is necessary to identify and qualify the core depressive syndrome and evaluate the presence of individual symptoms that may have adverse prognostic significance as risk factors for recurrent suicide. These include impulsivity, agitation, anxiety, anhedonia, feelings of hopelessness, persistent insomnia, panic attacks, and manifestations of aggressive behavior.

A serious risk factor for suicidal behavior is a history of past suicide attempts. It is necessary not only to establish the mere fact of various types of suicidal behavior (suicide attempts, aborted suicides, self-destructive behavior), but also to conduct a comprehensive analysis thereof. This will help predict the dynamics of the patient's condition in the subsequent hours, days, and over a longer period. Detailed information must be gathered regarding all circumstances of the suicides, their frequency, semantic content, and the severity of any resulting injuries.

Another primary target for obtaining objective data is assessing the patient's presence of acute or chronic stress. Understanding the patient's current psychosocial status will help provide targeted assistance and support, which in turn will reduce the risk of re-attempting suicide.

The analysis of suicide includes the assessment of suicidal thoughts, suicidal intent, a suicide plan, and suicidal behavior. The severity of suicidal ideation must be determined. It is based on the ratio of intensity and frequency of occurrence. In this case, it is necessary to ascertain from the patient: when they occur, how frequently, whether they can control them, and whether they are obsessive in nature. The grounds for suicidal ideation, as well as the presence of deterrent factors, must also be analyzed. It is also necessary to evaluate the nature of suicidal ideation: whether they are passive (the desire to die / not to live, to fall asleep and not wake up...) or filled with active content reaching the level of concrete intent. If the patient refuses to discuss this topic, it is recommended to focus the questioning on the patient's future and ask them to talk about their plans.

It is crucial to establish the presence of a suicide plan, as well as its potential lethality. Mandatory rule: if, in the physician's opinion, the execution of the existing plan objectively may not lead to a fatal outcome, this must not be communicated to the patient.

The level of suicide risk is determined by the physician based on the synthesis of clinical data and their correlation with current psychosocial factors. Active identification of factors deterring the execution of suicide is also required. These include: therapeutic alliance, support from family and friends, having children, pregnancy, religiosity, awareness of family responsibilities, full employment, and coping psychological skills such as the ability to endure loss, bereavement, or humiliation; mental flexibility and a certain degree of life optimism. An important tool for assessing suicide severity and suicide risk is the Columbia-Suicide Severity Rating Scale (Appendix G1).

Urgent therapeutic measures are performed in 3 categories of patients:

- following a committed suicide attempt,

- depressed patients with suicidal behavior,

- patients with a manic or mixed state, or BD remission with a high risk of suicide.

Patients after a completed suicide attempt require thorough examination, monitoring of vital functions, and urine drug screening.

The primary therapeutic intervention is assessing the level of suicide risk (evaluation of individual risk and protective factors) and developing a plan to minimize it. Simultaneously, the setting for therapeutic interventions is selected. Absolute indications for hospitalization, as well as conditions where hospitalization is possible or appropriate, are specified in Table 1. In other cases, treatment may be provided in a day hospital setting or through other forms of active outpatient care. Finally, in individual cases, care may be provided in "routine" outpatient settings.

Table 4 Indications for hospitalization in suicide-risk states

A. Absolute indications for hospitalization:

Following a suicide attempt or parasuicide, when:

- the patient is psychotic

- severe suicide attempt with a high lethality risk

2) There was no suicide attempt, but there is:

- presence of a suicide plan with a high lethality risk

- active suicidal ideation

B. Hospitalization may be necessary: 1) Following a suicide attempt or parasuicide and in the presence of suicidal ideation, when:

2) There was no suicide attempt, and the patient does not report suicidal thoughts and/or planning. However, a high suicide risk is revealed during mental status examination or confirmed by objective data

C. Treatment in a day hospital setting may be possible:

Following a suicide attempt, as well as in the presence of a suicidal plan or thoughts, when:

they are a reaction to occurred events (interpersonal problems, exam failure, etc.), provided that the patient's perspective on the situation has changed

- the suicidal plan / thoughts carry a low lethality risk

- the patient has good familial/social support

- the patient is cooperative, follows recommendations, and a "treatment contract" is established

D. Other forms of care are preferable to hospitalization:

The patient has had suicidal thoughts for a very long time, and minor self-harm (superficial cuts, etc.) is also possible, provided there is good familial/social support and a developed outpatient treatment plan.

Clinical evaluation should aim both at determining a possible psychiatric diagnosis and at establishing risks and other factors influencing suicidal behavior. Early identification of individual factors capable of preventing repeated attempts will ensure the success of crisis intervention and psychotherapy. Psychotherapeutic treatment for patients with suicidal tendencies is advisable only with a relatively mild level of affective disorders [38,259]

Depending on the phase of the disease, personality traits, social situation, and set therapeutic tasks, various psychotherapy methods can be used for a patient with suicidal tendencies:

- individual (cognitive behavioral, psychodynamic,

suggestive, rational, etc.);

- group (interpersonal, reintegrating, etc.);

- family (supportive, etc.)

The choice of method depends on the patient's condition characteristics, the degree of social maladaptation, and the current social situation, as well as the stage of psychiatric care provision with an assessment of primary therapeutic tasks. The preferred approach is psychoeducational with elements of problem-solving techniques [38, 259].

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for specialized medical care in adults with bipolar affective disorder

(ICD-10 codes: F31, F31.0, F31.1, F31.2, F31.3, F31.4, F31.5, F31.6, F31.7, F31.8, F31.9)

Quality assessment criteria for primary health care in adults with bipolar affective disorder

(ICD-10 codes: F31, F31.0, F31.1, F31.2, F31.3, F31.4, F31.5, F31.6, F31.7, F31.8, F31.9)

References

Appendix A1. Working Group Composition

1. Elena G. Kostyukova, Candidate of Medical Sciences, Member of the Russian Society of Psychiatrists

2. Galina E. Mazo, Doctor of Medical Sciences, Member of the Russian Society of Psychiatrists

3. Sergey N. Mosolov, Doctor of Medical Sciences, Professor, Member of the Executive Committee of the Russian Society of Psychiatrists, Honored Scientist of the Russian Federation

4. Eduard E. Tsukarzi, Candidate of Medical Sciences, Member of the Russian Society of Psychiatrists

5. A.E. Bobrov, Doctor of Medical Sciences, Member of the Russian Society of Psychiatrists

Conflict of interest none

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 grading levels of evidence (LE) for diagnostic methods (diagnostic interventions)

2. Scale for grading levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines – revision once every 3 years and no more frequently than once every 6 months

Appendix A3. Reference Materials

1. Order of the Russian Ministry of Health No. 203n dated May 17, 2017 "On approval of criteria for assessing the quality of medical care"

2. Order of the Russian Ministry of Health No. 453n dated June 30, 2022 "Procedure for dispensary observation of a person suffering from a chronic and prolonged mental disorder with severe, persistent, or frequently relapsing disease manifestations"

Recommended drug doses

Table 1

Guidelines for initial selection of a mood stabilizer at the start of prophylactic therapy for bipolar affective disorder (BD)

Table 2. Clinical guidelines for initial selection of a mood stabilizer at the start of prophylactic therapy for bipolar affective disorder (BD)

Table 3. Precautions and contraindications for the use of lithium carbonate, carbamazepine**, valproic acid**, and lamotrigine.

Table 4. Selected comparative pharmacokinetic parameters of lithium carbonate, carbamazepine**, valproic acid**, and lamotrigine

Appendix B. Physician Action Algorithms

Appendix B1. Diagnostic algorithm for bipolar disorder

Appendix B2. Algorithm for biological therapy of manic states

Appendix B3. Algorithm for biological therapy of depressive states

Appendix B4. Algorithm for biological therapy of a mixed episode or rapid cycling

Appendix B5. Algorithm for prophylactic (maintenance) pharmacotherapy of bipolar disorder

Notes to the algorithm: (Maintenance therapy)

When choosing a mood stabilizer for the first stage of maintenance therapy, the dominant polarity of the disorder should be considered. If there are contraindications to first-line drugs, any of the listed mood stabilizers may be prescribed. The exception is lamotrigine, whose efficacy has been proven only for BD-II, meaning it cannot be a first-line drug in patients with predominant manic phases.

1. The minimum required period for the mood-stabilizing effect of the drug to establish is 1 year. Therefore, the minimum evaluation period for any maintenance therapy is at least one year. At the same time, it is determined individually for each patient depending on the course of the disease, specifically the length of the cycle, which includes a phase or double phase and an intermission. The individual time period required to evaluate the efficacy of maintenance therapy must be equivalent to three times the length of the last cycle. The evaluation of maintenance therapy efficacy is always performed by comparing the frequency and severity of affective phases over equal periods of time before the initiation of mood-stabilizing therapy and from its inception.

2. Partial effect: a reduction in the total duration of illness periods by at least 1/3 over equal periods of time before and after the start of maintenance therapy, and/or a decrease in the severity of persisting phases.

3. Any mood stabilizers can be combined with each other, except for carbamazepine** and valproic acid**, due to their pharmacokinetic interaction [393] at the level of hepatic enzymes (see the package leaflet of the medicinal products). For example, microsomal enzyme inducers (carbamazepine**) decrease the concentration of lamotrigine and valproic acid**, whereas valproic acid** increases the concentration of lamotrigine. Therefore, dosage adjustment of these drugs may be required.

4. In case of ineffectiveness of mood-stabilizing therapy or a high proportion of psychotic symptoms during exacerbation periods, certain atypical antipsychotics may be used, primarily those that have proven effective in the acute management of affective manifestations.

5. Discontinuation should occur only upon the initiative and insistent request of the patient, or in the case of planned pregnancy in women, if the potential harm to the fetus upon continuing therapy outweighs the benefit to the mother. Upon discontinuation, discussing the risks and benefits of the decision and alternative therapeutic strategies with the patient is mandatory.

Appendix B6. Algorithm for the treatment of bipolar disorder with rapid-cycling or continuous course

List of abbreviations for the "Rapid-cycling course" algorithm

BD – bipolar disorder

AD – antidepressants

SGA – second-generation antipsychotic

VAL – valproic acid**

LAM – lamotrigine

CAR – carbamazepine**

QUE – quetiapine**

OLZ – olanzapine**

ECT – electroconvulsive therapy

Notes to the Rapid-cycling course algorithm

1. Prior to initiating therapy, antidepressant therapy must be discontinued (if present in the treatment regimen), comorbid disorders (hypothyroidism and other endocrine diseases) and provoking factors (alcohol, psychoactive substances, systemic hormonal contraceptives, and thyroid hormones) must be ruled out, and patient adherence to the mood-stabilizer regimen must be verified (plasma concentrations checked if necessary). The choice of a mood stabilizer is made taking into account the greater efficacy of anticonvulsants compared to lithium carbonate in rapid cycling, based on the course of the disease and the patient's somatoneurological status. If a mood stabilizer has already been prescribed for phase management, it is advisable to continue its use.

In rapid-cycling bipolar disorder with predominant manic phases or insufficient efficacy of the initially prescribed mood stabilizer for controlling manic phases, preference should be given to valproic acid** and lithium carbonate. Given the insufficient efficacy of lithium carbonate in rapid cycling, yet its clear efficacy in managing manic symptoms, lithium carbonate in a combination regimen should be used with antiepileptic drugs (valproic acid**, #topiramate**). If combination mood-stabilizer therapy is insufficiently effective, introducing atypical antipsychotics or calcium channel blockers (#nifedipine**, #verapamil**) into the regimen is advisable.

In rapid-cycling bipolar disorder with predominant depressive phases or in type II bipolar disorder, preference should be given to carbamazepine** and lamotrigine. If mood-stabilizing therapy is insufficiently effective, adding #levothyroxine sodium** or atypical antipsychotics to the regimen is possible. Upon the onset of a subsequent depressive phase and established ineffectiveness of mood stabilizers and atypical antipsychotics for its management, the adjunctive use of SSRIs is possible. Following the resolution of depressive symptoms, antidepressants must be discontinued.

2.3.4.5.6 – see comments (notes) to Appendix B – Algorithm for prophylactic (maintenance) pharmacotherapy of bipolar disorder.

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:

• name of the medicinal product;

• the necessity of its regular intake for the treatment of the disease or management of specific symptoms;

• how to determine whether the use of the drug is effective and what to do in the absence of these signs;

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

• what to do if a dose is missed;

• duration of administration;

• most probable adverse effects and what to do if they occur;

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

• alternative therapies and the estimated cost of the course of treatment.

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 to motivate the patient to consult a doctor upon their appearance. This will provide a chance for faster relapse management outside the inpatient setting. The frequency of medical appointments should be discussed in advance, and a visit schedule should be established.

Maintaining a patient self-monitoring mood chart can be a substantial help (Appendix G2).

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

Appendix G 1. Assessment of Suicide Risk and Suicidal Behavior

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):

Columbia-Suicide Severity Rating Scale (C-SSRS)

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.

Appendix G2. HCL-32. Hypomania Checklist

Russian title: HCL-32. Hypomania Checklist

Original title (if any): Hypomania Checklist (HCL-32)

Source (official developer website, validation publication):

Angst J., Adolfsson R., Benazzi F. et al. The HCL-32: Towards a self-assessment tool for hypomanic symptoms in outpatients // J Affect Dis. – 2005. – Vol. 88, No 22. – P. 217–233;

Mosolov S.N., Ushkalova A.V., Kostyukova E.G., Shafarenko A.A., Alfimov P.V., Kostyukova A.B., Kursakov A.A., Obraztsova L.V. Validation of the Russian version of the HCL-32 questionnaire for identifying patients with bipolar II disorder among patients observed with a diagnosis of recurrent depressive disorder // Social and Clinical Psychiatry. – 2015. – Vol. 25, Iss. 1. – P. 22–30.

Type (underline):

-

rating scale

-

index

-

questionnaire

-

other (specify):______________________________________________________

Purpose: a self-assessment questionnaire aimed primarily at detecting a history of hypomanic symptoms in a patient. It allows the identification of patients with BP II among patients who have been mistakenly diagnosed or may be diagnosed with recurrent depressive disorder. Testing versions of this questionnaire in various countries has demonstrated its high sensitivity in differentiating BP and RDD along with brevity and ease of use, making HCL-32 recommended for screening use in medical practice. The completion time is 5–10 min.

Content (template): the questionnaire consists of three parts.

Part 1 contains 7 options characterizing the subject's current state, of which they can choose only one.

Part 2 contains 8 options characterizing the subject's self-assessment regardless of their current well-being, of which they can choose only one.

Part 3 is the main part. It contains 32 questions with "YES" or "NO" answer choices aimed at identifying a history of hypomania in the subject.

Parts 4-8 contain questions to assess objective signs of mood elevations, their duration, and onset timing.

Key (interpretation): 14 "YES" answers in the third part of the questionnaire indicate a high probability of a history of hypomania and serve as the basis for a thorough clinical examination of the subject aimed at diagnosing BP.

Notes: the subject fills out the questionnaire form independently. The questionnaire is a screening, not a diagnostic tool. The diagnosis of BP is made by a psychiatrist based on a clinical examination.

HCL-32. Vital Tone, Activity, and Mood

Everyone's life has periods of "ups" and "downs" accompanied by changes in vital tone, activity, and mood. The purpose of this questionnaire is to obtain a detailed description of the periods of "ups".

1) First of all, describe how you feel today compared to your usual state:

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

Do this regardless of how you feel today. Choose the wording that most accurately reflects your self-assessment compared to others.

3) Try to recall a period of "elevated" state. How did you feel back then? Please answer the questions regardless of how you feel now.

4) The impact of mood elevations on various aspects of your life:

5) People's reactions to your mood elevations.

How did your loved ones react when you were in an "elevated" state, and what did they say about it?

6) Duration of elevated periods (on average):

(Choose ONLY ONE of the suggested answer options)

7) Have you experienced such states in the past twelve months?

Yes                  No

8) If yes, what was the total duration of these periods (in the past twelve months)?

Appendix G.3 Young Mania Rating Scale

Russian title: Young Mania Rating Scale

Original title (if any): Young Mania Rating Scale

Source (official developer website, publication with

validation): Young RC, Biggs JT, Ziegler VE, Meyer DA (1978) A rating scale for mania: reliability, validity and sensitivity Br J Psychiatry. 133: 429—435 PMID 728692

Type (underline):

rating scale

index

questionnaire

other (specify):______________________________________________________

Purpose: for assessing the severity of manic symptoms

Content (template): The scale consists of 11 items quantitatively assessing the severity of objective and subjective symptoms of mania

Key (interpretation): Four items of the scale (irritability, speech, thought content, and aggressive behavior) are scored with double points from 0 to 8, while the remaining seven are scored from 0 to 4. Double-point scoring of the four items compensates for poor rapport with patients exhibiting severe manic symptoms. If the severity (or change in severity) of the patient's symptoms does not correspond to a double point, intermediate scores (1, 3, 5, 7 instead of 2, 4, 6, 8) may be used. The total score is calculated, which is used to assess the patient's condition and the dynamics of manic symptoms.

Total score evaluation

0—12 — Normal

13—21 — Hypomanic state

22—30 — Manic state

greater than 30 — Severe manic state

Notes: The scale is used only to assess the severity of manic symptoms in patients with a verified diagnosis of manic syndrome or bipolar disorder. The scale is completed by a trained rater during a clinical interview using the scale. The items are scored based on data regarding the patient's clinical state over the past 48 hours. Additional information used for the assessment is derived from clinical observation during the interview.

Young Mania Rating Scale

1. Elevated mood

0 - absent

1 - mildly or possibly increased, elicited upon questioning

2 - subjectively experienced elevation; patient appears optimistic, self-confident, cheerful, appropriate to the situation

3 - mood elevated, inappropriate to the situation, makes jokes

4 - patient is euphoric, inappropriately laughs, sings.

2. Increased motor activity, energy

0 - absent

1 - subjectively noted increase

2 - patient is animated, gestures increased

3 - excessive energy, periodic hyperactivity, restlessness (can be calmed)

4 - motor agitation, constant hyperactivity (cannot be calmed)

3. Sexual interest

0 - normal, not increased

1 - slightly or possibly increased

2 - subjectively noted increase

3 - sexual topics arise spontaneously in conversation, talks a lot about it, reports hypersexuality

4 - overtly sexual behavior (toward patients, staff, physician)

4. Sleep

0 - does not report decreased sleep duration

1 - reduction in sleep duration by less than 1 hour compared to usual

2 - reduction in sleep duration by more than an hour

3 - reports decreased need for sleep

4 - denies need for sleep

5. Irritability

1 - absent

2 - subjective increase

4 - irritable during the interview, recent episodes of anger or irritability in the ward

6 - frequently irritable during the interview, tries to terminate the conversation

8 - hostile, uncooperative, interview impossible

6. Speech (rate and amount)

0 - not increased

2 - subjectively noted talkativeness

4 - occasionally verbose, speech accelerated

6 - pressured speech, distinct acceleration of pace, highly talkative, difficult to interrupt

8 - "flight of words", impossible to interrupt, continuous speech

7. Thought disorder

0 - absent

1 - patient is circumstantial, somewhat distractible, thinking accelerated

2 - distractible, loses the goal of speech, frequently changes topic, "flight of ideas"

3 - rush of ideas, ideational confusion, incoherence; rhymes sentences; echolalia

4 - thinking is incoherent; incapable of productive contact

8. Content of thoughts

0 - normal

2 - questionable plans, new interests

4 - special projects, hyperreligiosity

6 - grandiose or paranoid ideas, ideas of reference

8 - delusions, hallucinations

9. Aggressive behavior

0 - absent, cooperates with the physician

2 - sarcastic in communication, periodically raises voice, tense

4 - makes demands, expresses threats in the ward

6 - threatens the physician, uses profanity, interview is difficult

8 - attacks, performs destructive actions, interview is impossible

10. Appearance

0 - appropriately dressed and groomed

1 - somewhat untidy appearance

2 - looks unkempt, sloppily dressed, inappropriate "dressiness"

3 - sloppy, incompletely dressed, flamboyant makeup

4 - dressed extremely casually, bizarrely, wearing many jewelry items

11. Insight into illness

0 - acknowledges being ill, agrees with the need for treatment

1 - agrees that they might be ill

2 - acknowledges changes in behavior, but denies illness

3 - acknowledges that changes in behavior are possible, but denies illness

4 - denies any changes in behavior

Score: ___________

Appendix G3. Hamilton Depression Rating Scale (HAM-D-17 items)

Russian title: Hamilton Depression Rating Scale

Original title (if applicable): has several title variants: Hamilton Rating Scale for Depression (HRSD), Hamilton Depression Rating Scale (HDRS). The most frequent abbreviation is HAM-D,

Source (official developer website, validation publication):

Hamilton, M (1960) A rating scale for depression. Journal of Neurology, Neurosurgery and

Psychiatry. 23: 56-62 PMID 14399272

Type (underline):

-

rating scale

-

index

-

questionnaire

-

other (specify):______________________________________________________

Purpose: for quantified assessment of the severity of depressive symptoms in patients with a verified diagnosis of depression. Widely used to assess the dynamics of depressive symptom severity during therapy.

Content (template): consists of 17 items evaluating various manifestations of depressive syndrome. For each item, scores range from 0–4 or 0–2, where 0 is normal. The rating is based on the following signs:

content of statements

tone

facial expression

patient's gestures during the interview

Key (interpretation): Total score of 17 items:

>    —7 — normal

>   —13 — mild depressive disorder

>   4—18 — moderate depressive disorder

>   9—22 — severe depressive disorder

above 23 — extremely severe depressive disorder

Notes: Completed based on the results of an interview conducted by an expert who is a psychiatrist with experience working with depressed patients and who has completed training on this scale. The patient's condition over the past 7 days is evaluated

Hamilton Depression Rating Scale (HAM-D-17 items)

>  Please inform the patient that to achieve the purpose of the survey, it is necessary to answer the questions very accurately.

>    Please review each item sequentially

>  The reference period for evaluation is the week preceding the survey, except for items 8, 9 (during the survey) 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: |___|___|

Appendix G4. Montgomery-Asberg Depression Rating Scale – MADRS

Russian title: Montgomery-Asberg Depression Rating Scale

Original title (if applicable). Montgomery – Asberg Depression Rating Scale (MADRS)

Source (official developers' website, validation publication): Montgomery SA, Asberg M (April 1979). "A new depression scale designed to be sensitive to change". British Journal of Psychiatry. 134 (4): 382-89. doi:10.1192/bjp.134.4.382. PMID 444788.

Type (underline):

-

rating scale

-

index

-

questionnaire

-

other (specify):______________________________________________________

Purpose: for rapid and accurate assessment of depression severity and its dynamics during therapy. Used to assess symptom severity in patients with an established diagnosis of depression.

Content (template): the scale consists of 10 items, each having 6 grades for assessing symptom severity.

Key (interpretation): scores are calculated as follows: each item of the scale is rated from 0 to 6 according to the increasing severity of the symptom. The maximum total score is 60 points. The sum of scores corresponds to:

• 0-15 points — absence of a depressive episode;

• 16-25 points — minor depressive episode;

• 26-30 points — moderate depressive episode;

• over 30 points — major depressive episode.

Notes: Completed based on the results of an interview conducted by an expert who is a psychiatrist with experience working with depressed patients and who has completed training on this scale. The patient's condition over the past 7 days is evaluated. The assessment should be based on a clinical interview ranging from least direct to clarifying questions about the condition and its severity.

The investigator must decide whether the severity of the symptom corresponds to the main scores — 0, 2, 4, 6 or intermediate ones — 1, 3, 5. If exact answers cannot be obtained from the patient themselves, it is recommended to use other sources of information (medical documentation, accounts from relatives, etc.). Evaluated based on data from the past 7 days. To assess the condition in dynamics, re-testing is performed at fixed intervals.

Montgomery-Asberg Depression Rating Scale

Appendix G5. HCL-33. Hypomania Checklist

Russian title: HCL-33. Hypomania Checklist

Original title (if applicable): Hypomania Checklist (HCL-33)

Source (official developer website, validation publication):

Mosolov S.N., Yaltonskaya P.A., Senko O.V., Kursakov A.A., Alfimov P.V., Angst J.

Detection of 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 (please specify):

Purpose: detection of history of hypomania.

Content (template):

HCL-33 SELF-QUESTIONNAIRE (completed by the patient)

Energy, activity, and mood

At different periods in 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 examine "periods of highs". 1) First, please indicate how you feel today compared to your usual state: (please select only one statement from the list)