DEPRESSION AND DIABETES

Version 2 updated as per June 2021

EPIDEMIOLOGY OF DEPRESSION IN DIABETES
AND DISEASE BURDEN
 EPIDEMIOLOGY OF DEPRESSION IN DIABETES

• High rates of co-morbidity of depression and diabetes have been reported.

Compared to people without diabetes, the prevalence rates of depression are1:
- more than 3-4 times higher in type 1 diabetes: 12% (range 5.8-43.3%) vs. 3.2%
(range 2.7- 11.4%)
- nearly twice as high in people with type 2 diabetes: 19.1% (range 6.5-33%) vs.
10.7% (range 3.8-19.4%)
- women with diabetes and also women without diabetes experience a higher
prevalence of depression than men

• The prevalence of clinically relevant depressive symptoms is 31% and that of major
depression 11% 2

• Most of the studies have been performed in US and UK

1
Roy T , Lloyd CE. J Affect Disord . 2012 Oct;142 Suppl:S8-21. 2
Anderson et al., Diabetes Care, 2001
 PREVALENCE OF DEPRESSIVE DISORDERS
IN TYPE 2 DIABETES OUTSIDE UK & US:
THE INTERPRET-DD STUDY RESULTS
(Argentina, Bangladesh, Brazil, China, Germany, India, Italy, Kenya, Mexico,
Pakistan, Poland, Russia, Serbia, Thailand, Uganda, Ukraine) 1

• 2783 people with Type 2 diabetes from primary care

• Current major depressive disorder: 10.6%

(standardized psychiatric interview)
Moderate/ severe levels of depressive symptoms 17.0%
(Patient Health Questionnaire scores >9)

• In a multivariate analysis after controlling for country,

current major depressive disorder was significantly
associated with:
- female gender - lower level of education
- doing less exercise - higher levels of diabetes distress
- previous diagnosis
of major depressive disorder

• The proportion of those with either current major depressive disorder or moderate to severe levels
of depressive symptomatology who had a diagnosis or any treatment for their depression recorded
in their medical records was extremely low and non-existent in many countries (0–29.6%)

1 Lloyd et al. Diabetic Medicine, 2018

 PEOPLE WITH BOTH DEPRESSION AND DIABETES HAVE
A GREATER DECREMENT IN SELF-REPORTED HEALTH THAN
THOSE WITH DEPRESSION AND ANY OTHER CHRONIC DISEASE

Moussavi et al., Lancet 2007;370:851-858

 HEALTH CARE UTILIZATION IS SIGNIFICANTLY HIGHER
AMONG DEPRESSED COMPARED TO NON-DEPRESSED
DIABETES PATIENTS (US 1996 data)

Egede LE. Medical costs of depression and diabetes. In: Depression and Diabetes. Katon W, Maj M, Sartorius N (eds). Chichester: Wiley, 2010.
 PROGNOSIS OF COMORBID DEPRESSION AND DIABETES
The prognosis of both diabetes and depression (in terms of complications, treatment resistance and
mortality) is worse when the two diseases are comorbid than when they occur separately 1-3

Survival functions in a nondiabetic population stratified by Centers for Epidemiologic Studies

Diabetic population
Survival functions in a diabetic population stratified by Centers for Epidemiologic Studies
Depression (CES-D) Scale score, NHANES I Epidemiologic Follow-up Study, 1982-1992
Non-diabetic population
Depression (CES-D) Scale score, NHANES I Epidemiologic Follow-up Study, 1982-1992

Zhang, X. et al. Am. J. Epidemiol. 2005 161:652-660; doi:10.1093/aje/kwi089 Zhang, X. et al. Am. J. Epidemiol. 2005 161:652-660; doi:10.1093/aje/kwi089

A strong association has been found between depressive symptoms (as assessed by the Center for
Copyright restrictions may apply. Copyright restrictions may apply.
Epidemiological Studies - Depression Scale, CES-D) and increased mortality in people with diabetes,
but not in those without diabetes, after adjusting for socio-demographic and lifestyle factors 1, 4.

1 Lloyd CE et al. The epidemiology of depression and diabetes. In: Depression and Diabetes. Katon W, Maj M, Sartorius N (eds).
Chichester: Wiley, 2010. 2 Lustman PJ et al. Diabetes Care 2000; 23: 934–943. 3 Egede LE et al. Diabetes Care 2005; 28: 1339–1345.
4 Zhang et al., Am. J. Epidemiol. 2005;161:652-660
 BI-DIRECTIONAL LINK
BETWEEN DEPRESSION AND DIABETES
 DEPRESSION AND DIABETIC COMPLICATIONS:
A BI-DIRECTIONAL RELATIONSHIP (1)

• Depressive symptoms are more common in diabetes patients with macro- and micro-vascular
problems, such as erectile dysfunction and diabetic foot disease 4
• Depressive symptoms are positively associated with the presence of diabetic nephropathy,
proliferative retinopathy, MACE in people with type 1 diabetes 5
• A prospective association has been documented between prior depressive symptoms and the
onset of coronary artery disease (angina) in people with diabetes 6
• A prospective association has been found between depression and the onset of retinopathy in
children with diabetes 7
• In a meta-analysis of data from 3898 individuals with type 2 diabetes, there was an association
between depression and neuropathy with an odds ratio of 2.01 (95% CI: 1.60-2.54; p < 0.001)
8

• In a systematic review and a meta-analysis, there was a 47.9% increase in cardiovascular

mortality, 36.8% increase in coronary heart disease and 32.9% increase in stroke in people
with diabetes and comorbid depression 9

4 Thomas et al. J Affect Disord 2004;79(1-3):81-95. 5 Ahola et al. Diabetes Res Clin Pract . 2020;170:108495
6 Orchard et al. Diabetes Care 2003; 26(5):1374-9 7 Kovacs et al. Diabetes Care . 1995 Dec;18(12):1592-9.
8 Bartoli et al. Int J Geriatr Psychiatry . 2016 Aug;31(8):829-36 9 Farooqi et al. Diabetes Res Clin Pract. 2019 ;156:107816
 DEPRESSION AND DIABETIC COMPLICATIONS:
A BI-DIRECTIONAL RELATIONSHIP (2)

The relationship between depression and diabetes complications appears bi-directional.

However, the risk of developing diabetes complications in depressed people is higher than the
risk of developing depression in people with diabetes complications:

• In a systematic review and meta-analysis, depression was associated with an increased risk
of incident macrovascular (HR = 1.38; 95% CI: 1.30-1.47) and microvascular diabetic
complications (HR = 1.33; 95% CI: 1.25-1.41) (16 studies)

• In a systematic review and meta-analysis, diabetes complications increased the risk of

incident depressive disorder (HR = 1.14; 95% CI: 1.07-1.21) (2 studies with more than 230
000 participants).

Nouwen A. Longitudinal associations between depression and diabetes complications: a systematic review and meta-analysis . Diabet
Med . 2019;36(12):1562-1572.
 DEPRESSION AND DIABETES:
A BI-DIRECTIONAL RELATIONSHIP

• People with depressive disorders have a 34% to 65% increased risk of developing
diabetes 1, 2, 3

• People with diabetes patients have a 15% to 28% higher risk of depression
than nondiabetic subjects 2, 3

1 Campayo et al. Am J Psychiatry 2010;167(5):580-8.

2 Zhuang et al. Oncotarget. 2017;8:23389–400
3 Mezuk B. Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care. 2008 Dec;31(12):2383-
90
 THE DEPRESSION-DIABETES LINK
BEHAVIORAL FACTORS:
• Depression is associated with reduced physical activity, which increases the risk for
obesity and consequently for type 2 diabetes.
• Depression is associated with poor diabetes self-care (including oral medication taking,
dietary modifications, exercising and monitoring of blood glucose).
• Emotional problems related to diabetes may lead to the development of depression.

BIOLOGICAL FACTORS:
• Depression is a phenotype for a range of stress-related disorders which lead to an
activation of the hypothalamic-pituitary-adrenal axis, a dysregulation of the
autonomic nervous system and a release of pro-inflammatory cytokines, ultimately
resulting in insulin resistance
• Metabolic programming at the genetic level and undernutrition (in utero and
childhood) may predispose to both diabetes and depression

Lloyd CE et al. The epidemiology of depression and diabetes. In: Depression and Diabetes. Katon W, Maj M, Sartorius N (eds). Chichester:
Wiley, 2010.
Ismail K. Unravelling the pathogenesis of the depression-diabetes link. In: Depression and Diabetes. Katon W, Maj M, Sartorius N (eds).
Chichester: Wiley, 2010.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
 DSM-5 DIAGNOSTIC CRITERIA
FOR MAJOR DEPRESSIVE DISORDER
A. Five (or more) of the following symptoms have been present during the same 2-week period and
represent a change from previous functioning;

1*. Depressed mood most of the day, nearly every day

2*. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly
every day

3. Significant weight loss when not dieting or weight gain (> 5% of body weight in a month), or
decrease or increase in appetite nearly every day
4. Insomnia or hypersomnia nearly every day
5. Psychomotor agitation or retardation nearly every day (observable by others)
6. Fatigue or loss of energy nearly every day
7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day
8. Diminished ability to think or concentrate, or indecisiveness nearly every day
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation, or a suicide attempt,
or a specific plan for committing suicide

B. The symptoms cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.

C. The episode is not attributable to the physiological effects of a substance or to another medical
condition.

* At least one of two main criteria is obligatory for the diagnosis

 PHYSICAL SYMPTOMS OF DEPRESSION
OVERLAP WITH THOSE OF UNCONTROLLED DIABETES
- Dry mouth and thirst
- Decreased or increased appetite
- Sexual dysfunction (loss of libido,
erectile dysfunction, dysmenorrhea)
- Fatigue and decreased productivity
- Decreased or increased bodyweight
- Increased rate of infections
- Pains and aches

• HbA1 as a measure of diabetes control is poorly correlated with 9 of 11 symptoms

of uncontrolled diabetes and is significantly associated only with polyuria
• In contrast, depression is moderately correlated with 9 symptoms and significantly
correlated with 2 of 3 symptoms of hyperglycemia, 5 of 6 symptoms of
hypoglycemia and with nonspecific symptoms of poor glycemic control
• Many reported symptoms often attributed to diabetes are more related to
depressive mood than to a conventional clinical measure of blood glucose control
(HbA1c)
• Diabetes symptoms may be unreliable indicators of poor metabolic control when
features suggestive of depression are present.

Lustman et al. Int J Psychiatry Med 1988;18(4):295-303

 THE DEPRESSION-DIABETES SYMPTOM ASSOCIATION IS
STRONGER THAN THE ASSOCIATION OF DIABETES
SYMPTOMS WITH MEASURES OF GLYCEMIC CONTROL
AND DIABETES COMPLICATIONS
• In a survey of 4168 patients with diabetes, those with major depression reported
significantly more diabetes symptoms (mean=4.40) than participants without
depression (mean=2.46) after adjusting for demographic characteristics, objective
measures of diabetes severity and medical comorbidity

• The overall number of diabetes symptoms was significantly related to the number of
depressive symptoms

• Depression was significantly related to each of the 10 diabetes symptoms (all P<0.001)

Therefore, depression should be on the list of differential diagnoses in any individual

with diabetes reporting many “diabetes-related” symptoms, especially when blood glucose
self-monitoring and/or HbA1c measurements are not easily available or done as
recommended

Ludman et al. General Hospital Psychiatry 2004, 26(6):430-436

 OTHER ISSUES OF THE DIFFERENTIAL DIAGNOSIS
IN A DIABETIC INDIVIDUAL WITH DEPRESSION AND
ASSOCIATED MENTAL DISORDERS
Common mental Differential Similar symptoms for Measures to be taken to
comorbidities diagnosis with… both differentiate
Depression with Diabetic painful Leg and feet pain, Assess for objective signs of
somatic neuropathy restless legs diabetic neuropathy (vibration
symptoms of sensation measurement, etc.).
pains and aches Consider that depression is
frequently comorbid with
diabetic painful neuropathy
Depression + Diabetic Palpitations, Perform orthostatic tests for
generalized autonomous tachycardia, BP autonomous neuropathy, ECG
anxiety disorder neuropathy, fluctuations, heart monitoring, assess other signs
cardiovascular and arrhythmias, and symptoms of diabetic
gastrointestinal type increased gut neuropathy
movements
Depression + Hypoglycemia Identical adrenergic Immediately measure glycemia
panic attacks and vagal symptoms during the episode
Depression + Hypoglycemia Hunger attacks, Measure glycemia as soon as
binge eating frequently with possible during the binge episode
disorder adrenergic symptoms
 MANAGEMENT OF A PATIENT WITH
COMORBID DIABETES AND DEPRESSION
 PRACTICAL PROBLEMS ARISING FROM DEPRESSION-
DIABETES COMORBIDITY - I

Problem Impact

• Depression and diabetes symptoms • Patient and clinician may be unaware of depression, and
overlap may primarily attribute changed status to worsening
• Depression symptoms mimic diabetes self-care
diabetes symptoms

• Depression may be associated with • Patient may not sense he/she is fully understood or
onset or amplification of physical supported by his/her clinician during health care visits when
symptoms physical or lab results do not correspond to subjective
complaints

• Depression is commonly associated • Patient may feel resigned about the ability to make changes,
with difficulties with diabetes self- e.g. “I know what I am supposed to do and what I am not
management and treatment supposed to do, but I still do the wrong things and I don’t
adherence know why!”
• Clinician may feel discouraged about the ability of the
patient to make relevant changes in his/her care

Hellman R, Ciechanowski P. Diabetes and depression: management in ordinary clinical conditions. In: Depression and Diabetes. Katon
W, Maj M, Sartorius N (eds). Chichester: Wiley, 2010.
 PRACTICAL PROBLEMS ARISING FROM DEPRESSION-
DIABETES COMORBIDITY - II
Problem
• Individuals with depression may attempt to
regulate emotions with food or substances
• Stressors that interfere with self-management
strategies and worsen diabetes status may also
precipitate or exacerbate depression
• Depression may reduce the ability of affected
individuals to trust others or to be satisfied with
health care
• Depression is commonly associated with changes
in health care seeking patterns and follow-
through with appointments
Hellman R, Ciechanowski P. Diabetes and depression: management in ordinary clinical conditions. In: Depression and Diabetes. Katon
W, Maj M, Sartorius N (eds). Chichester: Wiley, 2010.
Impact
• A clinician not understanding the underlying
depressive symptoms and patient’s desperation to
regulate emotional pain may come across as
judgmental because of the stigma and associated
response to these behaviors
• Patient and clinician may attribute poor diabetes
outcomes to a decrease in self-management
because of a busy lifestyle but may not appreciate
the insidious development of depression and its
consequences
• Patient may be reluctant to make appointments,
show up for appointments, seek support of health
care providers or collaborate with health care
providers during appointments
 PRACTICAL PROBLEMS ARISING FROM DEPRESSION-
DIABETES COMORBIDITY - III
Problem Impact

• Depression may be associated
with poor blood glucose control
irrespective of behavioral actions
• This may lead to hopelessness, guilt, loss of empowerment, or a
decreased sense of control of illness and may influence the
motivation of the patient to engage in further clinical treatment
recommendations
• Unsuspecting clinicians may unwittingly blame the patient for a
situation the patient now has little control over

• Depression is commonly • What might have been easily understood in the past may need to
associated with difficulty be written, repeated and checked for comprehension while the
organizing tasks patient is depressed

• Depression leads to a more • Clinicians may need to help depressed patients break down tasks
pessimistic view of the future into manageable action steps that my have shorter-term pay-off
(e.g., reduction of physical symptoms)

• Depression is commonly • Clinicians need to consider presence of anxiety which heightens a

associated with anxiety patient’s uncertainty around decision-making and increases a
general sense of dread about the likelihood of success
Hellman R, Ciechanowski P. Diabetes and depression: management in ordinary clinical conditions. In: Depression and Diabetes. Katon
W, Maj M, Sartorius N (eds). Chichester: Wiley, 2010.
EFFICACY TRIALS OF PSYCHOTHERAPIES FOR DEPRESSION
IN DIABETES
Study Interventions
Lustman et al., Cognitive-behavioural therapy (CBT) plus
1998 diabetes education vs. diabetes
education alone
Huang et al., 2002 Antidiabetics + diabetic education +
psychological treatment + relaxation and
music treatment vs. antidiabetics only
Li et al., 2003 Antidiabetics + diabetic education +
psychological treatment vs. antidiabetics
only
Lu et al., 2005 Diabetes and cerebrovascular accident
education + electromyographic treatment
+ psychological treatment vs. usual care
Simson et al., 2008 Individual supportive psychotherapy vs.
usual care
From Katon W, van der Felz-Cornelis C. Treatment of depression in patients with diabetes. In: Depression and Diabetes. Katon W,
Maj M, Sartorius N (eds). Chichester: Wiley, 2010.
Uchendu, Blake, Systematic review and meta-analysis of
2017 CBT in depression and diabetes
Uchendu C, Blake H. Diabet Med. 2017;34(3):328-339
Outcome
Improvement in depression as well as glycemic
control in CBT vs. control group
Improvement in depression as well as glycemic
control in treatment vs. control group
Improvement in depression as well as glycemic
control in treatment vs. control group
Improvement in depression as well as glycemic
control in treatment vs. control group
Improvement in depression as well as glycemic
control in supportive psychotherapy vs. control
group
Improvement of short-term and medium-term
glycemic control, although no significant effect for
long-term glycemic control. Improvement in short-
and medium-term anxiety and depression, and
long-term depression. Mixed results for diabetes-
related distress and quality of life.
 EFFICACY TRIALS OF MEDICATIONS FOR DEPRESSION
IN DIABETES
Study Interventions Outcome

Lustman et al., 1997 Glucometertraining + Improvement in depression but not in glycemic control with
nortriptyline vs. placebo nortryptiline vs. placebo
Lustman et al., 2000 Fluoxetine vs. placebo Improvement in depression but not in glycemic control with
fluoxetine vs. placebo
Paile-Hyvärinen et al., Paroxetine vs. placebo After initial improvement in paroxetine group at 3 months,
2003 no significant improvement for both outcomes at the end of
follow-up
Xue et al., 2004 Paroxetine vs. placebo Improvement in depression but not in glycemic control with
paroxetine vs. placebo
Gülseren et al., 2005 Fluoxetine vs. paroxetine Both groups improved significantly in depression but not in
glycemic control
Paile-Hyvärinen et al., Paroxetine vs. placebo No significant improvement in depressive outcomes and
2007 glycemic control

Katon W, van der Felz-Cornelis C. Treatment of depression in patients with diabetes. In: Depression and Diabetes. Katon W, Maj M,
Sartorius N (eds). Chichester: Wiley, 2010.

Roopan, Larsen, 2017 Systematic review of 18 Reduction in depressive symptoms after treatment with an
trials antidepressant in the acute as well as during maintenance
phase. Depression improvement had a favorable effect on
glycemic control that was weight independent.
Roopan S, Larsen ER. Acta Neuropsychiatr . 2017;29(3):127-139.
 DEPRESSION CARE IN PATIENTS WITH DIABETES: STEP 1
Screen for:

• Depression with the Patient Health Questionnaire - 9 (PHQ-9)

• Helplessness/”giving up” or sense of being overwhelmed about disease self-
management
• Comorbid panic attacks, post-traumatic stress disorder, GAD and phobia of
hypoglycemia
• Inability to differentiate anxiety symptoms from diabetes symptoms (e.g.,
hypoglycemia)
• Associated eating concerns
• Emotional eating in response to sadness/loneliness/anger
• Binge eating/purging
• Night eating

Katon W, van der Felz-Cornelis C. Treatment of depression in patients with diabetes. In: Depression and Diabetes. Katon W, Maj M,
Sartorius N (eds). Chichester: Wiley, 2010.
 DEPRESSION CARE IN PATIENTS WITH DIABETES: STEP 2

Improve self-management:

• Explore “loss of control” of disease self-management

• Explore understanding of bidirectional link between stress and suboptimal disease self-
management and outcomes
• Define depression and how it overlaps with and is distinct from “stress”
• Review symptoms of depression and how these symptoms overlap with or mimic diabetes
symptoms
• Discuss depression-related medical symptom amplification
• Break down tasks in self-management of diabetes, depression, other illnesses
• Help patient prioritize order of importance of specific tasks

Katon W, van der Felz-Cornelis C. Treatment of depression in patients with diabetes. In: Depression and Diabetes. Katon W, Maj M,
Sartorius N (eds). Chichester: Wiley, 2010.
 DEPRESSION CARE IN PATIENTS WITH DIABETES: STEP 3

Support:

• Consider adjunctive brief psychotherapy for:

- emotional eating (cognitive-behavioural therapy)
- breaking down problems (problem-solving therapy)
- improving treatment adherence (motivational interviewing)

Katon W, van der Felz-Cornelis C. Treatment of depression in patients with diabetes. In: Depression and Diabetes. Katon W, Maj M,
Sartorius N (eds). Chichester: Wiley, 2010.
 DEPRESSION CARE IN PATIENTS WITH DIABETES: STEP 4
Consider medication:

• Comorbid depression and anxiety: SSRI, SNRI 1 or TCA (amitriptyline). Consider adding a
2 to 4 weeks’ course of an anxiolytic if anxiety increases in the beginning of SSRI or SNRI

• Sexual dysfunction: use bupropion or, if already responding to SSRI, add buspirone 1

• Comorbid depression and binge eating: fluoxetine

• Comorbid depression and painful neuropathy: choose duloxetine* due to effectiveness

in treating neuropathic pain. For augmentation of analgesia or in cases of anxiety,
consider adding pregabalin due to effectiveness in neuropatic pain and anxiety 2. Tricyclic
antidepressants and venlafaxine, although not approved for the treatment of painful
diabetic neuropathy, may be effective and considered for the treatment 2

1 Katon W, van der Felz-Cornelis C. Treatment of depression in patients with diabetes. In: Depression and Diabetes. Katon W, Maj M,
Sartorius N (eds). Chichester: Wiley, 2010
2 American Diabetes Association. Standards of Care Guidelines. Diabetes Care 2021 ; 44(Supplement 1): S151-S167.
* Duloxetine if the only antidepressant approved for the treatment of painful diabetic neuropathy both by FDA and EMA
SSRI, selective serotonin reuptake inhibitors; SNRI, serotonin and noradrenalin reuptake inhibitors; TCA, tricyclic antidepressants
 WHAT ELSE TO CONSIDER WHEN CHOOSING
AN ANTIDEPRESSANT IN A PERSON WITH DIABETES
• Some antidepressants (especially amitriptyline, clomipramine, mianserin,
mirtazapin), as well as antipsychotics and normotymics prescribed in combination
with antidepressants (especially olanzapine, clozapine, risperidon, valproates, etc)
can lead to excessive weight gain and hyperglycemia (to the extent requiring insulin,
if not used before). These medications should be used in a person with diabetes only
if strictly necessary

• Some antidepressants (most SSRI, especially fluoxetine, less frequently duloxetine,

MAO inhibitors) can lead to decreased appetite and promote hypoglycemia

• Successful treatment of depression per se may change eating habits, increase

physical activity and change compliance to anti-diabetic treatments, which all may
act on blood glucose levels

• The resultant fluctuations in blood glucose in a given patient is difficult to predict.

Therefore, treatment of depression, in particular in the above mentioned situations,
requires more frequent self-monitoring of blood glucose, HbA1c measurement and
modification of anti-diabetic treatment, when necessary
 POTENTIAL COST SAVINGS DUE TO
TREATMENT OF DEPRESSION IN DIABETES

$25 000

$20 000

Total Medical
Costs Over a 2-

Usual Care
$15 000

Intervention
Year Period

Intervention
Usual Care
$10 000

Savings

Savings
$5 000

$0
Katon et al., 2006 Simon et al., 2007

Enhanced treatment of depression in patients with diabetes is associated with lower health care
costs over a 2-year period

Katon W, van der Felz-Cornelis C. Treatment of depression in patients with diabetes. In: Depression and Diabetes. Katon W, Maj
M, Sartorius N (eds). Chichester: Wiley, 2010.
 ACKNOWLEDGEMENTS

This synopsis is part of the WPA program aiming to raise the awareness of the
prevalence and prognostic implications of depression in persons with physical diseases.
The support to the program of the Lugli Foundation, the Italian Society of Biological
Psychiatry, Eli-Lilly and Bristol-Myers Squibb is gratefully acknowledged. The WPA is
grateful to Professor Andrea Fiorillo, MD, PhD (Naples, Italy) and Professor Elena
Starostina, MD, PhD (Moscow, Russia) for their help in the preparation of this synopsis