Behavioral Genetics-mood Disorder

The picture was painted by: Vincent Willem van Gogh

Hussein Sabit, Ph.D 2009

Mood Disorders

Mood Episodes • Major Depressive Episode: – Severely depressed mood characterized by loss of interest in typical activities, self-deprecation, inability to concentrate

• Manic Episode: – elevated and expansive mood characterized by grandiosity, distractability, excessive involvement in pleasurable activities

Major depressive episode is a key symptom of major depressive disorder. It is characterized by severe, highly persistent depression, which is often manifested by lack of appetite, chronic fatigue, lethargy, and sleep disturbances (somnipathy). The victim may think about suicide, and in fact an increased risk of actual suicide is present. In addition to the emotional pain endured by those suffering from depression, significant economic costs are associated with depression.

Manic episode • Mania is generally characterized by a distinct period of an elevated, expansive, or irritable mood state. • People commonly experience an increase in energy and a decreased need for sleep. • Attention span is low and a person in a manic state may be easily distracted. • Judgment may become impaired; sufferers may go on spending sprees or engage in behavior that is quite abnormal for them.

Cont.. • They may indulge in substance abuse, particularly alcohol or other depressants, cocaine or other stimulants, or sleeping pills. • Their behavior may become aggressive, intolerant or intrusive. People may feel out of control or unstoppable. • People may feel they have been "chosen", are "on a special mission", or other grandiose or delusional ideas.

Signs of depressive episode • In order to be diagnosed as suffering from a major depressive episode, the patient must meet the following criteria: • Over a two week period, the patient has consistently experienced five or more of the following symptoms, and these behaviours must be outside the parameters of the patient's normal behaviour. Either depressed mood or decreased interest or pleasure must be one of the five (although both are frequently concomitant).

[] Eating disorders and weight gain/loss [] Sleep [] Motor activity [] Fatigue [] Concentration [] Thoughts of death

Biological clock human being

Mood Disorders • Major Depression • (Unipolar depression): – one or more major depressive episodes.

• Bipolar Disorder: – One or more manic episodes

major depressive disorder Unipolar disorders • •

Major Depressive Disorder Major depressive disorder is diagnosed after a single episode of major depression. It is characterized by emotional changes, primarily depressed mood, and by so-called vegetative changes, consisting of alterations in sleep, appetite, and energy levels.

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Epidemiology The lifetime prevalence (will occur at some point in a person’s life) rate for major depressive disorder is 5% to 20%. The female-male ratio is 2: 1. Race distributions appear equal, and socioeconomic variables do not seem to be a factor. The incidence (rate of new cases) is greatest between the ages of 20 and 40 and decreases after the age of 65.

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bipolar disorders • • •

There are two types; bipolar 1 disorder, bipolar II disorder. Bipolar I Disorder Bipolar I disorder is the most serious of the bipolar disorders and is diagnosed after at least one episode of mania. Patients with bipolar I disorder typically also have major depressive episodes in the course of their lives

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Bipolar II disorder is similar to bipolar I disorder except that mania is absent in bipolar II disorder and hypomania (a milder form of elevated mood than mania) is the essential diagnostic finding. Epidemiology Lifetime prevalence is about 0.5%. Bipolar II disorder may be more common in women.

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Definition of Bipolar Disorder • Bipolar Disorder, or BP, was previously called manic-depression or manic depressive disorder. BP is characterized by extreme moods - highs and lows. • Symptoms cycle from clinical or major depression, to mania and manic behavior. • Bipolar Disorder can significantly affect a patient's ability to function, and can result in strained or broken relationships, poor job performance, and poor performance in school or group settings. • Symptoms do not go away in a week or two. If left untreated, the disorder can even result in suicide.

Causes of Bipolar Disorder • Mental health disorders typically stem from more than one cause, and Bipolar Disorder (BP) is no exception to this rule. • Research on Bipolar Disorder indicates links to hereditary or genetic factors and environmental factors. • Those with a family history of depression, bipolar disorder or other mental disorders seem more likely to suffer from a mental disorder, and specifically from depression or bipolar disorder. Other research indicates a chemical imbalance in the brain of the bipolar patient. In some patients, symptoms appear after a stressful event in the patient's life, e.g. the death of a spouse, a divorce, or the loss of a job.

Symptoms of Bipolar Disorder • • • • • • • • • • • • • •

There are two types of Bipolar Disorder. Bipolar I is characterized by severe, debilitating symptoms, with extreme episodes, including some or all of the following: Manic Symptoms Agitation, nervousness, irritability, feeling edgy, short-tempered, Feeling you can 'do no wrong', inflated sense of self, grandiose feelings, inappropriate or poor judgment Increased sex drive or desire, loss of inhibition Dressing or speaking in an extreme, or unusual manner Inability to focus Delusions, hallucinations Euphoria, or feeling 'high' Heavy use of drugs or alcohol Boundless energy, sleeplessness, insomnia Rage, aggression or combative behavior Racing or disassociated thoughts, extreme talkativeness, rapid speech Reckless spending, high speed driving, high risk activities, decisions made without considering consequences

Basic Epidemiology of UP and BP • Typical age of onset – Late 20s to 30s for UP – Late teens to early 20s for BP

• Lifetime Morbid Risk – greater for UP than BP • Sex Difference for UP but not BP • Cross-cultural stability for BP not UP

Cross-national Rates of Depression 25 Men Women

20 15 10

NZ

Korea

Taiwan

Lebanon

Italy

Ger

France

PR

CA

0

U.S.

5

Cross-national Rates of Bipolar 5 Men Women

4 3 2

NZ

Korea

Taiwan

Ger

PR

CA

0

U.S.

1

Cohort Effects on Depression

Conclusions re Epidemiology • UP and BP are distinguished in terms of their: – – – –

Typical age of onset Frequency Sex ratio Cross-cultural stability

Evidence For Genetic Influence • Twin studies have consistently reported greater MZ than DZ concordance • Adoption studies indicate affective disorder is associated with biological not adoptive family background

Investigating Overlap of BP & UP • Are two disorders differentially heritable? • Is there cross-family transmission? • Is there cross-MZ twin transmission? If there is it would  shared etiology

Family Studies of Mood Disorders • Risk to Relatives of UP Proband: – Clear excess UP – Slight excess BP

• Risk to Relatives of BP Proband – Clear excess risk of BP – Clear excess risk of UP

Rates of Affective Disorder in MZ Cotwins 50 40 30

BP UP

20 10 0 Population

Cotwins of UP

Cotwins of BP

McGuffin, P. (2003). Heritability of bipolar affective disorder and the Genetic relationship to unipolar depression. Arch Gen Psychiatry, 6: 497-502.

Summary of Overlap Data • Evidence supporting shared etiology – Cross-family transmission – Cross-MZ twin transmission

• Evidence supporting distinct etiologies – Differential heritability – UP MZ twins tend to be concordant for polarity

Two Types of Mood Disorder • Less common, more severe and more heritable. Typically manifested as BP, but can also manifest as UP • More common, less heritable, and manifested as UP only.

Sex Differences in UP Depression • Differential heritability • Cross-sex transmission • Variable Expressivity? Substance Use disorders in men and depression in women?

Risk of Depression in Male and Female First Degree Relatives (Kendler et al., 1999) 0.5 0.4 0.3

LMR Female Proband Male Proband

0.2 0.1 0 Men

Women

Relatives

Gene Identification in Depression • Serotonin (5-HT) system –Serotonin Transporter (SERT, 5-HTT) • Serotonin Transporter Gene (SLC6A4) –Serotonin transporter gene-linked polymorphic region (5-HTTLPR) • 20-23bp repeated either 16 (=long) or 14 (=short) times

• s allele produces fewer 5-HTT molecules –Lesch (1996) showed that s was associated with neuroticism in two samples –Recent meta-analyses suggest a modest effect of the s allele on neuroticism; association with depression less clear (Schinka et al. 2004)

G x E Interaction and Depression

Caspi, A. et al. (2003). Influence of life stress on depression: Moderation By a polymorphism in the 5-HTT gene. Science, 301: 386-389.

Is the GxE Replicable? • Kendler et al. (2005) showed that only scarriers susceptible to low-threat events • Hariri et al. (2005) – s allele on amygdala reactivity to angry faces • Serretti et al. (2007) meta-analysis of SSRI tretament response

Linkage Analyses in Depression

Gene Identification for BP • Multiple rather than a single gene • X-linked Hypothesis – Reduced father-son transmission (Winokur, 1969)

• Anticipation? – Age of onset earlier in successive generations – No evidence of trinucleotide repeat expansion

• Linkage studies

Multiple Genes

Regions/Genes Implicated in BP Genome-Wide Linkage

Chromosomal Anomalies

1q31-32 4p16 6pter-p24 10p14 10q25-26 12q23-24 13q31-32 18p11 18q21-23 21q22 22q11-13 Xq24-28

1q31-32

Candidate Gene

11q21-25 15q11-13 21q22 22q11-13 Xq27-28

Highlighted – regions also implicated in schizophrenia

Summary •

Although in some cases UP does appear to be assoc with BP, the two are generally distinct: – Distinct epidemiology – Differentially heritable – UP MZs are generally concordant for polarity

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UP is more common in women than men – More heritable in women than men – Greater like-sex versus unlike-sex transmission implies genetic factors differ in two sexes – Recent molecular genetic research gives preliminary support to this hypothesis

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Gene identification in Depression – SLC6A4 and GxE interaction – “Genome-wide” LD mapping

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Gene identification efforts for BP – Multiple genes – Anticipation, unstable mutation – Multiple regions have been implicated