3.4 Affective Disorders
Week 4
Bipolar Disorder
,Bipolar Disorder → Lifetime Perspective
Carvalho et al (2020)
Bipolar Disorder
Introduction
● Mood fluctuations are common in normal daily life as a result of life events
● Severe and persistent, result in distress & behavioral impairment → underlying disorder
● Bipolar I
○ Presence of overt manic episodes
○ Overconfidence, grandiosity, talkativeness, extreme disinhibition, irritability,
decreased need for sleep, highly elevated mood
○ Psychotics symptoms and delusions occur in 75% of episodes
○ Episode needs to be at least 1 week long for diagnosis
● Bipolar II
○ Presence of episodes of depression alternating with hypomania (instead of
mania)
○ Episode should be at least 2 weeks long for diagnosis
● Cyclothymic disorders
○ Recurrent depressive & hypomanic states lasting for 2 years
● Atypical bipolar-like phenomena → other specified bipolar related disorder category
● Bipolar can also be affected by depressive symptoms
● Onset is typical at age 20
○ Earlier onset associated with poorer prognosis, longer treatment delays, severe
depressive episodes, higher prevalence of concurrent anxiety & substance abuse
○ First episode of bipolar is usually depressive, depressive episodes usually last
longer than manic or hypomanic
■ Because of this often misdiagnosed as depression
● Evidence of overdiagnosis → when there is reliance on self-reported screening
instruments (high rates of false positives)
● In up to ⅓ of patients, bipolar is not diagnosed until 10 years after the onset
Epidemiology and burden of illness
● 17th leading source of disability
● Prevalence
○ Lifetime prevalence → 2.4%
○ 12 month prevalence → 1.5%
○ Varying levels per country → cultural differences
○ Bipolar I no gender difference
○ Bipolar II more often in females
○ Prevalent in primary care practice
, ● Risk factors have been identified, but not often high quality evidence
○ IBS, childhood adversity
● Typically arises during formative years in children & adolescents → often affects
achievements
○ Cognitive & psychosocial dysfunction
● 6-7% commit suicide (rates are 20-30 times higher than in the population)
● High rates of coexisting psychiatric conditions (anxiety, substance abuse, personality
disorders, ADHD
○ Increase burden & worsen prognosis
● Chronic medical conditions are more prevalent
○ Metabolic syndrome, migraine, obesity, diabetes type 2
○ Twice the risk of death
Genetic & neurobiologic features
● Heritability 70-90%
● Many genes with small effect sizes contribute
○ 30 significant loci
○ Sets involved in regulation of insulin secretion & endocannabinoid signaling
○ Common variants only account for 25% of the disorder
○ Thought to interact with environmental factors
● Kindling hypothesis
○ Explains stress sensitization leading to recurring affective episodes
○ The first episode occurs after exposure to a stressor
○ Subsequent episodes can occur without exposure to a stressful event
○ Mechanisms strengthened if illness is not treated or if person is exposed to
psychoactive substances or has lifestyle risks
○ Epigenetic mechanisms could also contribute
● Neuroprogression → changes in brain structure & cellular function
○ Observed in studies of recurrent affective disorder
○ Reduced cortical thickness in brain regions like PFC (stress regulation)
○ Epigenetic mechanisms, deregulation of mitochondrial function, pathways
subserving neuroplasticity, inflammation, increase in oxidative & nitrosative stress
have been proposed as factors that proposed neuroprogression in bipolar
○ Changes in HPA axis play a role
○ May account for worsening cognitive & functional impairments
○ May contribute to higher prevalence of coexisting conditions
○ Evidence for further progression of disorder being associated with worsened
response to mood-stabilizing medication
○ A subgroup of people experience no cognitive and psychosocial differences
(heterogeneous disorder)
Management
● General principles
○ Most patients seek primary care help
, ○ Other disorders that mimic affective episodes should be ruled out (substance
abuse & psychotic disorders)
○ Factors influencing treatment
■ Patients preference
■ Coexisting conditions
■ Safety of patients during episodes should be ensured
■ Discuss pharmacological & non pharmacologic treatments
■ Monitor adherence
● Treatment of acute episodes
○ Acute mania
■ Pharmacologic treatment is first step
■ If resistant or severe → combined with nonpharmacologic
■ Mood stabilizers (eg lithium)
■ Antipsychotics (eg aripiprazole, risperidone)
■ No meaningful differences found in the efficacy of the medications
■ If there is no response to medication after 1-2 weeks, different medication
is considered
● Combination of antipsychotic with mood stabilizer is more effective
for severe mania
■ Antipsychotics can have metabolic adverse effects
■ Electroconvulsive therapy has been reported to be effective for refractory
mania & aggressive/psychotic symptoms
○ Acute depression
■ Patients with bipolar are depressed more of the time than they are
manic/hypomanic
■ Greater presence of unwanted side effects of drugs during depressive
episodes than manic episodes
● Low initial dose and gradual upward dose recommended
● Only limited number are approved for episodes (4)
■ Other treatments are usually used alongside drugs (antipsychotic with
mood stabilizers)
■ Efficacy of ketamine & anti inflammatory drugs suggested in RCTs
■ Controversy
● Treatments with antidepressants may carry risk of switches to
(hypo)mania during treatment (affective switches)
● Acceleration of cycling between episodes
■ Nevertheless SSRIs have been demonstrated to be effective in short term
(small effect sizes, no significant differences in response or remission)
● Effects are limited
■ Risk of switches is higher among bipolar I than bipolar II → less use of
antidepressants but if necessary, combined with mood stabilizers
■ ECT is effective for treatment resistant depression
Week 4
Bipolar Disorder
,Bipolar Disorder → Lifetime Perspective
Carvalho et al (2020)
Bipolar Disorder
Introduction
● Mood fluctuations are common in normal daily life as a result of life events
● Severe and persistent, result in distress & behavioral impairment → underlying disorder
● Bipolar I
○ Presence of overt manic episodes
○ Overconfidence, grandiosity, talkativeness, extreme disinhibition, irritability,
decreased need for sleep, highly elevated mood
○ Psychotics symptoms and delusions occur in 75% of episodes
○ Episode needs to be at least 1 week long for diagnosis
● Bipolar II
○ Presence of episodes of depression alternating with hypomania (instead of
mania)
○ Episode should be at least 2 weeks long for diagnosis
● Cyclothymic disorders
○ Recurrent depressive & hypomanic states lasting for 2 years
● Atypical bipolar-like phenomena → other specified bipolar related disorder category
● Bipolar can also be affected by depressive symptoms
● Onset is typical at age 20
○ Earlier onset associated with poorer prognosis, longer treatment delays, severe
depressive episodes, higher prevalence of concurrent anxiety & substance abuse
○ First episode of bipolar is usually depressive, depressive episodes usually last
longer than manic or hypomanic
■ Because of this often misdiagnosed as depression
● Evidence of overdiagnosis → when there is reliance on self-reported screening
instruments (high rates of false positives)
● In up to ⅓ of patients, bipolar is not diagnosed until 10 years after the onset
Epidemiology and burden of illness
● 17th leading source of disability
● Prevalence
○ Lifetime prevalence → 2.4%
○ 12 month prevalence → 1.5%
○ Varying levels per country → cultural differences
○ Bipolar I no gender difference
○ Bipolar II more often in females
○ Prevalent in primary care practice
, ● Risk factors have been identified, but not often high quality evidence
○ IBS, childhood adversity
● Typically arises during formative years in children & adolescents → often affects
achievements
○ Cognitive & psychosocial dysfunction
● 6-7% commit suicide (rates are 20-30 times higher than in the population)
● High rates of coexisting psychiatric conditions (anxiety, substance abuse, personality
disorders, ADHD
○ Increase burden & worsen prognosis
● Chronic medical conditions are more prevalent
○ Metabolic syndrome, migraine, obesity, diabetes type 2
○ Twice the risk of death
Genetic & neurobiologic features
● Heritability 70-90%
● Many genes with small effect sizes contribute
○ 30 significant loci
○ Sets involved in regulation of insulin secretion & endocannabinoid signaling
○ Common variants only account for 25% of the disorder
○ Thought to interact with environmental factors
● Kindling hypothesis
○ Explains stress sensitization leading to recurring affective episodes
○ The first episode occurs after exposure to a stressor
○ Subsequent episodes can occur without exposure to a stressful event
○ Mechanisms strengthened if illness is not treated or if person is exposed to
psychoactive substances or has lifestyle risks
○ Epigenetic mechanisms could also contribute
● Neuroprogression → changes in brain structure & cellular function
○ Observed in studies of recurrent affective disorder
○ Reduced cortical thickness in brain regions like PFC (stress regulation)
○ Epigenetic mechanisms, deregulation of mitochondrial function, pathways
subserving neuroplasticity, inflammation, increase in oxidative & nitrosative stress
have been proposed as factors that proposed neuroprogression in bipolar
○ Changes in HPA axis play a role
○ May account for worsening cognitive & functional impairments
○ May contribute to higher prevalence of coexisting conditions
○ Evidence for further progression of disorder being associated with worsened
response to mood-stabilizing medication
○ A subgroup of people experience no cognitive and psychosocial differences
(heterogeneous disorder)
Management
● General principles
○ Most patients seek primary care help
, ○ Other disorders that mimic affective episodes should be ruled out (substance
abuse & psychotic disorders)
○ Factors influencing treatment
■ Patients preference
■ Coexisting conditions
■ Safety of patients during episodes should be ensured
■ Discuss pharmacological & non pharmacologic treatments
■ Monitor adherence
● Treatment of acute episodes
○ Acute mania
■ Pharmacologic treatment is first step
■ If resistant or severe → combined with nonpharmacologic
■ Mood stabilizers (eg lithium)
■ Antipsychotics (eg aripiprazole, risperidone)
■ No meaningful differences found in the efficacy of the medications
■ If there is no response to medication after 1-2 weeks, different medication
is considered
● Combination of antipsychotic with mood stabilizer is more effective
for severe mania
■ Antipsychotics can have metabolic adverse effects
■ Electroconvulsive therapy has been reported to be effective for refractory
mania & aggressive/psychotic symptoms
○ Acute depression
■ Patients with bipolar are depressed more of the time than they are
manic/hypomanic
■ Greater presence of unwanted side effects of drugs during depressive
episodes than manic episodes
● Low initial dose and gradual upward dose recommended
● Only limited number are approved for episodes (4)
■ Other treatments are usually used alongside drugs (antipsychotic with
mood stabilizers)
■ Efficacy of ketamine & anti inflammatory drugs suggested in RCTs
■ Controversy
● Treatments with antidepressants may carry risk of switches to
(hypo)mania during treatment (affective switches)
● Acceleration of cycling between episodes
■ Nevertheless SSRIs have been demonstrated to be effective in short term
(small effect sizes, no significant differences in response or remission)
● Effects are limited
■ Risk of switches is higher among bipolar I than bipolar II → less use of
antidepressants but if necessary, combined with mood stabilizers
■ ECT is effective for treatment resistant depression
