VI.

BIPOLAR DISORDERS
The DSM-5 includes three types of bipolar disorder:
● Bipolar I Disorder
● Bipolar II Disorder
○ They differ on the severity and duration of the episodes of mood elevation
○ Typically, depressive disorders alternate with manic or hypomanic episodes
● Cyclothymic Disorder

Recurrent disorders: single episodes are extremely rare

BIPOLAR I DISORDER

- At least one manic episode during lifetime

- Episodes of major depression are common but not required for the diagnosis !
- Criteria have been met for at least one manic episode (may have been precedes by and
may be followed by hypomanic or major depressive disorder)

Manic episode: a distinct period of abnormally and persistently elevated, expansive, or irritable
mood and abnormally and persistently increased goal-directed activity or energy, lasting at least
1 week and present most of the day, nearly every day (or any duration if hospitalisation is
necessary) - may also develop psychotic symptoms
- During the period of mood disturbance and increased energy or activity, three (or more)
of the following symptoms (four if the mood is only irritable) are present to a significant
degree and represent a noticeable change from usual behaviour:
- Inflated self-esteem or grandiosity
- Decreased need for sleep (e.g., feel rested after only 3 hours of sleep)
- More talkative than usual or pressure to keep talking
- Flight of ideas or subjective experience that thoughts are racing
- Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external
stimuli), as reported or observed
- Increase in goal-directed activity (either socially, at work or school, or sexually) or
psychomotor agitation (i.e., purposeless non-goal-directed activity)
- Excessive involvement in activities that have a high potential for painful
consequences (e.g., engaging in unrestrained buying sprees, sexual
indiscretions, or foolish business investments)
- The mood disturbance is sufficiently severe to cause marked impairment in social or
occupational functioning or to necesitate hospitalisation to prevent harm to self or others,
or there are psychotic features
(Hypomanic symptoms - no psychotic symptoms)
- Manic episodes may come on rapidly (hours), but there are more often preceded by
some days with attenuated symptoms
 - If not treated, manic episodes last some days/4-6 months
- Sudden return to euthymia (normal mood) or switch to depressive episode
- Hypomanic episodes are common in bipolar I disorder but are not required for the
diagnosis of bipolar I disorder
- Mean age on onset: 18 years
- But onset can occur throughout the life cycle
- It is a severely debilitating disorder
- ⅓ of patients remain unemployed 1 year after hospitalization
- High suicide risk 0.2-0.4% (more than 15-20x that of the
general population ⮕ 0.01% WHO, 2014)
- ¼-⅓ attempt suicide
- Higher rick in the depressive phase or in mixed episodes
- More than 50% of patients experience 4 or more episodes during lifetime
- Lifetime prevalence: about 0.6%
- 12-month prevalence: 0.4%
- Male-female ratio: 1.1:1

BIPOLAR II DISORDER

- At least one episode of major depression

- At least one episode of hypomania
It is necessary to meet the criteria for a current or past hypomanic episode and the criteria for a
current or past major depressive episode

Hypomanic episode: distinct period of abnormally and persistently elevated, expansive, or

irritable mood and abnormally and persistently increased activity or energy, lasting at least 4
consecutive days, and present most of the day, nearly every day.
- During the period of mood disturbance and increased energy and activity, three (or
more) of the following symptoms (four if mood is only irritable) have persisted, represent
a noticeable change from usual behaviour, and have been present to a significant
degree:
- Inflated self-esteem or grandiosity
- Decreased need for sleep (e.g., feel rested after only 3 hours of sleep)
- More talkative than usual or pressure to keep talking
- Flight of ideas or subjective experience that thoughts are racing
- Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external
stimuli), as reported or observed
- Increase in goal-directed activity (either socially, at work or school, or sexually) or
psychomotor agitation (i.e., purposeless non-goal-directed activity)
- Excessive involvement in activities that have a high potential for painful
consequences (e.g., engaging in unrestrained buying sprees, sexual
indiscretions, or foolish business investments)
- The same episode is associated with an unequivocal change in functioning that is
uncharacteristic of the individual are not symptomatic
- The disturbance in mood and the change in functioning are observable by others
- The hypomanic episode is not severe enough to cause marked impairment in social or
occupational functioning or to necessitate hospitalization. If there are psychotic features,
the episode is, by definition, manic !

- The symptoms of depression or the unpredictability caused by frequent alternation

between periods of depression and hypomania causes clinically significant distress or
impairment in social, occupational, or other impairment areas of functioning
- The clinical course of recurring mood episodes consists of one or more major depressive
episodes and at least one hypomanic episode
- Many individuals experience several episodes of major depression prior to the
first recognised hypomanic episode
- About 12% of individuals with an initial diagnosis or major depressive disorder
will later be diagnosed with Bipolar II disorder
- It is not a milder form of Bipolar I disorder !
- The recurrent major depressive episodes are often more frequent and lengthier than
those occurring in Bipolar I disorder
- Episodes with mixed features and the rapid cycling pattern are frequent
- More commonly among women
- The number of lifetime episodes (both hypomania and major depressive episodes) tends
to be higher for Bipolar II disorder than for Major Depressive Disorder or Bipolar I
disorder
- The interval between mood episodes tends to decrease as the individual ages
- Depressive episodes are more enduring and disabling over time
- About 5-15% of individuals with Bipolar II disorder will develop a manic episode, which
changes the diagnosis to Bipolar I disorder
- At least 15% continue to have some inter-episode dysfunction, and 20% transition
directly into another mood episode without inter-episode recovery
- Often associated with impulsivity (contributes to suicide attempts and substance use
disorder)
- Heightened levels of creativity during hypomanic episodes in such individuals
- High suicide rates
- ⅓ report a lifetime history of suicide attempt (similar to Bipolar I disorder)
- Lethality of attempts is higher compared with Bipolar I disorder
- Average age-at-onset: mid 20s
- Often begins with a depressive episode and is not recognised as Bipolar II
disorder until a hypomanic episode occurs
- Many individuals experience several episodes of major depression prior to the
first recognised hypomania episode
- Childhood or adolescent onset of the disorder may be associated with a more
severe lifetime course
- Lifetime prevalence: 0.4%
 - 12-month prevalence: 0.3%
- Some, but not all, clinical samples suggest that Bipolar II disorder is more common in
women than in men
- Females are more likely than males to report hypomania with mixed depressive
features and a rapid-cycling course
- Childbirth may be a specific trigger for a hypomanic episode, which can occur in
10-20% of females in no clinical populations and most typically in the early
postpartum period
- Among women with Bipolar II disorder, about 40% experience a mood episode in
pregnancy or the postpartum period (hypomania, psychotic depression,
nonpsychotic depression)
- Postpartum hypomania may predict the onset of a depression that occurs in
about 50% of females who experience postpartum “highs”
- Comorbidity:
- About 60% of individuals with Bipolar II disorder have three or more co-occurring
mental disorders
- 75% have an anxiety disorder
- 37% have a substance abuse disorder
- About 14% have at least one lifetime eating disorder, with binge-eating
disorder being more common than bulimia nervosa or anorexia nervosa

CYCLOTHYMIC DISORDER
For at least 2 years (at least 1 year in children and adolescents) there have been numerous
periods with hypomanic symptoms that do not meet criteria for a hypomanic episode and
numerous periods with depressive symptoms that do not meet criteria for a major depressive
disorder.

- “Depressive” (dysthymia-like) symptoms: low energy, social withdrawal, pessimism, loss

of interest and pleasure
- They are of insufficient number, severity, pervasiveness, or duration to meet full
criteria for a major depressive episode
- “Hypomanic” symptoms: increased energy, greater productivity
- They are of insufficient number, severity, pervasiveness, or duration to meet full
criteria for a hypomanic episode
- Perceived by others as moody, temperamental, unpredictable, unreliable
- During the above 2-year period (1 year in children and adolescents), the hypomanic and
depressive periods have been present for at least half the time and the individual has not
been without the symptoms for more than 2 months at a time
- The symptoms cause clinically significant distress or impairment in social, occupational,
or other important areas of functioning
- Milder and chronic type of bipolar disorder
- Lifetime prevalence: 0.4-1%
 - Onset: adolescence or early adulthood
- In children, mean age of onset is 6/7 years
- 15-50% risk of developing of developing Bipolar I disorder or Bipolar II disorder
- Equally common in males and females
- Comorbidity:
- Sleep disorders
- Substance-related disorders
- Children with Cyclothymic disorder are more likely than other paediatric patients
with mental disorders to have comorbid attention-deficit/hyperactivity disorder
(ADHD)

Neurobiological factors in bipolar disorders

● Genetic factors
○ High heritability
■ For bipolar I disorder, 70-90% of variance is accounted for by genes
■ First-degree relatives have a 8-10 times greater likelihood to develop the
disorder
■ Possible candidate genes have not been reliably identified yet
● Neurotransmitters
○ Norepinephrine, dopamine, serotonin
■ Early models focused on absolute levels
■ High levels of norepinephrine and dopamine in manic states, low levels of
serotonin in both depressive and manic states
○ More recent models focused on the sensitivity of postsynaptic receptors
■ Substances that increase the levels of dopamine may trigger manic
symptoms in individuals with bipolar disorder - hypersensitivity of
dopaminergic postsynaptic receptors
■ Tryptophan depletion trigger greater mood changes in relative of
individuals with bipolar disorders - reduced sensitivity of serotonergic
postsynaptic receptors
● Needed to synthesise serotonin
● Alterations of neuronal membrane function and synaptic transmission
○ Overactive protein-kinase C and high levels of G-proteins
■ Modulate neurotransmitter release, ion fluxes, synaptic plasticity,
neuronal excitability
● Defective regulation of cortisol level
○ High levels of cortisol during depressive (not manic) episodes
○ About half of patients do not show suppression in the dexamethasone (synthetic
cortisol) test during depressive episodes (much less during manic episodes)
○ Increase of pro-inflammatory cytokines in the manic phase (interfere with the
negative feedback mechanism) - keeping the activity of the HPA axis
● Brain structure abnormalities
○ Increased volume in:
 ■ Basal ganglia
■ Amygdala
○ Related to illness duration:
■ Enlargement of cerebral ventricles
■ Hippocampal atrophy - high levels of the circulating cortisol
● Brain function abnormalities
○ Overactivity
■ Striatum
■ Amygdala
■ Thalamus
● Not clearly related to mood states; emotional tasks
● Abnormalities are still there even in the euthymic states
○ Under activity
■ DlPFC and ventrolateral PFC
● Particularly during mania; both cognitive and emotional tasks

Social and psychological factors in bipolar disorders:

- Trigger/vulnerability factors for depressive episodes in bipolar disorders are similar to
those of major depression episodes
- Stressful events, neuroticism, negative cognitive styles, high levels of expressed
emotion, poor social support
- Stressful events can also precipitate manic episodes
- Predictors of manic symptoms
- High reward sensitivity
- Vulnerability to bipolar disorder is the result of a reward system that is
overly sensitive and reactive to goal- and reward- relevant stimuli
- In response to life events involving goal-striving and attainment of
rewards, reward hypersensitivity leads to excessive approach-related
affect and reward motivation, which, n turn, leads to a hypo/maniac
symptoms
- Predicts more severe course of mania
- Sleep deprivation and alteration of circadian rhythms
- Especially for manic symptoms; not really on depression

How are bipolar disorders treated?

● Lithium carbonate - first treatment choice
○ Efficacy in the treatment of acute mania and in long-term mood stabilisation and
prophylaxis
○ Antimanic effects are observed after 6-10 days
○ Up to 80% of patients show at least partial reduction of symptoms
○ Effective in preventing relapse
○ The mechanism of action has not been fully clarified yet
■ Competes with ions sodium, potassium, calcium and magnesium during
transmembrane ion transport in neurons
 ■ Interferes with metabolism of biogenic amines implicated in need
disorders (norepinephrine, adrenaline, serotonin, dopamine)
○ Potentially severe short- and long- term side effects due to high toxicity (lethargy,
weight gain, trembling, hypothyroidism, gastrointestinal problems, permanent
kidney dysfunction)
○ Regular monitoring of plasma concentrations is necessary
○ Adding antidepressants to lithium for treating depressive episodes is
controversial (manic or hypomanic shift in 20-40% of cases)
● Other mood stabilisers
○ Anticonvulsants (carbamazepine, valproate)
■ Increased attempts and completed suicide
○ Antipsychotics
■ In association with mood stabilisers or antidepressants if psychotic
symptoms are pregnant
○ Prescribed to patients who fail to respond to lithium or do not tolerate its side
effects
● Electroconvulsive therapy
○ Effective to treat manic episodes
○ About 80% of treated patients show remission or marked improvements
○ Maintenance on mood stabilisers to prevent relapse (the effects do not last for
very long)

Psychological treatment of bipolar disorders

● Psychoeducational approaches
○ Provide Informaționale about symptoms, time course, trigger factors, treatments
■ Improve compliance to pharmacological treatment
● Family-focused therapy
○ Educate the family about the disorder, enhance family communication, improve
problem-solving abilities
● Interpersonal and social rhythms therapy
○ Individuals with bipolar disorders are biologically vulnerable to disruption in
circadian rhythms
○ Recognise the effects of “zeitgeber” interpersonal events (work hours, meals,
leisure activities), and the effects of their desynchronization on circadian rhythms
○ Implement and maintain regular daily social rhythms and routines
○ Effective as an adjunct to medications
● CBT
○ 10-25 sessions; started after stabilisation, when the patient is euthymic or has
only residual symptoms
○ Cognitive restructuring for depressive symptoms includes modules on psycho
education, self-esteem, coping skills, assertiveness and life organisation
○ Indications of efficacy (in combination with medication)
● Mindfulness-based cognitive therapy
○ Preliminary indicators or usefulness for treating patients during inter-episodic
intervals