Mood Stabilizers

Contents
• Bipolar Affective Disorder • Mood stabilizers
o Clinical features o Lithium
o Diagnosis o Other mood stabilizers
o Aetiology • Non-pharmacological mood stabilizers
o Neurochemical basis • Summary

Bipolar Affective Disorder (manic-depressive illness)

• A lifetime psychiatric illness with high recurrence rate
• Bipolar disorder is a serious mental illness in which common emotions become intensely and often
unpredictably magnified
• Recurrent episodes of sudden mood swings from extremes of happiness, energy and clarity to
sadness, fatigue and confusion
• Episodes of mania occurs alternatively or simultaneously with depressive symptoms – differs from
major depression
• Patients are at high risk for suicide

Aetiology
• Unclear
o Genetics
 Multiple gene mutations
o Stressful triggers
 Relationship issues  Sleep disturbances
 Death of a close family member or  Physical, sexual or emotional abuse
loved one  Chronic illnesses

Clinical features/ Symptoms

Symptoms of manic episode Symptoms of depressive episode

• Irritable mood • Depressed mood

• Hyperactivity • Diurnal variation
• Impulsivity • Sleep disturbance
• Disinhibition • Anxiety
• Racing thoughts • Sometimes, psychotic symptoms
• Diminished need for sleep (Psychotic symptoms –
• Cognitive impairment Disordered thinking manifested by delusions &
• Sometimes, psychotic symptoms flight of ideas with rapid speech)

• In addition to mania & depression, bipolar disorder can cause a range of moods
 Hypomania
• Has increased energy & activity levels not as severe as typical mania
• Feel very good, be highly productive & function well; increased talkativeness
• Difficult to recognize as bipolar disorder
• Without proper treatment, may develop into severe mania or depression

Diagnosis
• Based on guidelines from the Diagnostic & Statistical Manual of Mental Disorders (DSM)
• Four basic types of bipolar disorder according to DSM:
1. Bipolar I Disorder:
o Manic or mixed episodes that last at least seven days or severe manic symptoms that needs
immediate hospital care
o Mania or depression symptoms must be a major change from the person’s normal behavior
2. Bipolar II Disorder
o Depressive episodes shifting back and forth with hypomanic episodes
3. Bipolar Disorder not otherwise specified
o Symptoms may not last long enough or too few symptoms
o Symptoms that do not meet diagnostic criteria for either bipolar I or II
4. Cyclothymic Disorder or Cyclothymia
o Mild form of bipolar disorder
o Episodes of hypomania that shift back and forth with mild depression for at least two years
o Symptoms do not meet diagnostic requirements for any other type of bipolar disorder

Rapid-cycling bipolar disorder –

Four or more episodes of depression, mania, hypomania, or mixed symptoms within a year; may even
change within hours or days

Neurochemical basis of bipolar disorder

Biogenic amine hypothesis
• “Mood disorders result from abnormalities in serotonin, norepinephrine or dopamine
neurotransmission”
• Impaired serotonin neurotransmission " Decrease cortical responsiveness to emotional activation "
affective dysfunction & depression
  Antidepressant drugs increase serotonin, norepinephrine or dopamine neurotransmission in the
brain

Melatonin hypothesis
• “Abnormal circadian rhythms and melatonin regulation are associated with bipolar disorder”
• Melatonin suppresses the activity of serotonergic neurons
• Excess melatonin production " Depression
• Abnormalities in melatonin & serotonin metabolism contribute to sleep disturbances in
affective disorders
 Seasonal affective disorder usually occurs during winter months, when daylight is reduced &
melatonin levels are increased

Mood stabilizers
• Mood stabilizers reduce both manic & depressive symptoms
o Normalize the mood in patients with bipolar disorder
• Normally, greater activity against manic symptoms than depression
o Used to treat or prevent manic phase of bipolar disorder
Lithium – Classic drug Other approved mood stabilizers:
Antiepileptic drugs
Atypical antipsychotics

Lithium
• Earlier used in the treatment for gout to dissolve urate crystal deposits
o Tried in manic patients & calming effect was discovered
• Maximal response often requires several days or weeks of treatment (slow onset of action)
• Has narrow therapeutic index
o Serum concentration should be monitored after initiating therapy & at periodic intervals thereafter
• Therapy is usually continued for 9 to 12 months after the initial manic episode & then can be slowly
tapered, with continued monitoring of symptoms
MoA
• Not clearly understood
• May act by suppressing the formation of second messengers involved in neurotransmitter signal
transduction
o Reduces the formation of inositol triphosphate (IP3)
Reduces neuronal response to serotonin & norepinephrine
o Inhibits glycogen synthase kinase-3 (GSK-3)
• Also inhibits hormone-induced cAMP production & blocks other cellular responses
Lithium – Pharmacokinetics
• The lightest alkali metal element & readily forms monovalent cation (Li+)
• Absorbed rapidly & completely from the gut
• Widely distributed (high concentration in thyroid gland, bone & some areas of brain)
• Not metabolized nor bound to plasma proteins
• Plasma half-life is about 20 hours
• Excreted in urine - extensively reabsorbed from renal tubules
• Sodium competes with lithium for renal tubular reabsorption
o Increase the excretion of lithium
• Renal clearance increases during pregnancy
• Cause problems in patients with renal impairment

Lithium – Monitoring
• Plasma Lithium concentration: Before initiation & at periodic intervals
o Narrow therapeutic index " Regular Serum-Level Monitoring
o Safe & effective range: 0.6 – 1.5 mmol/L (acute mania); 0.6–1.0 mmol/L (maintenance dose)
o Usually measured from samples withdrawn 10–12 h after last oral dose of the day
o Once plasma concentration is at steady state & within therapeutic range, it should be measured every
3 months
• Toxicity monitoring: Before initiation & every 3–6 months during therapy
o Thyroid function (especially in women)
Renal function (plasma creatinine & electrolytes)

Lithium – Drug Interactions

• Diuretics
o Thiazide diuretics – Significant reductions in Li + clearance
o K+ sparing diuretics – Modest effects on excretion of Li +, with smaller increases in serum levels
o Loop diuretics – Limited impact on Lithium levels
o Osmotic diuretics – Increases renal excretion of Li+
• NSAIDs (Indomethacin, Ibuprofen, Naproxen)
o Through alteration of renal perfusion, some agents facilitate renal proximal tubular resorption of Li + &
increase serum concentrations
• ACEIs (particularly lisinopril)
o Li + retention
• Amiloride
Blocks entry of Li + into renal distal tubule

Lithium – Adverse Effects

 Lithium – Acute toxicity & Overdose
• Due to the rise in serum concentration of Li+ (> 2 mmol/L)
o Mostly by therapeutic overdose
o Common reasons: Reduction in serum sodium level, diuretics usage, impaired renal function
• Acute intoxication – Characterized by vomiting, profuse diarrhea, coarse tremor, ataxia, coma &
convulsions
• Serious effects – Involve nervous system: mental confusion, hyperreflexia, gross tremor, dysarthria,
seizures progressing to coma & death
• Other toxic effects – Cardiac arrhythmias, hypotension & albuminuria

Treatment of Lithium Intoxication

• No specific antidote for Lithium intoxication
• Supportive treatment
o Electrolyte balance
o Renal function monitoring
o Control of convulsion
o Intubation if indicated & continuous cardiac monitoring
• Dialysis
o The most effective means of removing Li+ in severe poisonings (≥ 3 mmol/L)
o Especially with impaired renal function

Lithium – Clinical uses

• Treatment of Bipolar Affective Disorder
o Effective in treatment of manic phase (acute mania, prophylaxis & maintenance therapy)
o Prophylaxis – Prevents recurrence of manic & depressive episodes
o Maintenance therapy – Decreases manic behavior & reduces frequency & magnitude of mood
swings; also prevents relapse & suicidal thoughts
Combined treatment in severe cases – Due to slow onset of action (concurrent use of antipsychotics or
potent benzodiazepines)
Benzodiazepines – Relieve manic symptoms & promote sleep
Antipsychotics – Suppress delusions & other psychotic symptoms

• Adjunct therapy in treatment-resistant major depression

o To increase the response to standard antidepressants during acute major depression in patients with
inadequate response to monotherapy
o Treatment of recurrent depression with a cyclic pattern
o Treatment of Schizoaffective disorder or Schizophrenia (especially in treatment-resistant
patients)
o In combination with antipsychotics
 Other Mood Stabilizers
• Lithium is the primary drug used in bipolar disorder
o Usually controls an acute manic episode within 1 or 2 weeks after initiation of therapy
o Other drugs may be required to control acute symptoms while awaiting the full effect of lithium to
develop

Antiepileptic drugs
• Have fewer side effects than Lithium
• Used in treatment of acute mania (Valproic acid & carbamazepine) & for bipolar maintenance
(Lamotrigine)

Valproic acid
• Antimanic action equivalent to Lithium
• Effective in some patients who have failed to respond to lithium
o Rapid cycling of manic & depressive episodes
o Patients with coexisting substance abuse

Carbamazepine
• Has antimanic, antidepressant & prophylactic effects
• Less effective than Lithium & Valproic acid
• Used in combination with lithium

Lamotrigine
• Used in prophylaxis of bipolar affective disorder (especially when depressive episodes predominate)

Atypical Antipsychotics
• Used to suppress delusions, other psychotic symptoms & acute behavioural disturbances, especially in
extremely agitated patients
o Effective against mania o Long-term prevention of manic relapse
• Often used in combination with Lithium or Valproic acid
• Commonly used drugs: Risperidone, Olanzapine, Ziprasidone, Aripiprazole & Quetiapine
Quetiapine – Useful in preventing depressive relapse

Non-pharmacological mood stabilisers

• Sleep-wake cycle stabilisation, exercise
• Substance abstinence (illicit drugs, alcohol, nicotine & caffeine)
• Specific psychological interventions (cognitive behavioural therapy, interpersonal-social rhythm
therapy, family-focused therapy, mindfulness-based therapies and psychoeducation)
• Non-specific psychosocial interventions (sleep hygiene, social skills training, problem-solving &
basic stress management)
Summary
• Bipolar affective disorder:
THE BUILDING BLOCKS OF LIVING WITH BIPOLAR