BIPOLAR AFFECTIVE BIPOLAR AFFECTIVE DISORDER DISORDER

AND MOOD STABILISERS AND MOOD STABILISERS

KEALEBOGA D. SMITH KEALEBOGA D. SMITH

MBBS IVMBBS IV

ObjectivesObjectives1.1. DefinitionsDefinitions

2.2. Classifications of BipolarClassifications of Bipolar

3.3. EpidemiologyEpidemiology

4.4. Etiology & pathophysiologyEtiology & pathophysiology

5.5. Clinical features (Diagnostic criteria)Clinical features (Diagnostic criteria)

6.6. Differentiating hypomania vs manic Differentiating hypomania vs manic episodesepisodes

7.7. Cormobities in BipolarCormobities in Bipolar

8.8. Differential diagnosesDifferential diagnoses

9.9. ManagementManagement

10.10.MOOD STABILISERSMOOD STABILISERS

DefinitionsDefinitions

Bipolar disorder is a cyclical mood Bipolar disorder is a cyclical mood disorder characterised by disorder characterised by abnormally elevated mood or abnormally elevated mood or irritability which alternates with irritability which alternates with depressed mood.depressed mood.

It is an episodic, potentially life-long, It is an episodic, potentially life-long, disabling disorder that can be disabling disorder that can be difficult to diagnosedifficult to diagnose

Definitions…Definitions… It is a spectrum of affective episodes It is a spectrum of affective episodes

including:including: Major depressive episodeMajor depressive episode Manic episodeManic episode Hypomanic(less severe w/o psychotic Hypomanic(less severe w/o psychotic

symptoms)symptoms) Mixed episode(less usual)-features of Mixed episode(less usual)-features of

both mania & depression present or both mania & depression present or alternate rapidlyalternate rapidly

Rapid cycling(4 episodes of Rapid cycling(4 episodes of mania/depresn per year) mania/depresn per year)

Definitions by ICD-10 & Definitions by ICD-10 & DSM-IV-TRDSM-IV-TR ICD-10-define it as atleast 2 ICD-10-define it as atleast 2

episodes, including atleast 1 episodes, including atleast 1 hypomanic or manic episodehypomanic or manic episode

DSM-IV-TRDSM-IV-TRPatterns of recurrence can be classified as:Patterns of recurrence can be classified as:Bipolar I disorder: Bipolar I disorder: one or more manic or one or more manic or mixed episodes (+/- major depressive mixed episodes (+/- major depressive episodes)episodes)Bipolar II disorder: Bipolar II disorder: recurrent major recurrent major depressive & hypomanic BUT not manic depressive & hypomanic BUT not manic episodesepisodesCyclothymic disorder: Cyclothymic disorder: chronic mood chronic mood fluctuations over atleast 2 yr, with fluctuations over atleast 2 yr, with episodes of depression & hypomania (BUT episodes of depression & hypomania (BUT not mania) of insufficient severity to meet not mania) of insufficient severity to meet diagnostic criteriadiagnostic criteria

EpidemiologyEpidemiology

Lifetime prevalences are:Lifetime prevalences are:

I.I. Bipolar I disorder 1%Bipolar I disorder 1%

II.II.Bipolar II disorder 1.5-2%Bipolar II disorder 1.5-2%

III.III.Cyclothymia 2.5%Cyclothymia 2.5% F:M 1.5:1.0, but F>M in the bipolar II F:M 1.5:1.0, but F>M in the bipolar II

groupgroup F>M are “rapid cyclers”F>M are “rapid cyclers” Peak age of onset: early 20s. Illness often Peak age of onset: early 20s. Illness often

start in childhood & adolescencestart in childhood & adolescence

Etiology & Etiology & pathophysiologypathophysiology

GeneticsGenetics: 50% have +ve FHx. Lifetime risk ↑ : 50% have +ve FHx. Lifetime risk ↑ in 1in 1stst degree relatives (40-70% for degree relatives (40-70% for monozygotics; 5-10% for other 1monozygotics; 5-10% for other 1stst degree degree relatives)relatives)

Biochemical factorsBiochemical factors: ↑ levels of serotonin, : ↑ levels of serotonin, norepinephrine or dopamine can trigger norepinephrine or dopamine can trigger mania. Hormonal imbalances & disruptions mania. Hormonal imbalances & disruptions in hypothalamic-pituitary-adrenal axis in hypothalamic-pituitary-adrenal axis involved in the homeostasis & the stress involved in the homeostasis & the stress response may contribute to clinical picture response may contribute to clinical picture of bipolar disorder.of bipolar disorder.

Etiology & Etiology & pathophysiology…pathophysiology… Hx of Hx of childhood sexual or physical abusechildhood sexual or physical abuse

(appear to have worse prognosis)(appear to have worse prognosis) Sleep disturbanceSleep disturbance: can induce mania: can induce mania ↑ ↑ risk of manic episodes in the early risk of manic episodes in the early

postpartumpostpartum weeks weeks ““secondary” mania may be precipitated by secondary” mania may be precipitated by

severe physical illness, particularly strokesevere physical illness, particularly stroke MRI findings include smaller prefrontal MRI findings include smaller prefrontal

lobes & enlarged amygdala & globus lobes & enlarged amygdala & globus palliduspallidus

Psychodynamic models of mania suggest Psychodynamic models of mania suggest denial of lossdenial of loss 2 avoid depress is implicated 2 avoid depress is implicated in bipolarin bipolar

Clinical features (Diagnostic Clinical features (Diagnostic criteria)criteria)

Hypomania vs manic Hypomania vs manic episodesepisodes

Mania Mania DurationDuration: symptoms last : symptoms last

atleast one week atleast one week Severity: Severity: severe enough 2 severe enough 2

cause marked social or cause marked social or occupational impairment occupational impairment or necessitate or necessitate hospitalizationhospitalization

Psychotic symptoms: Psychotic symptoms: present in 50% of manic present in 50% of manic pts and those with severe pts and those with severe depressiondepression

hypomaniahypomania Symptoms last atleast 4 Symptoms last atleast 4

daysdays

NOT severe enough 2 NOT severe enough 2 cause marked social or cause marked social or occupational impairment occupational impairment & hospitalization is not & hospitalization is not necessary necessary

Psychotic symptoms: Psychotic symptoms: AbsentAbsent

Cormobities in BipolarCormobities in Bipolar

Anxiety (30-50%)Anxiety (30-50%) Substance misuse disorders (drugs Substance misuse disorders (drugs

and alcohol) 30–50% and alcohol) 30–50% Personality disorders, in particular Personality disorders, in particular

borderline personality disorderborderline personality disorder

NB! NB! Bipolar II pts tend to have a high Bipolar II pts tend to have a high rate of co-morbidity with other rate of co-morbidity with other disordersdisorders

Differential diagnosesDifferential diagnoses

Schizophrenia, Schizoaffective disorderSchizophrenia, Schizoaffective disorder Substance Abuse Substance Abuse Pseudo-Unipolar Disorder Pseudo-Unipolar Disorder

Steroids Steroids Syphilis, Hyperparathyroidism Syphilis, Hyperparathyroidism Borderline, Narcissistic and Histrionic Borderline, Narcissistic and Histrionic

Personality disorder Personality disorder

General principles of General principles of Management Management

Hospitalization for mania, severe depressionHospitalization for mania, severe depression Mood stabilizersMood stabilizers, antipsychotics (covered b4) , antipsychotics (covered b4)

and antidepressants(beware depresn--and antidepressants(beware depresn-->mania) >mania)

ECT – most effective treatment when pt ECT – most effective treatment when pt unresponsive to meds unresponsive to meds

Supportive psychotherapy and CBT Supportive psychotherapy and CBT Lifestyle change (avoiding substance abuse Lifestyle change (avoiding substance abuse

and effective coping mechanisms) and effective coping mechanisms)

RECOMMENDATIONS FOR THE MANAGEMNT OF MANIC PATIENT

1. Hospitalize the patient for effective sedation2. Initiate lithium tx so that therapeutic blood

levels can be attained as soon as possible3. Start antipsychotic meds immediately and

discontinue them gradually after remission4. Maintenance with lithium should continue for

years. Blood levels, thyroid function and cardiovascular status should be checked regular

5. Psychotherapy should address all stressful and traumatic life events

6. Family should receive psychosocial support as well and be informed about the illness of the patient

7. Genetic counselling is important

MOOD STABILISERSMOOD STABILISERS Used prophylactically in bipolar

depression, mood-stabilising drugs prevent the swings of mood and thus reduce both the depressive and the manic phases of the illness

They are given over long periods, and their beneficial effects take 3-4 weeks to develop

The mechanism of action of antimanic The mechanism of action of antimanic drugs is poorly understood.drugs is poorly understood.

It is not as clear what neural systems are It is not as clear what neural systems are involved in the mechanism of antimanic involved in the mechanism of antimanic drugs. drugs.

Most mood stabilisers are used to treat Most mood stabilisers are used to treat various seizure d/o types, migraines, various seizure d/o types, migraines, chronic pain syndromes, aggression, chronic pain syndromes, aggression, impulsivity, augmentation of impulsivity, augmentation of antidepressants and antipsychoticsantidepressants and antipsychotics

Older mood stabilisers Older mood stabilisers include: lithium, include: lithium, carbamazepine and valproic acidcarbamazepine and valproic acid

Newer mood stabilisersNewer mood stabilisers: lamotrigine, : lamotrigine, oxcarbazepine, topiramateoxcarbazepine, topiramate

Lithium Lithium First original mood stabilizer (available as First original mood stabilizer (available as

lithium carbonate) & most commonly used lithium carbonate) & most commonly used drugdrug

Only mood stabilizer w/o significant Only mood stabilizer w/o significant anticonvulsant propertiesanticonvulsant properties

MOA: inhibition of MOA: inhibition of (GSK-3b)>>↑ ↑ levels of the neuroprotective protein bcl-2

up to 70% response rate & up to 70% response rate & clinically effective at a plasma concentration of 0.5-1 mmol/l

demonstrated effectiveness in reducing demonstrated effectiveness in reducing suicidalitysuicidality

less effective in rapid cycling (valproate less effective in rapid cycling (valproate preferred) & mixed bipolar statespreferred) & mixed bipolar states

Lithium-side effectsLithium-side effects fine tremor, weight gain, nauseafine tremor, weight gain, nausea increased thirst and urinationincreased thirst and urination more severe toxicitiesmore severe toxicities include coarse tremor, include coarse tremor,

gait instability, vomiting, diarrhea, confusiongait instability, vomiting, diarrhea, confusion increased risk of toxicity with fluid or salt increased risk of toxicity with fluid or salt

restriction, hot weather/sweating, use of anti-restriction, hot weather/sweating, use of anti-inflammatory drugs, ace inhibitors & inflammatory drugs, ace inhibitors & angiotensin receptor blockers, diuretics angiotensin receptor blockers, diuretics

may cause kidney and thyroid dysfunction so may cause kidney and thyroid dysfunction so regular monitoring of creatinine, BUN and regular monitoring of creatinine, BUN and TSH are necessaryTSH are necessary

females are at much greater risk of lithium females are at much greater risk of lithium related thyroid dysfunctionrelated thyroid dysfunction

CarbamazepineCarbamazepine used in acute mania and bipolar used in acute mania and bipolar

maintenance maintenance more effective than lithium in rapid more effective than lithium in rapid

cycling & mixed statescycling & mixed states less effective in bipolar related less effective in bipolar related

depressiondepression multiple significant drug-drug multiple significant drug-drug

interactions (DDI) affecting both other interactions (DDI) affecting both other medications (reducing their levels) & medications (reducing their levels) & other medications affecting it other medications affecting it (increasing carbamazepine levels)(increasing carbamazepine levels)

induces its own metabolism so may induces its own metabolism so may need to adjust dose over several weeksneed to adjust dose over several weeks

Carbamazipine-side Carbamazipine-side effectseffects GI: nausea, constipation, diarrhea, GI: nausea, constipation, diarrhea,

appetite lossappetite loss CNS: sedation, dizziness, CNS: sedation, dizziness,

unsteadiness, confusion unsteadiness, confusion benign rashes common, benign rashes common,

catastrophic rashes rarecatastrophic rashes rare many possible serious abnormalities many possible serious abnormalities

in CBCin CBC may reduce sodium levels may reduce sodium levels

(hyponatremia)(hyponatremia) liver function abnormalities rare but liver function abnormalities rare but

possiblepossible

Valproate Valproate can be dosed rapidly to treat acute maniacan be dosed rapidly to treat acute mania more effective than lithium in rapid more effective than lithium in rapid

cycling & mixed statescycling & mixed states used by some to treat aggression and used by some to treat aggression and

impulsivity in other psychiatric disordersimpulsivity in other psychiatric disorders approved for migraine prophylaxisapproved for migraine prophylaxis serum levels can be helpful in guiding serum levels can be helpful in guiding

dosingdosing lab draws 8-12 hours after last doselab draws 8-12 hours after last dose commonly used at top or above levels commonly used at top or above levels

stated for seizure controlstated for seizure control some suggest supplementation with some suggest supplementation with

carnitine, selenium and others to reduce carnitine, selenium and others to reduce side effectsside effects

Valproate-SEValproate-SE nausea, weight gain, unsteadiness (ataxia), hair

loss, tremor liver dysfunction, decreased platelets

(thrombocytopenia) pancreatitis (rare but potentially serious) polycystic ovary disease suggested by some reports ammonia levels can be increased particularly in

those rare individuals with genetic metabolic deficits drug-drug interactions by various mechanisms with

numerous other anticonvulsants, aspirin and others

Newer mood stabilisersNewer mood stabilisers Lamotrigine:Lamotrigine:

Minimally sedating unlike most other mood stabilizers Minimally sedating unlike most other mood stabilizers Appears to be especially effective in treated bipolar Appears to be especially effective in treated bipolar

depression but unproven to treat maniadepression but unproven to treat mania Initiating lamotrigine is done very slowly to decrease Initiating lamotrigine is done very slowly to decrease

rash riskrash risk valproate greatly increases lamotrigine levels valproate greatly increases lamotrigine levels carbamazepine greatly decreases lamotrigine levelscarbamazepine greatly decreases lamotrigine levels

Oxcarbazepine: Oxcarbazepine: Used primarily in combination with Used primarily in combination with other mood stabilizers although efficacy not clearly other mood stabilizers although efficacy not clearly substantiatedsubstantiated

Topiramate: Topiramate: Research questions its use as a mood Research questions its use as a mood stabilizer although scattered reports suggest possible stabilizer although scattered reports suggest possible benefit. SE: weight ↓, cognitive dulling, kidney benefit. SE: weight ↓, cognitive dulling, kidney stones, metabolic acidosisstones, metabolic acidosis

References References 1.1. Psychiatry at a Glance, 5Psychiatry at a Glance, 5thth ed. Pg 25-25 ed. Pg 25-25

2.2. Textbook of Psychiatry for Southern Africa. Textbook of Psychiatry for Southern Africa. Pg111-133Pg111-133

3.3. Essentials of Psychiatry. (2006). Chapter 46-7Essentials of Psychiatry. (2006). Chapter 46-7

4.4. Toronto notes. (2011). Mood disordersToronto notes. (2011). Mood disorders

5.5. Kim Cater. Bipolar Disorder lecture. Kim Cater. Bipolar Disorder lecture. Appalachian State UniversityAppalachian State University

6.6. Rang and Dale’s Pharmacology. 6Rang and Dale’s Pharmacology. 6thth ed. Pg ed. Pg 571-4571-4

7.7. Lippincott's Illustrated Reviews: Lippincott's Illustrated Reviews: Pharmacology, 4Pharmacology, 4thth. Pg 149. Pg 149

8.8. DSM-IV & ICD-10DSM-IV & ICD-10

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