Bipolar Disorders, Schizophrenia, and Anxiety

Ibrahim Sales, Pharm.D.Assistant Professor of Clinical Pharmacy

King Saud Universityisales@ksu.edu.sa

Objectives

Review state of the art drug therapy for common adult psychiatric & mood disorders with an emphasis on: Drugs of choice and alternatives for specific

situations Common and severe adverse effects Cost and compliance issues

Bipolar Disorder

Introduction

First diagnosed in adolescence or early adulthood after several years of symptoms

Symptoms: Periods of mania, hypomania, psychosis, or

depression with periods of relative wellness Patients rarely experience a single episode

Relapse rates at more than 70% over 5 years Most patients are depressed most of the time

Bipolar - Diagnostic Features

Four subtypes: Bipolar I Bipolar II Cyclothymia Bipolar disorder not otherwise specified

Specifiers (i.e. rapid-cycling) 4 or more episodes of mania or depression / year

Diagnostic Features

One or more Manic or mixed episodes Drug-induced conditions or other psychiatric

diagnoses ruled out Individuals most often have multiple Major

Depressive episodes throughout their life span Usually a recurrent disorder with shifts in

polarity observed over time

Definitions of Bipolar DisordersDisorder Definition

Bipolar I disorder Manic or mixed episode with or without psychosis and/or major depression

Bipolar II disorder Hypomanic episode with major depression; no history of manic or mixed episode

Cyclothymia Hypomanic and depressive symptoms that do not meet criteria for bipolar II disorder; no major depressive episodes

Bipolar disorder not otherwise specified Does not meet criteria for major depression, bipolar I disorder, bipolar II disorder, or cyclothymia (i.e. less than one week of manic symptoms without psychosis or hospitalization)

Therapeutic Goals

Acute Mania Control symptoms Return patient to normal level of psychosocial

function Control agitation, aggression, and impulsivity to

ensure safety of self and others Depression

Remission of symptoms Avoid precipitation of hypomania/mania

Therapeutic Goals

Maintenance Relapse prevention Reduction of suicide risk Reduce cycling frequency Reduce mood instability Improve overall functioning Promote treatment adherence

Drug Therapy for Patients with Bipolar Disorders

Medication Indication CommentsAcute mania

Maintenance Bipolar depression

Antipsychotics, atypicalAripiprazole (Abilify)Olanzapine (Zyprexa)Quetiapine (Seroquel)Risperidone (Risperdal)Ziprasidone (Geodon)

YesYesYesYesYes

NoYesYesYesNo

No Yes (+SSRI)

YesNoNo

Antipsychotic medication plus lithium or an anticonvulsant is superior to monotherapy for acute mania

Olanzapine and aripiprazole are effective in preventing manic relapse

Quetiapine plus lithium or valproate is superior to monotherapy for maintenance treatment

Antipsychotics, typicalHaloperidol lactate (Haldol)

Yes No NoNo difference in response rates among haloperidol, risperidone, olanzapine, carbamazepine, and valproate for acute mania

BenzodiazepinesLorazepam (Ativan) Yes No No

Used as combination therapy in patients with acute mania to reduce agitation

Carbamazepine (Tegretol) Yes Yes Yes Evidence for carbamazepine is not as strong as that for lithium and valproate

Divalproex (Depakote), valproic acid (Depakene)

Yes Yes Yes Valproate appears to be more effective than lithium for mixed states

Lamotrigine (Lamictal) No Yes Yes Acceptable agent in pregnancy; associated with weight loss in obese patients with bipolar I disorder

Lithium Yes Yes Yes Lithium lowers suicide risk compared with valproate or carbamazepine

Lithium appears to be protective against dementia

Adding an SSRI or bupropion (Wellbutrin) does not improve depressive symptoms

Drug Therapy

Mood Stabilizers Lithium standard treatment

With depression is protective against self harm Mono or combination therapy with anticonvulsants MANY adverse effects (see later slides)

Anticonvulsants widely used Carbamazepine (Tegretol XR, Carbatrol, EquetroFDA) Valproate (Depakote, Depakote ER, Depakene)

Lithium

Mechanism of Action Inhibits signal transduction – modifies G proteins

or enzymes Therapeutic Uses

Treatment of acute episodes of mania, hypomania, and depression

Prevents recurrent mood episodes Dosage Forms

Lithium carbonate: regular release, slow release Lithium citrate: syrup

Lithium

Pharmacokinetics Peak serum levels in 0.5 – 2 hours Distributed throughout body water Eliminated renally via filtration t1/2 ~20 hours; steady state reached in 5 – 7 days

Dosing Usual starting dose: 300mg TID Usual dosing range: 900-2100 mg/day; lower

doses for elderly and renally impaired

Lithium Target serum concentrations (12 hrs post last

dose) Acute episode: 0.8 – 1.2 mEq/L Non-responders: up to 1.5 mEq/L Maintenance: 0.4 – 0.8 mEq/L Elderly: as low as 0.3 mEq/L

Lithium Side effects:

Early Nausea & fatigue Long term Tremor, thirst, polyuria,

edema, weight gain Tremor beta-blocker like propranolol

or use lower dose Severe

Confusion, ataxia, renal toxicity, dermatologic…

Lithium Contraindications

Unstable renal function Recent myocardial infarction – due to

bradycardia Sinus node dysfunction Ulcerative Colitis, Crohn’s Disease – may

worsen GI symptoms Psoriasis – may be worsened on lithium

Lithium Contraindications

Cerebellar disorders – effects on coordination Hypothyroidism – increased monitoring

needed Pregnancy – increased risk of congenital

anomalies (~4-12%)

Lithium MonitoringInitial Workup Efficacy

Renal function testsElectrolytesThyroid panelCBCEKG (elderly, cardiovascular disease)Pregnancy test

Resolution of symptoms Assessments for adverse effectsWeightNeurologic examPatient report on GI symptoms, urinary frequency, etc. Periodic serum lithium levels

Valproate

Mechanism of Action Inhibits sodium and calcium channel function Enhances GABA; inhibits glutamate Exerts effects on second messenger systems

Therapeutic Uses Treats manic and depressive episodes Superior to lithium for rapid cycling, mixed

episodes, and psychotic episodes Synergistic use with other mood stabilizers

Valproate

Dosage forms IR (valproic acid): oral capsules and liquid

concentrate DR, ER (divalproex sodium): oral tablets and

sprinkle capsules Dosing and Administration

Starting dose: 750-1000mg in 2-3 divided doses Oral loading 20mg/kg/day x 5 days Target conc. : 50-100mcg/mL; up to 150 mcg/mL

may be tolerated

Valproate

Adverse Effects GI – N/V/D (less with Depakote) CNS – sedation, tremor Hepatic – elevated LFT’s; rare liver failure Hematologic – thrombocytopenia Pancreatitis Rash Weight gain Alopecia

Valproate

Contraindications Pregnancy Age < 10 years

Drug Interactions ASA/warfarin – increased risk of bleeding Anticonvulsants

Displacement from protein binding sites Inhibition of AED metabolism May potentiate activity of other anticonvulsants Augmented CNS depressant effects

Carbamazepine

Mechanism of Action Interferes with sodium and potassium channel

function Enhances inhibitory action of GABA Varied inhibitory effects on the cAMP signaling

pathway Therapeutic Use

Treatment of manic episodes May be more effective than lithium for rapid

cycling and mixed episodes

Carbamazepine

Pharmacokinetics Slow and erratic oral absorption Moderate protein binding Metabolized by P450 system to active epoxide

metabolite; auto-inducer t1/2 ~33 hours (acute); ~15-25 hours (chronic)

Dosage Initial: 400-600mg/day in divided doses Usual range: 800-1600mg/day Therapeutic range: 6-12mcg/mL

Carbamazepine

Adverse effects Hematologic – aplastic anemia, agranulocytosis Dermatologic – urticaria, rash, exfoliative

dermatitis GI – nausea, vomiting, constipation CNS – confusion, ataxia, sedation, tremor,

myoclonus Cardiovascular – SIADH, edema, HF

Carbamazepine

Monitoring Drug levels – 4-6 weeks after dose change CBC, lytes – every 2 weeks for 2 months; quarterly

thereafter LFT, renal function – months 1, 4, 7, 10; annually

thereafter D/C drug for – WBC < 3000; neutrophils < 1500,

Hct < 32

Carbamazepine

Drug Interactions CYP 450 3A4 inducer – increases clearance of

substrates Anticonvulsants (PHT, VPA, barbituates) Theophylline, warfarin, cyclosporine

CYP 450 substrate – clearance inhibited by concomitant drugs

Erythromycin Cimetidine Isoniazid

Lamotrigine MOA – Sodium channel antagonist; reduced

excitatory action of glutamate Therapeutic Use

Best data for use in prevention and treatment of recurrent depressive episodes

Approved for use for maintenance therapy in bipolar I disorder

AE CNS depression, hematologic abnormalities, rash Risk of adverse effects increases with use of

enzyme inhibitors or rapid titration

Lamotrigine

Available dosage forms Tablets ER tablets Chewable tablets Orally disintegrating tablets

Dosing Set titration schedules for initiation Max dose 200mg/day as monotherapy Max dose of 100mg/day with valproic acid Max dose of 400mg/day with carbamazepine

Antipsychotics

Mechanism of Action Traditional agents – D2 blockade

Haloperidol Chlorpromazine

Second-generation (Atypical) agents D2 and 5-HT2 blockade

Olanzapine Risperidone Quetiapine Asenapine Paliperidone

Antipsychotic Indications

Treatment of manic episodes ± psychotic sx Initiated with mood stabilizer for antimanic effects

for faster resolution in cases of severe mania May be used as monotherapy for acute mania

Useful as an adjunct (on PRN basis) for acute agitation

Antipsychotic Indications

Maintenance (atypicals) Schizoaffective disorder Increasing evidence for maintenance in bipolar

affective disorders (aripipazole, olanzapine) Depression – quetiapine and olanzapine-

fluoxetine combination is FDA approved

Antipsychotics

Adverse effects ↑ risk of tardive dyskinesia (movement disorder) May worsen depressive episodes Weight gain or metabolic effects may be

exacerbated with concomitant lithium or valproate

Treatment Guidelines Guidelines for each phase of illness

Acute Mania Acute Depression Mixed Episodes

Several guidelines in the literature Texas Implementation of Medication Algorithms

2005 Expert Consensus Guidelines 2004 American Psychiatric Association 2005 Canadian Network for Mood and Anxiety

Treatments 2009

Acute Manic EpisodesLevel TIMA EXC APA CANMAT

First-line LiVPASGAsAlt: CBZ

LiVPALi or VPA + SGA

LiVPASGAsAlt: CBZ

LiVPASGAsLi or VPA + SGA

Second-line Combination of 2: Li, VPA, SGA

Combination of Mood stab. + RISP, QTP or OLAN

Add another mood stab., OXC or switch SGA

CBZECTLi + VPA AsenapineLi or VPA + asenapine or paliperidone

Third-line Combination of 2: Li, VPA, SGA, CBZ, OXC, FGA

Combination: add another mood stab.

Combination: Switch SGA, clozapine, ECT

HAL, CPZ,Li or VPA + HALLi + CBZClozapineOXC, LAM

Acute Depressive EpisodesLevel TIMA EXC APA CANMAT

First-line Mono: LAMCombo: LAM + Mood stabilizer

Mono: LAM or LiSevere: Li + LAM or SSRIRapid cycling: LAMPsychotic features: SGA

Mono: LAM or LiSevere: Li + SSRIPsychotic features: SGA

Li, LAM, QTP, Li or VPA + SSRIOLAN + SSRILi +VPALi or VPA +BUP

Second-line Switch to QTP or OLAN + fluoxetine

Combo: add LAM to mood stab., Li +SSRI, switch SSRI

Add another med: LAM, BUP, SSRI, MAOI, venlafaxine

QTP + SSRILi or VPA + LAM

Acute Mixed EpisodesLevel TIMA EXC APA CANMAT

First-line VPA, ARI, RISP, ZIPAlt: OLAN, CBZ

VPA Combo: Li or VPA + SGA

Li, VPA, OLAN, RISP, QTP, ARI, ZIP, Li or VPA + SGA

Second-line Combo of 2: Li, VPA, SGA

Combo: Mood stab. + SGA

Add another Mood stab., OXC, switch SGA

CBZ, ECT, Li + VPA, Asenapine, Li or VPA + asenapine or paliperidone

Treatment Pearls

Mood stabilizer treatment is long-term and considered to be maintenance treatment to reduce time to subsequent mood episodes

Treatment is limited by tolerability to medications and medication adherence

Treatment Pearls

Adherence can be affected by Adverse effects Loss of pleasurable effects of mania Poor motivation during depression Lack of insight into the need for treatment

Suicide attempt risks are high in both poles of the illness – must monitor closely

Schizophrenia

Diagnostic Features of Schizophrenia

At least two of the following characteristic symptoms lasting at least one month: Delusions, Hallucinations, Disorganized speech,

Grossly disorganized or catatonic behavior, Negative symptoms, such as affective flattening Only one characteristic symptom is required if delusions

are bizarre or hallucinations consist of a voice keeping up a running commentary on the person’s behavior or thoughts or two or more voices conversing with each other

Diagnostic Features of Schizophrenia

Dysfunction in work, interpersonal relationships, or self-care throughout most of the illness; a level of functioning markedly below the level the patient had achieved or might reasonably have been predicted to achieve before the onset of illness

Any of the above symptoms lasting, in full or attenuated form, at least six months

Schizophreniathought disorder

“Positive Symptoms” Hallucinations & Delusion

“Negative Symptoms” Apathy, Social withdrawal & blunted affect

Acute psychotic symptoms May resolve quickly to treatment

Chronic psychosis Improve slowly over months on treatment

Therapy

Psychosocial support needed Only 30% have good response to drug therapy

30% partial, 30% minimal response Drug therapy still essential and should be used

First generation (conventional) antipsychotics Atypical (second generation) antipsychotis

Mechanism Type of Agent Result

Dopamine D2 antagonism

First-generation(haloperidol)

Blockade of dopamine facilitation of pyramidal-neuron response

D2 and 5-HT 2a antagonism

Second-generation (olanzapine, risperidone,quetiapine, ziprasidone)

Blockade of dopamine facilitation of pyramidal-neuron responseand serotonin facilitation of glutamate release

Multiple actions Clozapine D1, D2, and 5-HT 2-3 antagonism, leading to decreased pyramidal-neuron responses; increased acetylcholine release and norepinephrine antagonism, leading to increased interneuronregulation of pyramidal neurons

Mixed dopaminergic Agonismand antagonism

Aripiprazole Facilitation of low-level stimulation of dopamine receptors,blockade of higher levels of stimulation

Schizophrenia & Psychoses

Conventional Antipsychotics D2 >> 5-HT2A , 5-HT1A

Effective for positive symptoms Extrapyramidal symptoms (EPS) Sexual dysfunction Hyperprolactinemia Neuroleptic malignant syndrome (NMS) Tardive dyskinesia (TD) Increased risk of DVT

Extrapyramidal Symptoms (D2 )

Dystonias (muscle spasm) Akathisia (motor restlessness) Pseudoparkinsonism Tardive Dyskinesia (TD)

Extrapyramidal Symptoms (D2 )

Dystonias (muscle spasm) Treat with anticholinergic

benztropine,diphenhydramine Akathisia (motor restlessness)

No effective treatment

Extrapyramidal Symptoms (D2 )

Pseudoparkinsonism Kinesia, tremor, cogwheel rigidity, postural abnormalities Treat with anticholinergic

Tardive Dyskinesia Starts with tongue movements & can progress to whole

body 5% incidence in 1st year with conventional antipsychotics Sometimes irreversible if not caught early

Conventional AntipsychoticsAll: Sexual dysfunction, hyperprolactinemia, NMS & TD Chlorpromazine (Thorazine)

sedation, postural hypotension, weight gain, anticholinergic effects common, occasional EPS

Perphenazine (Trilafon) & Thioridazine (Mellaril) cardiotoxic, sexual dysfunction, retinopathy but fewer acute EPS

Thiothixene (Navane) & Trifluoperazine (Stelazine)

Less sedation, hypotension, anticholinergic effects but more EPS Fluphenazine (Prolixin) Haloperidol (Haldol)

Typical Doses

Drug Initial Daily Dose Usual Daily DoneChlorpromazine 10-50 mg bid 200 mg bidThioridazine 50-100 mg tid 150 mg bidFluphenazine 2.5-5 mg 10 mg onceHaloperidol 5 mg once or divided 5 mg bid

Atypical Antipsychotics

D2 > 5-HT2A

Effective for positive & negative symptoms Better tolerated, Less EPS’s Metabolic effects

Hyperglycemia, Diabetes, Weight gain Increase risk of death in elderly patients with

dementia (also seen with typicals) More $$$

Atypical Antipsychotics Aripiprazole (Abilify)

Anxiety, headache, nausea, constipation, lightheadedness Much less D2 effects, less metabolic effect or weight gain

Avoid with typical agents or risperidone

Oral dissolving tablets and solution are available Ziprasidone (Geodon)

Less weight gain, 5% EPS, QT Available in IM

Atypical Antipsychotics

Quetiapine (Seroquel) Good if concurrent depression

Olanzapine (Zyprexa) More Effective in some but more ADE

Hyperlipidemia & diabetes mellitus (DM) Weight gain, hypotension, constipation

Available in a rapid-dissolving and IM formulations

Atypical Antipsychotics

Risperidone (Risperdal) Typicals > EPS > Atypicals M-Tab and oral solution formulations

Paliperidone (Invega) Active metabolite of risperidone

Iloperidone (Fanapt) 1mg BID on day 1, then 2, 4, 6, 8, 10, and 12mg

BID on days 2, 3, 4, 5, 6, and 7 respectively Prolongs the QT interval more than other atypicals

Atypical Antipsychotics Clozapine (Clozaril)

Most effective; Effective in treating negative sx BOXED WARNING: Agranulocytosis; orthostatic

hypotension, bradycardia, and syncope; seizure; myocarditis and cardiomyopathy; increased mortality in elderly patients with dementia-related psychosis

No reports of tardive dyskinesia; drooling (~35%) CBC every week for 1st 6 months, every 2 weeks

2nd 6 months… Liquid formulation is available

Atypical Antipsychotics

Lurasidone (Latuda) Minimal clinically relevant changes in blood

glucose, lipids or QT interval No clinical benefit seen above 80 mg per day

Monitoring SGA’s

Baseline 4 wks 8wks 12 wks Quarte

rlyAnnually

Every 5 years

Personal/Family Hx X X

Weight X X X X X

Waist X X

BP X X X

Fasting Glucose X X X

Fasting Lipids X X X

Typical Atypical DosesDrug Initial Daily Dose Usual Daily DoseAripiprazole 10-15 mg once 10-30 mg onceZiprasidone 20-40 mg bid 40-80 mg bidQuetiapineQuetiapine XR

25 mg bidUp to 300 mg daily

150-750 mg/day divided800 mg daily

Risperidone 1 mg bid 4 mg onceOlanzapine 5-10 mg once 10-20 mg onceClozapine 12.5-25 mg bid 100-200 mg tidLurasidone 40mg daily 80 – 160 mg dailyAsenapine 5 mg twice daily 5 mg twice dailyIloperidone 1 mg twice daily 12 -24 mg daily

Comparative efficacy Clinical Antipsychotic Trials of Intervention

Effectiveness (CATIE) Government sponsored, compared perphenazine,

olanzapine, quetiapine, risperidone, ziprasidone. Olanzapine more effective, more side effects (DM)

Patients stayed on longer (despite side effects) & less likely to be hospitalized.

Other drugs (typical and atypical) comparable...

Monitoring Response

Takes 4 – 6 weeks for response Only 30 % will have a good response

Assess using scoring system Positive & Negative Symptom Scale (PANSS) Brief Psychiatric Rating Scale (BPRS) Clinical Global Impression (CGI) scale

Consider non-compliance Problem in about 50%

Long – Acting Injectables DO NOT USE unless tolerating oral form first!

Risk EPS, NMS etc. that will last WEEKS! Bridge with PO when starting

Medication Frequency

Haloperidol Deconate Monthly

Fluphenazine Deconate Q 2 – 4 weeks

Risperidone Long-acting(Risperdal Consta)

Q 2 weeks

Olanzapine Long-acting(Zyprexa Relprevv)

Q 2 – 4 weeks

Aripiprazole Long-acting(Abilify Maintena)

Monthly

Paliperidone Long-acting(Invega Sustenna)

Monthly

Stepwise ApproachStage 1

• Trial of single SGA

Stage 2

• Trial of different single SGA or FGA

Stage 3

• Clozapine

Stage 4

• Clozapine + (FGA, SGA or Electroconvulsive therapy (ECT))

Stage 5

• Trial of different single FGA or SGA

Stage 6

•Combination therapy: SGA + FGA; SGA + ECT et al

Generalized Anxiety Disorder

Anxiety Defined

Excessive anxiety & worry more days than not for > 6 months for multiple events / activities

Difficulty in controlling worry Associated with > 3 of the following:

Restlessness or feeling keyed up or on edge Being easily fatigued Difficulty concentrating or mind going blank Irritability, muscle tension Sleep disturbance (difficulty falling or staying

asleep, or restless, unsatisfying sleep)

Anxiety Defined (2)

Not another type of psychiatric disorders e.g., panic disorder, social phobia, obsessive–

compulsive disorder, separation anxiety disorder, anorexia nervosa, or post-traumatic stress disorder

Causes clinically significant distress or impairment in social, occupational, or other important areas of functioning

Not due to other causes (thyroid etc.)

Anxiety Disorders

29% lifetime prevalence Most common psychiatric disorder

Females 2 X Males Older > younger

Therapeutic Goals

Short term goals: Reduction in the frequency and severity of

somatic symptoms of anxiety (e.g., insomnia, fatigue, restlessness, GI symptoms) and psychic symptoms of anxiety (e.g., overwhelming worry)

Symptom improvement of 70% from baseline on HAM-A

Minimize adverse drug effects both in the short term (e.g.,agitation, worsening insomnia) and long term (e.g., sexual dysfunction, weight gain)

Therapeutic Goals

Long-term goals: Achieving disease remission, returning to

functional status without anxiety, improving quality of life (QOL), and preventing relapse or recurrence of anxiety

Benzodiazepines

Most evidence of safety and efficacy for anxiety GAD is chronic requiring long-term therapy Use should be limited to acute treatment (2-4

weeks) With an antidepressant or buspirone, then tapered Alprazolam (Xanax, Xanax XR), lorazepam (Ativan)

Sedation, addiction, withdrawal Rapid onset

Reduce somatic sx earlier than psychic sx

Buspirone

Comparable to BZDs in efficacy Slower onset; maintains sx improvement No affect on comorbid conditions (depression,

social phobia) No withdrawal concerns with abrupt d/c

Buspirone

Initial dose: 15 mg daily (7.5 mg BID) May increase by 5 mg every of 2 to 3 days Titrate as needed to a maximum daily dosage

of 60 mg per day (maximum)

Antidepressants

Demonstrated efficacy in GAD Considered first-line therapy

FDA approved: Duloxetine Escitalopram Paroxetine Venlafaxine extended-release

Duloxetine

Acute and maintenance treatment Initial dose/target dose: 60mg QD or divided

doses

Escitalopram

Acute and maintenance treatment Initial dose: 10mg QD; increase to 20mg per

day after 7 days

Paroxetine

Efficacy in acute management, achieving full remission, and preventing relapse

Effective against comorbid depression and other anxiety disorders

Initial dose: 20mg QD; increase by 10mg/day every 7 days up to 20 to 50mg daily

Must be tapered to prevent withdrawal effects

Decrease the daily dose by 10mg/day each week

Venlafaxine Extended-Release

Effective in acute and maintenance treatment Facilitates remission

Effective in treating comorbid major depression

Initial dose: 75mg/day; increase every 4 days by 75mg to 225mg/day

Anxiolytic effect may be apparent within 1 week

Other Therapies

SSRIs Citalopram

20mg QD up to 40mg after 1 week Sertraline

50mg QD; increase by 50mg per day after 7 days to 200mg daily

Fluvoxamine 50mg at bedtime; increased by 25mg weekly to 200mg

Fluoxetine 20mg daily; increased by 10 or 20mg monthly to 40mg

QD or BID (insomnia)

Other Therapies

Imipramine (TCA) Effective, equivalent to BZDs in anxiolytic effect ADEs/Toxicity: Postural hypotension, blurred vision,

constipation, sedation; weight gain Trazodone – poor tolerability Mirtazapine Bupropion Pregabalin 300-600mg daily

Onset of activity after 1 week; prevents relapse