Bipolar Disorders, Schizophrenia, and Anxiety

Name: Bipolar Disorders, Schizophrenia, and Anxiety
Uploaded: 2017-08-09T00:25:47+00:00
Duration: PTM41S45
Channel: Lilian Baker
Description: Bipolar Disorders, Schizophrenia, and Anxiety

Bipolar Disorders, Schizophrenia, and Anxiety
Ibrahim Sales, Pharm.D. Assistant Professor of Clinical Pharmacy King Saud University

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 Disorders
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 Depression 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
Comments Acute mania Maintenance Bipolar depression Antipsychotics, atypical Aripiprazole (Abilify) Olanzapine (Zyprexa) Quetiapine (Seroquel) Risperidone (Risperdal) Ziprasidone (Geodon) Yes No Yes (+SSRI) 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, typical Haloperidol lactate (Haldol) No difference in response rates among haloperidol, risperidone, olanzapine, carbamazepine, and valproate for acute mania Benzodiazepines Lorazepam (Ativan) Used as combination therapy in patients with acute mania to reduce agitation Carbamazepine (Tegretol) Evidence for carbamazepine is not as strong as that for lithium and valproate Divalproex (Depakote), valproic acid (Depakene) Valproate appears to be more effective than lithium for mixed states Lamotrigine (Lamictal) Acceptable agent in pregnancy; associated with weight loss in obese patients with bipolar I disorder Lithium 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 Therapeutic Uses Dosage Forms
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 Dosing 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: 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 Monitoring Initial Workup Efficacy Renal function tests
Electrolytes Thyroid panel CBC EKG (elderly, cardiovascular disease) Pregnancy test Resolution of symptoms Assessments for adverse effects Weight Neurologic exam Patient report on GI symptoms, urinary frequency, etc. Periodic serum lithium levels

Valproate Mechanism of Action Therapeutic Uses
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 Dosing and Administration
IR (valproic acid): oral capsules and liquid concentrate DR, ER (divalproex sodium): oral tablets and sprinkle capsules Dosing and Administration Starting dose: mg in 2-3 divided doses Oral loading 20mg/kg/day x 5 days Target conc. : mcg/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 Drug Interactions 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 Therapeutic Use
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 Dosage 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: mg/day in divided doses Usual range: mg/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 Dosing 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 Episodes Level TIMA EXC APA CANMAT First-line Li VPA SGAs
Alt: CBZ Li 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 CBZ ECT Li + VPA Asenapine Li 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 + HAL Li + CBZ Clozapine OXC, LAM

Acute Depressive Episodes
Level TIMA EXC APA CANMAT First-line Mono: LAM Combo: LAM + Mood stabilizer Mono: LAM or Li Severe: Li + LAM or SSRI Rapid cycling: LAM Psychotic features: SGA Severe: Li + SSRI Li, LAM, QTP, Li or VPA + SSRI OLAN + SSRI Li +VPA Li 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 + SSRI Li or VPA + LAM

Acute Mixed Episodes Level TIMA EXC APA CANMAT First-line
VPA, ARI, RISP, ZIP Alt: 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

Schizophrenia thought 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 Second-generation (olanzapine, risperidone, quetiapine, ziprasidone) and 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 interneuron regulation of pyramidal neurons Mixed dopaminergic Agonism and 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)

Dystonias (muscle spasm) Treat with anticholinergic benztropine,diphenhydramine Akathisia (motor restlessness) No effective treatment

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 Antipsychotics
All: 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 Done Chlorpromazine
10-50 mg bid 200 mg bid Thioridazine mg tid 150 mg bid Fluphenazine 2.5-5 mg 10 mg once Haloperidol 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 $$$

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

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

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

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

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 Every 5 years Quarterly Baseline Annually 12 wks
Personal/Family Hx X Weight Waist BP Fasting Glucose Fasting Lipids

Typical Atypical Doses
Drug Initial Daily Dose Usual Daily Dose Aripiprazole 10-15 mg once 10-30 mg once Ziprasidone 20-40 mg bid 40-80 mg bid Quetiapine Quetiapine XR 25 mg bid Up to 300 mg daily mg/day divided 800 mg daily Risperidone 1 mg bid 4 mg once Olanzapine 5-10 mg once 10-20 mg once Clozapine mg bid mg tid Lurasidone 40mg daily 80 – 160 mg daily Asenapine 5 mg twice daily Iloperidone 1 mg twice daily 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) Aripiprazole Long-acting (Abilify Maintena) Paliperidone Long-acting (Invega Sustenna) Risk Evaluation and Mitigation Strategy (REMS) – Unpredictable postinjection delerium syndrome

Stepwise Approach Trial of single SGA
Stage 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 Females 2 X Males
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 FDA approved:
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 Sertraline Fluvoxamine Fluoxetine
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) Trazodone – poor tolerability
Effective, equivalent to BZDs in anxiolytic effect ADEs/Toxicity: Postural hypotension, blurred vision, constipation, sedation; weight gain Trazodone – poor tolerability Mirtazapine Bupropion Pregabalin mg daily Onset of activity after 1 week; prevents relapse

Bipolar Disorders, Schizophrenia, and Anxiety

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