Bipolar Disorders, Schizophrenia, and Anxiety
Ibrahim Sales, Pharm.D.Assistant Professor of Clinical Pharmacy
King Saud [email protected]
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
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