Physical Effects of Antipsychotics - Canadian Society of …cshp-ab.ca/_CMS/files/CSHP Antipsychotics.pdf · · 2016-09-15Physical Effects of Antipsychotics . ... Neurological Exam

C L A U D I N E L A N G - H O D G E P H A R M D , B C P P C L I N I C A L P H A R M A C I S T

A L B E R T A C H I L D R E N ’ S H O S P I T A L S E P T 1 0 , 2 0 1 6

C L A U D I N E . L A N G - H O D G E @ A H S . C A

Physical Effects of Antipsychotics

mailto:[email protected]



Disclosures

I have no current or past relationships with commercial entities

Speaking Fees for current program:

– I have received a complimentary registration for today’s conference

Objectives

Review of antipsychotic pharmacology/uses

Discuss metabolic side effects of APs

Discuss movement side effects of APs

Highlight emergency reactions to APs

Determine monitoring/treatment for side effects

Antipsychotics: 1st Generation

• Also known as “Typical Antipsychotics”

• Introduced between 1955-1980 Haldol (haloperidol)

Loxapac (loxapine)

Clopixol (zuclopenthixol)

Orap (pimozide)

Fluanxol (flupenthixol decanoate)

Modecate (fluphenazine decanoate)

Piportil (pipotiazine palmitate)

Largactil (chlorpromazine)

Nozinan (methotrimeprazine)

Antipsychotics: 2nd Generation

Also called “Atypical Antipsychotics” Newer, only available since 1990

- Clozaril (clozapine) - Riperdal (risperidone) - Zyprexa (olanzapine) - Seroquel (quetiapine) - Invega (paliperidone) - Zeldox (ziprasidone) - Saphris (asenapine) - Latuda (lurasidone)

• 3rd generation

- Abilify (aripiprazole)

(NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)

“To the extent that antipsychotics differ, it is more in their side effects than therapeutic effects.”

LIEBERM, J.A, STROUP, T..S.; Commentary :Am J Psychiatry 168:8, August 2011

Antipsychotic Uses

Schizophrenia Schizoaffective d/o Bipolar mania Depression Acute agitation/aggression Sleep Anxiety Dementia Eating disorders Tics

Neurotransmitter Pathways Review

Schizophr Bull, image, viewed May2016 <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669582/figure/fig1/>

Dopamine Hypothesis of Schizophrenia

Medication Overview: Antipsychotics

Excessive dopamine in specific areas of the brain causes psychoses

Antipsychotics: block various dopamine receptors in the brain

Attempt to regulate: Positive symptoms

Negative symptoms

Mood

Mechanism of Action of Antipsychotics

Exact mechanisms of action are unknown

The primary actions have been attributed to D2 dopamine blocking

3rd generation (aripiprazole) acts as partial agonist

The different actions at the neurotransmitters account for the different efficacy and side effect profiles

Aripiprazole: 3rd Generation AP: Partial Agonist

Third generation antipsychotic drugs: partial agonism or receptor functional selectivity?; image, viewed May 2016 <http://pubmedcentralcanada.ca/pmcc/articles/PMC2958217/figure/F3/>

Pharmacological Effects of APs on Neurotransmitters/Receptors

• Dopamine Blockade D2

• in mesolimbic =antipsychotic effect (controlling positive symptoms of schizophrenia) • in nigrostriatal tract=EPS and TD • in tuberoinfundibular area= prolactin elevation

• Histamine Blockade Sedation, drowsiness, hypotension, weight gain, antiemetic

• Acetylcholine Blockade Dry mouth, blurred vision, constipation, urinary retention, anticholinergic delirium

• Serotonin Blockade May decrease negative symptoms of schizophrenia, anxiolytic, antidepressant, modulate EPS,

hypotension, sedation, weight gain

• Alpha Blockade Hypotension, reflex tachycardia, sedation, hypersalivation, sexual disturbance

Lieberman, Jeffrey Effectiveness of Antipsychotic Drugs in Patients With Chronic Schizophrenia: Efficacy and Safety Outcomes of the CATIE Trial, image, viewed May 2016 <http://www.medscape.org/viewarticle/529174>

Organ Systems Affected by Antipsychotics

• Endocrine system

• Central nervous system CNS Effects

EPS

Neuroleptic Malignant Syndrome

Seizures

• Cardiovascular system

• Hepatic system

• Dermatologic system

• Hematologic system

• Genitourinary system




EPS


Seizures


• Hepatic system




Endocrine System Effects

Metabolic Effects

Prolactin Effects

Metabolic Effects of APs

• Weight gain

• Increased blood pressure

• Increased lipids Increased total cholesterol

Increased LDL

Increased triglycerides

Decreased HDL

• Increased fasting glucose Increased risk for insulin resistance, type 2 DM

• Increased prolactin

Monitoring for Metabolic Effects

Baseline monitoring: before start of medication or as soon as possible

This includes Personal and family history of obesity, diabetes, dyslipidemia,

hypertension, or cardiovascular disease

Weight and height (so that BMI can be calculated)

Waist circumference (at the level of the umbilicus)

Blood pressure

Fasting plasma glucose

Fasting lipid profile

+/- Prolactin level (depending on medication)

Follow up Monitoring Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5

years

Personal/ Family History

X X

Weight (BMI)

X X X X X

Waist Circum- ference

X X

Blood Pressure

X X X

Fasting Plasma Glucose

X X X

Fasting Lipid Profile

X X X

Pediatric/Adolescent Metabolic Monitoring

CAMESA Guidelines Canadian Alliance for Monitoring Effectiveness and Safety of

Antipsychotics in Children

CAMESA is led by Dr. Tamara Pringsheim, neurologist and clinical epidemiologist at the University of Calgary

http://camesaguideline.org/



Metabolic Monitoring Form

Example: Risperidone

http://camesaguideline.org/information-for-doctors






Parameter Pre-Treatment

Baseline 1 Month 2 Month 3 Month 6 Month 9 Month 12 Month

General Information:

Assessment Date (YYYY/MM/DD):

Patient Age at Assessment:

Daily Dose of risperidone: mg mg mg mg mg mg mg

Physical Examination Maneuvers:

Height (cm)

Height percentile1 Round to nearest 5, 10,

25, 50, 75, 90, or 95 %ile

Weight (kg)

Weight percentile1 Round to nearest 5, 10,

25, 50, 75, 90, or 95 %ile

BMI (kg/m2)1 #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0! #DIV/0!

BMI percentile1 Use CDC calculator to

calculate value1

Waist Circumference (at level of umbilicus) (cm)

Waist Circumference percentile2 >90, or round to nearest

10, 25, 50, 75, or 90 %ile

Systolic Blood Pressure (mm Hg)

Systolic Blood Pressure percentile3 Provide range (<50, 50-

90, 90-95, 95-99, or ≥99)

Diastolic Blood Pressure (mm Hg)

Diastolic Blood Pressure percentile3 Provide range (<50, 50-

90, 90-95, 95-99, or ≥99)

Neurological Examination:

Neurological Exam completed?4

Neurological Exam Normal or Abnormal?

Laboratory Evaluations:

Test Normal Values

Fasting Plasma Glucose5 ≤ 6.1 mmol/L 5

5

5,8

5,7

Fasting Insulin6, 7 ≤ 100 pmol/L 6

6

6,8

6, 7

Fasting Total Cholesterol7, 8 < 5.2 mmol/L 8

7

Fasting LDL-C7, 8 < 3.35 mmol/L 8

7

Fasting HDL-C7, 8 ≥ 1.05 mmol/L 8

7

Fasting Triglycerides7, 8 < 1.5 mmol/L 8

7

AST7 7

7

ALT7 7

7

Prolactin9, 10 10

10

Amylase11 11

11

11

11

11

11

11

Other (e.g. A1C, OGTT, etc.); Please

List

Prolactin Effects

D2 blockade in tuberoinfundibular area in brain

risp=pali>FGA>olanz>zipr>quet≥cloz>arip

In women can lead to: galactorrhea, amenorrhea, irregular menses, anovulation, osteoporosis

In men: impotence and azoospermia, and gynecomastia with or without lactation

Prolactin Elevation

If asymptomatic, typically watch and wait No intervention

If symptomatic, preferred treatment is to switch to another antipsychotic agent with reduced risk- caution with relapse potential

Other options:

Add aripiprazole – D2 partial agonist

Add other dopamine agonists: bromocriptine, cabergoline


• Endocrine system • Central nervous system

CNS Effects EPS Neuroleptic Malignant Syndrome Seizures

• Cardiovascular system • Hepatic system • Dermatologic system • Hematologic system • Genitourinary system

CNS Effects of Antipsychotics

CNS Effects

Drowsiness, sedation

Insomnia, agitation

Movement Disorders

Extrapyramidal symptoms

Neuroleptic Malignant Syndrome (NMS)

Seizures

All APs lower the seizure threshold, use with caution in patients with seizure disorder (typically dose related)

Higher risk with chlorpromazine and clozapine


CNS Effects


Insomnia, agitation

Movement Disorders



Seizures



Movement Disorders Associated with Antipsychotics (EPS)

D2 Blockade in nigrostriatal tract leads to extrapyramidal symptoms

Extrapyramidal Symptoms (EPS)

Drug induced movement disorders that include acute and tardive symptoms Dystonia – continuous spasms and muscle contractions

Akathisia – state of excessive restlessness

Pseudoparkinsonism – rigidity, bradykinesia, tremor

Tardive dyskinesia – abnormal involuntary movement

The Extrapyramidal Symptom Rating Scale (ESRS) to assess four types of drug-induced movement disorders

FGA> risp=pali>olan=zipr=arip>quet>cloz

Chouinard, G, Margolese HC: Manual for the Extrapyramidal Symptom Rating Scale (ESRS); Schizophr Res,2005 Jul 15;76(2-3):247-65. Epub 2005 Apr 18

Extrapyramidal Symptoms (EPS)- Dystonia

Dystonia (10-30%)

Rapid onset 1 or 4 days of start or increase of antipsychotics

Prolonged muscle spasms / contractions

- Oculogyric crisis – rotating of eyeballs

- Opisthotonus- tension in neck, spine, arching

- Tongue spasms or protrusion

- Torticollis – twisted neck

- Trismus-unable to open mouth (forced jaw opening)

- Pharyngeal-laryngeal spasm https://www.youtube.com/watch?v=2krwEbm5hBo

https://www.youtube.com/watch?v=2krwEbm5hBo

Extrapyramidal Symptoms (EPS)-Dystonia

Treatment/ Recommendation for Acute Dystonia

Anticholinergics:

- Benztropine (PO,IM,IV)

- Procyclidine (PO)

- Trihexyphenidyl (PO)

Diphenhydramine (PO,IM,IV)

Reduce dose of antipsychotics

Symptoms will resolve within minutes with IV therapy

Extrapyramidal Symptoms (EPS)-Akathisia

Akathisia (20-40%)

Usually in first 10 days of start or increase of antipsychotics

Restlessness, pacing, fidgeting, subjective jitteriness, associated with suicide

Most common: Movements affecting the legs

May describe vague sensations of internal restlessness, discomfort, or anxiety

Resembles psychotic agitation, agitated depression

Extrapyramidal Symptoms (EPS)- Akathisia

Treatment / Recommendations for Akathisia

Lower antipsychotic dose if possible

- Greater risk with high dose vs. lower dose

Change to different drug (atypical antipsychotic)

- Higher risk with FGA

- Quetiapine, clozapine – less EPS

Beta-blocker (propranolol)

Benzodiazepines

Extrapyramidal Symptoms (EPS) Pseudoparkinsonism

Pseudoparkinsonism (15-35%)

Onset may be as late as 30 days after initiation/increase

Represents symptoms of Parkinson’s disease:

akinesia, bradykinesia, decreased movement initiation, shuffling gait

micrographia, decreased arm swing, masklike faces

postural abnormalities

Extrapyramidal Symptoms (EPS) -Pseudoparkinsonism

Treatment /Recommendation for Pseudoparkinsonism

Lower antipsychotic dose if possible - SGA

Change to different drugs

- Low risk with SGAs and TGA

Antiparkinsonian medications (anticholinergics)

– Benztropine, trihexphenidyl, or procyclidine

Extrapyramidal Symptoms (EPS)-Tardive Dyskinesia

Tardive Dyskinesia (5%) Late onset: after 3 or more months of treatment Abnormal involuntary movements: - Often begins with tongue or fingers –> face -> limbs -> gait -> trunk -> posture - Tongue thrusting, fly catching, lateral jaw movement, abnormal hand movement - Can interfere with eating/swallowing Major risk factors:

-High doses, long duration of treatment, increased age, history of parkinsonian side effects

-https://www.youtube.com/watch?v=BRbjRctgj_k&list=PLz27Rlp3y6XvE3f-GYukCjfI5ArXjAoJ6&index=65

https://www.youtube.com/watch?v=BRbjRctgj_k&list=PLz27Rlp3y6XvE3f-GYukCjfI5ArXjAoJ6&index=65



Extrapyramidal Symptoms (EPS)-Tardive Dyskinesia

Treatment / Recommendation for Tardive Dyskinesia

Remission: likely with prompt discontinuation of antipsychotic therapy

No treatment with proven efficacy

- suggestion: switch to an SGA or TGA

- clozapine?

Discontinue anticholinergic med if pt is taking concurrently (benztropine, trihexphenidyl, or procyclidine)


CNS Effects


Insomnia, agitation

Movement Disorders



Seizures




Life threatening neurologic emergency associated with a class of medications that block dopamine transmission

Characterized by fever, severe muscle rigidity, and autonomic and mental status changes

Incidence of 0.01-0.02% of pts treated with antipsychotics

Mortality estimated 10-20% (was 76% in 1960s)


Pathophysiological mechanism

Antipsychotic-induced dopamine blockade likely plays a pivotal triggering role in the condition - central dopamine receptor blockade in the hypothalamus =

hyperthermia and other signs of dysautonomia

- Interference with nigrostriatal D2 blockade = rigidity, tremor


Associated Medications

Neuroleptic agents

- Greater risk: High potency FGA (haloperidol, fluphenazine)

Other drugs with anti-dopaminergic activity

- eg, Antiemetic drugs – metoclopramide, promethazine, domperidone

Withdrawal of L-dopa or dopamine agonist therapy


Onset of symptoms

Within first two weeks of initiation or change in dose of neuroleptics

Predisposing factors

Increased use of higher doses, rapid dose escalation, a greater number of IM injections (long acting)

However, NMS usually occurs within the therapeutic dosage range of antipsychotics


Tetrad of distinctive Clinical Features: (DSM-V Diagnostic Features)

ever

utonomic Instability

Severe Muscle igidity

ental status changes

Mental status changes

Rigidity Hyperthermia Autonomic dysfunction

o Analysis of 340 Cases: 70% of patients followed the symptoms below in order:


Differential diagnosis Prime importance because NMS is a diagnosis of exclusion

Lab abnormalities Elevated serum CK >1000IU/L

Leukocytosis: WBC count 10,000 to 40,000/mm

Mild elevations of lactate dehydrogenase, alkaline phosphatase, liver transaminases

Electrolytes abnormalities: hypocalcemia, hypomagnesemia, hypernatremia, hyperkalemia, metabolic acidosis

Myoglobinuric acute renal failure resulting from rhabdomyolysis

Low serum iron conc

Differential Diagnosis- NMS

Stawn, J. Keck, Jr, P. and Caroff, S. Neuroleptic Malignant Syndrome. Am J Psychiatry 164:6, June 2007


Treatment Discontinue antipsychotic drug (do not taper)

Supportive Care/Hydration

- eg. control of fever, intravenous fluid support, correction of electrolyte abnormalities

Use benzodiazepines to control agitation, if necessary

Specific pharmacotherapy:

- Dopaminergic agents

bromocriptine

amantadine

dantrolene (especially, for patients with extreme temperature elevations and rigidity)

ECT


Drug Treatment for NMS Bromocriptine – start with 1 or 2.5mg doses. If ineffective,

increase to 15-20mg TID or QID

Amantadine – 100mg once daily to TID

Dantrolene – 4-8mg/day IV divided QID or 25-600mg/day PO

Once patients respond to drug treatment it should be continued for 1-2 weeks.

NMS- Prognosis

• Most episodes resolve within two weeks

• Reported mean recovery time 7-11 days

• Cases persisting for 6 months with residual catatonia and motor signs are reported

• Risk factors for a prolonged course: depot antipsychotic use and concomitant structural brain disease

• Most patients recover without neurologic sequelae except severe hypoxia or grossly elevated temperatures for long duration

NMS- Restarting Antipsychotics

Minimize risk by: Waiting for at least 2 weeks before restarting therapy

Using low-potency rather than high-potency drugs

Starting with low doses and titrating upward slowly

Avoiding concomitant lithium

Avoiding dehydration

Carefully monitoring for symptoms of NMS


CNS Effects


Insomnia, agitation

Movement Disorders



Seizures



Seizures

Most agents lower seizure threshold and may produce seizures

Predisposing factors for antipsychotic induced seizures:

Pre-existing seizure disorder

Abnormal EEG without a history of seizure

Pre-existing CNS pathology

Rapid increases in antipsychotic dosage

Clozapine greatest risk of 2nd gen AP (dose dependent)




EPS


Seizures


• Hepatic system




Cardiovascular Effects of APs

QTc prolongation

Tachycardia

Orthostatic hypotension

Cardiomyopathy (reported with clozapine)

QT prolongation

Sudden Arrythmia Death Syndromes Foundation, image viewed May 2016 <http://www.sads.org/library/long-qt-syndrome#.V45cp9QrK9I>

Normal QTc intervals

• Mean daily variation is approximately 75msec

• Males: Prolonged if >440msec

• Female: Prolonged if >450msec

• Or any increase of >40ms from baseline for either gender

• If >500ms, at increased risk for Torsade de pointes (4x greater risk)

Risk Factors for QTc prolongation

• Hypokalemia

• Hypomagnesemia

• Age

• Female sex

• Advanced heart disease

• Congenital and acquired long-QT syndromes

• Family history of sudden death

• Anorexia

• Bradycardia

Examples of QTc Prolongation Associated With Select Antipsychotics

Antipsychotic Approximate QTc interval prolongation in millisecondsb

Aripiprazole -1 to -4

Clozapine 10

Haloperidol 7 to 15

Olanzapine 2 to 6.5

Paliperidone 2 to 4

Pimozide 19

Quetiapine 6 to 15

Risperidone 3.5 to 10

Thioridazine 33 to 41

Ziprasidone 16 to 21 aList is not comprehensive. Other antipsychotics may be associated with QTc prolongation bQTc prolongation interval may depend on the route of administration

<http://www.currentpsychiatry.com/the-publication/past-issue-single-view/which-psychotropics-carry-the-greatest-risk-of-qtc-prolongation/a6b37aa6714c13dfa41d94c68bd26bb8.html?tx_ttnews%5bsViewPointer%5d=3>

Monitoring for QTc Prolongation

Obtain history for congenital or acquired long QT syndromes

Identify other QT prolonging medications (crediblemeds.org)

Obtain baseline ECG

If borderline prolongation or combining with other QT prolonging agents, obtain second ECG after initiation

Usually wait for steady state (3-5 days) before repeating

If concern, can repeat sooner

crediblemeds.org

Crediblemeds.org Example

Recap: Objectives

Review of antipsychotic pharmacology/uses

Discuss metabolic side effects of APs

Discuss movement side effects of APs

Highlight emergency reactions to APs

Determine monitoring/treatment for side effects

References

1. Alvarez PA, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf. 2010;5(1):97-104. 2. American Psychiatric Association. Desk Reference to the Diagnostic Criteria from DSM-5TM. London: American Psychiatric Publishing;

2013 3. Bezchlibnyk-Butler KZ, Virani AS. Clinical Handbook of Psychotropic Drugs for Children and Adolescents. 3rd ed. Ashland: Hogrefe &

Buber Publishers 4. Boyer EW, Shannon M. The Serotonin Syndrome. N Engl J Med 2005;352:1112-20 5. Boyer EW. Serotonin Syndrome. 2015 UpToDate [cited 2015 Sep 14] 6. Chouinard, G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS); Schizophr Res,2005 Jul 15;76(2-3):247-65.

Epub 2005 Apr 18 7. Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care February 2004vol. 27 no. 2 596-601 8. Elbe, Dean et al. Clinical Handbook of Psychotropic Drugs for Children and Adolescents, 3rd edition, 2015 Hogrefe Publishing 9. Leucht S et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.

www.thelancet.com Vol 382; September 14, 2013 10. Lieberman JA. Managing Anticholinergic Side Effects. Prim Care Companion J Clin Psychiatry. 2004; 6(suppl 2): 20-23. 11. Muench J, Hamer AM. Adverse Effects of Antipsychotic Medications. American Family Physician. March 1, 2010. Volume 81, No 5 12. Nielsen J, Graff C, Kanters JK, et al. Assessing QT interval prolongation and its associated risks with antipsychotics. CNS Drugs.

2011;25(6):473-490. 13. Pringsheim T. Extrapyramidal Symptoms Associated with Second Generation Antipsychotic Use 14. Strawn JR, Keck PE, Caroff SN. Neuroleptic Malignant Syndrome. AM J Psychiatry 164:6, June 2007 15. Taylor DM. Antipsychotics and QT prolongation. Acta Psychiatr Scand. 2003;107(2):85-95. 16. Vieweg WV. New generation antipsychotic drugs and QTc interval prolongation. Prim Care Companion J Clin Psychiatry. 2003;5(5):205-

215. 17. Weiden PJ. EPS Profiles: The Atypical Antipsychotics Are Not All the Same. Journal of Psychiatric Practice Vol. 13, No. 1. January 2007 18. Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of torsade de pointes. Dtsch Arztebl Int.

2011;108(41):687-693. 19. Wijdicks E. Neuroleptic malignant syndrome. 2015 UpToDate [cited 2015 Sep 14] 20. Yatham, LN et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and international Society of CANMAT guidelines for

the management of patients with bipolar disoder: update 2013. Bipolar Disorders 2013: 15:1-44

http://www.thelancet.com/

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Documents

Physical Effects of Antipsychotics - Canadian Society of …cshp-ab.ca/_CMS/files/CSHP Antipsychotics.pdf · · 2016-09-15Physical Effects of Antipsychotics . ... Neurological Exam