Pharmacologic Considerations in
the Treatment of Schizophrenia and
Psychosis
Presented by: Ann M. Hamer, PharmD, BCPP
Date: 3/19/2015
Disclosures and Learning Objectives
• Learning Objectives
–
–
–
Be able to discuss attributes of traditional
antipsychotics
Be able to identify/manage EPS
Be able to monitor for metabolic side
effects
Disclosures: Dr. Ann Hamer has nothing to disclose.
Traditional Antipsychotics
Generic
Brand
Chlorpromazine
Thorazine
Thioridazine
Mellaril
Mesoridazine
Serentil
Loxapine
Loxitane
Molindone
Moban
Perphenazine
Trilafon
Thiothixene
Navane
Trifluoperazine
Stelazine
Haloperidol
Haldol
Fluphenazine
Prolixin
Droperidol
Inapsine
Prochlorperazine
Compazine
FGA—Pharmacology
• Characterized by strong antagonism of dopamine D2
receptors in both cortical and striatal areas
• Their dopamine D2 binding is highly correlated with
clinical potency
• The nonspecific localization of their dopamine binding is
consistent with their risk of movement disorders and
prolactinemia.
FGA Overview
FGA
Usual
Dose
Range
Initial Oral
Dose
Max
Dose
Formulations
T1/2
Primary
metabolism
Enzyme
Inhibition
Chlorpromazine
400-600
25-200
800
Tab, IM
30
2D6, gluc
2D6
Fluphenazine
2 -15
2-10
12
Tab, IM, LAI, soln
33
2D6
2D6
Haloperidol
2-20
2-10
30
Tab, IM, LAI, soln
20
2D6, 3A4, gluc
2D6, 3A4
Loxapine
20-80
20
100
Cap, soln, inhalation
12
1A2, 2D6, 3A4,
gluc
None
Perphenazine
12-24
8-16
24
Tab
9-12
2D6, 3A4,
others
2D6
Pimozide
8-10
1-2
10
Tab
55
1A2, 2D6, 3A4,
others
2D6
Thiothixene
10-20
5-10
30
Cap
33
1A2, others
None
Thioridazine
200-600
150
600
Tab
21-25
2D6, others
2D6
Trifluoperazine
15-20
4-10
40
Tab
22
1A2
None
Comparison of Receptor Antagonism
FGA Side Effect Comparison
EPS
EPS
EPS
Parkinsonism
Drug-Induced Parkinsonism consists of six separate sets of
motor disturbances:
•
Rigidity
•
Tremor
•
Reduced facial expression/speech
•
Impaired gait/posture
•
Postural instability
•
Bradykinesia
Dystonia
Dystonia is a movement disorder in which muscles are
contracted and contorted.
• Symptoms may co-occur with dyskinesia.
• Symptoms may result in the patient’s assuming
abnormal postures or positions.
• Dystonia may be present at rest and/or during action.
• Dystonia is usually first seen during action.
• In more advanced cases, symptoms may appear both at rest
and during action
Akathisia
Akathisia is subjective feelings of inner restlessness with the urge
to move, and/or objective movements such as:
• Restless movement of one extremity
• Fidgeting
• Changing position
• The inability to sit down for long periods
• Pacing back and forth or marching in place
• Terminology used by the patient to describe these feelings may
often be confusing and even idiosyncratic.
Scales
•
Good EPS Review Article:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004713/
•
AIMS Rating Scale:
http://www.psychiatrictimes.com/clinical-scalesmovement-disorders/clinical-scales-movementdisorders/aims-abnormal-involuntary-movement-scale
•
Simpson Angus Scale:
http://cpnp.org/_docs/ed/movementdisorders/scale/msas.pdf
•
Barnes Akathisia Rating Scale:
http://keltymentalhealth.ca/sites/default/files/BARS.pdf
Tardive Dyskinesia
Tardive Dyskinesia
• About 5% of patients maintained on conventional antipsychotics will
develop tardive dyskinesia every year (i.e., about 25% of patients by
5 years)
• The risk of developing tardive dyskinesia in elderly subjects may be
as high as 25% within the first year of exposure to conventional
antipsychotics.
• If D2 receptor blockade is removed early enough, tardive dyskinesia
may reverse. This reversal is theoretically due to a “resetting” of
these D2 receptors by an appropriate decrease in the number or
sensitivity of them in the nigrostriatal pathway once the antipsychotic
drug that had been blocking these receptors is removed.
Tardive Dyskinesia
• However, after long-term treatment, the D2 receptors apparently
cannot or do not reset back to normal, even when conventional
antipsychotic drugs are discontinued.
• Patients who develop EPS early in treatment may be twice as likely
to develop tardive dyskinesia if treatment with a conventional
antipsychotic is continued chronically.
• Also, specific genotypes of dopamine receptors may confer
important genetic risk factors for developing tardive dyskinesia with
chronic treatment using a conventional antipsychotic.
Metabolic Syndrome in Psychiatrically
Hospitalized Patients
• Prevalence of metabolic syndrome w/ prior
antipsychotic treatment = 29.5%
•
Syndrome strongly associated with being overweight, older age,
long treatment exposure, schizoaffective diagnosis, more illnessepisodes or hospitalizations, polypharmacy, and higher total daily
CPZ-equivalent doses
•
Metabolic syndrome risk greater among young (<26 years) APtreated patients
• Prevalence of metabolic syndrome w/o prior
antipsychotic treatment = 7.20%
Hum. Psychopharmacol Clin Exp. 2012;27:521-26
Metabolic Syndrome in Psychiatrically
Hospitalized Patients
Hum. Psychopharmacol Clin Exp. 2012;27:521-26
Glucometabolic hormones and CV risk
markers in AP-treated patients
Key Points:
• Antipsychotic-treated patients display emerging
signs of dysmetabolism and a compromised CV risk
profile with an insulin resistant-like pattern including
beta cell hypersecretion and elevated glucosedependent insulinotropic polypeptide levels
•
The appetite-regulating hormone GLP-1 and ghrelin
appear not to be influenced by antipsychotic
treatment
J Clin Psych. 2014; 75:9c
Hyperglycemia and Diabetes
•
Indirect effect
•
•
•
Secondary to weight gain
Obesity is a risk factor for insulin resistance (precursor
for type 2 diabetes)
Direct effect
•
•
Hyperglycemia and diabetes without significant weight
gain has been identified
Inhibition of glucose transport into cells, increase cellular
levels of glucose transporters leading to hyperglycemia
and an increase in insulin release. Prolonged
hyperinsulinemia can eventually lead to insulin
resistance.
Weight Gain
•
Proposed mechanisms (in addition to lifestyle factors):
•
•
•
Increased caloric intake
Slowed basal metabolic rate
5HT2C plays a role in regulating appetite
•
•
Psychotropics with greater ability to block H-1 receptors often
show greater weight gain potential
•
•
Blockade may increase appetite (olanzapine, quetiapine, clozapine)
Possibly by deactivating brain satiety centers and increasing hunger
Weight gain associated with atypical antipsychotic agents
generally occurs within the first few months after initiation
and may not stabilize for more than a year
CNS Neuroscience & Ther. 2012;18:57-63
Antipsychotic Comparison
Weight Gain
Medication
Amount of Weight Gain
Olanzapine (Zyprexa)
2.3 kg/month average
4.2 - 12 kg total
Quetiapine (Seroquel)
1.8 kg/month
4.1 - 5.6 kg total
Risperidone (Risperdal)
1.0 kg/month
Ziprasidone (Geodon)
0.8 kg/month
Asenapine (Saphris)
0.9kg over 3 weeks
Iloperidone (Fanapt)
1.5-2.1 kg total
Aripiprazole (Abilify)
0.5 - 0.9 kg total
Clozapine (Clozaril)
1.7 kg/month
2.4 - 31.3 kg total
Lurasidone (Latuda)
0.75 kg
CNS Neuroscience & Ther. 2012;18:57-63
Metabolic Monitoring Protocol for Adult
Patients on AAPs
BC Med Journal. 2012;54(2)
Metabolic Monitoring Protocol for Children on
AAPs
BC Med Journal. 2012;54(2)
Lifestyle Interventions
•Lifestyle intervention improves AP-user health
•Patients randomized to STRIDE intervention or usual care for 6
months. The intervention included an additional 6-month reinforcement
phase.
•Assessments conducted at baseline, 6 and 12 months
Measurement
Intervention
Usual Care
Weight loss of at least 5%
of baseline weight
40%
17%
Fasting blood glucose
106.3mg/dL baseline to
100.4mg/dl at 12 mon
106mg/dL baseline to
109.5mg/dL at 12 mon
Medical hospitalization
6.7%
18.8%
Psychiatric hospitalization
Similar
Am J Psychiatry 2014; doi: 10.1176/appi.ajp.2014.14020173
Treatment Options for Metabolic Syndrome
• Selective monoamine transport inhibitors
• Bupropion, psychostimulants
• Insulin-promoting agents
• Metformin
• Specific anticonvulsants with anti-obesity effects
• Topiramate, zonisamide
• Other agents with effects on appetite and body
weight
• Orlistat, amantadine, modafinil, memantine
CNS Drugs. 2009;23(12)
Treatment Options for Metabolic Syndrome
• Bupropion
• Minor benefits in limiting weight gain
associated with other psychotropic,
but may reduce serum cholesterol
levels
• Caution with sympathomimetics (e.g.
phentermine)
CNS Drugs. 2009;23(12)
Treatment Options for Metabolic Syndrome
•
Metformin
•
•
•
•
•
Best evidence to support use
Can be combined with antipsychotics to manage
hyperglycemia by increasing insulin sensitivity and decreasing
leptin levels, ideally in combination with weight control
Lifestyle modification combined with metformin appears to be
more effective for weight loss than either tx alone
Metformin alone is more effective than placebo in improving
insulin sensitivity
Metformin 250mg tid, along with lifestyle modification, to
promote weight loss and decrease insulin resistance in patients
who gain >10% of their pretreatment body weight on
antipsychotic medications is recommended.
CNS Drugs. 2009;23(12)
JAMA. 2008;299:185-193
Beneficial Effects of Metformin
JAMA. 2008;299:185-193
Treatment Options for Metabolic Syndrome
• Topiramate
•
•
•
Can promote weight loss; add on strategy has
shown 10-15 lb weight loss in case studies
Adverse effects include perceptual and cognitive
abnormalities, metabolic acidosis, renal stones and
glaucoma
Dose range from studies 100-400mg/day.
• Zonisamide
•
•
Some ability to reduce weight
Effects on mood stabilization are weak
CNS Drugs. 2009;23(12)
CNS Neuroscience & Ther. 2012;13:57-63
Treatment Options for Metabolic Syndrome
• Orlistat
•
•
•
Pancreatic lipase antagonist that inhibits absorption
of dietary fats
May be effective at treating psychotropic-induced
weight gain. May improve dyslipidemia parameters
and improve glycemic control.
Dose typically 120mg TID. Must take a MVT.
• Amantadine
•
•
May limit weight gain with antipsychotics
Dose typically 300mg/day.
CNS Drugs. 2009;23(12)
CNS Neuroscience & Ther. 2012;13:57-63
Treatment Options for Metabolic Syndrome
• Modafinil
•
May produce weight loss with antipsychotics,
possibly with less risk of inducing mania or
worsening psychosis than standard
psychostimulants such as amphetamines or
methylphenidate
• Memantine
•
•
Uncompetitive glutamic acid NMDA receptor
antagonist
May contribute to weight control in addition to its
cognition-enhancing effects
CNS Drugs. 2009;23(12)
TREATMENT INITIATION
Treatment with antipsychotic medication should be considered an
explicit individual therapeutic trial.
• Discuss and record the side effects that the person is most willing to
tolerate.
• Record the indications and expected benefits and risks of oral
antipsychotic medication, and the expected time for a change in
symptoms and appearance of side effects.
• At the start of treatment give a dose at the lower end of the
licensed range and slowly titrate upwards within the dose range
• Justify/record reasons for dosages outside of normal dosage range.
• Record the rationale for continuing, changing or stopping
medication, and the effects of such changes.
• Trial of the medication at optimum dosage for at least 4–6 weeks.
MONITORING
AIMS Rating Scale: http://www.psychiatrictimes.com/clinical-scales-movementdisorders/clinical-scales-movement-disorders/aims-abnormal-involuntarymovement-scale
Simpson Angus Scale: http://cpnp.org/_docs/ed/movementdisorders/scale/msas.pdf
Barnes Akathisia Rating Scale:
http://keltymentalhealth.ca/sites/default/files/BARS.pdf
FGA
Usual Dose
Range (mg)
Initial Oral
Dose (mg)
Max
Dose
(mg)
Formulations
T1/2
(Hrs)
Primary
metabolism
Enzyme
Inhibition
Haloperidol
2-20
2-10
30
Tab, IM, LAI, soln
20
2D6, 3A4, gluc
2D6, 3A4
Perphenazine
12-24
8-16
24
Tab
9-12
2D6, 3A4, others
2D6
Ariprazole
10-15
10-15
30
Tab, ODT, IM, LAI, soln
75-94
2D6, 3A4
None
Asenapine
10-20
10
20
SL tab
24
1A2, gluc
None
Clozapine
150-600
25-50
900
Tab, ODT, susp
12
1A2, others,
gluc
2D6 (mod)
Iloperidone
12—24
2
24*
Tab
18-26
2D6, others
3A4 (mod)
Lurasidone
40-80
40+
160 ++
Tab
29-37
3A4
None
Olanzapine
10-20
5-10
30
Tab, ODT, IM, LAI
30-38
CYP1A2, gluc
None
Paliperidone
6-12
6
12
ER tab, LAI
23
Excreted mainly
unchanged#
None
Quetiapine
150-750 IR
400-800 ER
50
750 IR
800 ER
Tab, ER tab
6-12
CYP3A4
None
Risperidone
2-6
1-2
8
Tab, ODT, LAI, soln
20
2D6 to
paliperidone
2D6
Ziprasidone
40-160
40-80
200
Cap, IM
7 oral
2-5IM
3A4
None
*12 (CYP2D6 poor metabolizer or with 2D6 inhibitor
+20 (renal or hepatic insufficiency)
++80 (mod or severe renal insufficiency, mod hepatic insufficiency); 40 (severe hepatic insufficiency)
#Dose reduction necessary in renal insufficiency
The End!
Next Week:
Welcome Back
Dr. Betlinski