2 - Neuroscience Education Institute

Transcription

Handout for the Neuroscience Education Institute (NEI) online activity:
Lightning Round Cases:
What's New in Psychosis
and Antipsychotics
Copyright © 2015 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Evaluate recent data regarding the detection of
and intervention for ultra high risk state
psychosis
• Evaluate recent data regarding current
antipsychotic therapies with respect to brain
volume
• Evaluate the mechanisms of and latest clinical
data on new and emerging antipsychotics
Case Example: Henry
• Henry is a 21-year-old man who has been brought in
by his parents because he is not transitioning
successfully into independent adult life
• Henry has always been aloof and a loner, with
"strange ideas and behaviors"
• His language development in grade school
appeared normal, but he had difficulty reading and
was considered learning disabled by third grade
• As a child, he was suspected of having ADHD; no
response to methylphenidate
• As an adolescent, he was thought to have OCD; no
response to fluvoxamine or venlafaxine
Patient Intake
• Henry graduated from high school and began
working at a supermarket
• Six months ago, he began to exhibit difficulty
functioning, including losing things, trouble following
simple directions at work, and disorganization
• He displayed deterioration in reading and
communication, including using simple language
• These impairments led to his dismissal from his job
3 months ago
• He lives at home with his parent and does not
groom or change his clothes unless prompted by his
mother
Patient Intake
• Henry has withdrawn from his few high school
friends and is not dating
• He now avoids all social gatherings and feels
that people around him are talking about him
• He spends a lot of time sleeping, and he struggles
with daily functions
Family History
– Father: history of learning disabilities, but is a
successful small business owner now
– Sister: anxiety
– 2 maternal uncles: depression
Question 1
Would you consider Henry to be at ultra high risk (UHR) for
developing psychosis?
1. Yes
2. No
Ultra High Risk (UHR) Criteria
• Attenuated psychotic symptoms, having experienced
sub-threshold attenuated psychotic symptoms during the
past year
• Brief limited intermittent psychotic symptoms, having
experienced episodes of frank psychotic symptoms that
have not lasted longer than a week and have
spontaneously abated
• State and trait risk factor, having schizotypal personality
disorder or a first-degree relative with a psychotic disorder
and having experienced a significant decrease in
functioning during the previous year
Basic Symptoms (BS)
• Subjectively experienced disturbances of perception,
thought processing, language, attention
• Distinct from classic psychotic symptoms (independent
of abnormal thought content; insight is intact)
• COGDIS: Cognitive disturbances (e.g., thought
interference, disturbances of abstract thinking, receptive
speech disturbances, etc.)
• COPER: cognitive disturbances and a few predictive
perceptive disturbances
– Basic symptoms are currently assessed with the
Schizophrenia Proneness Instrument, Adult (SPI-A) or
Child & Youth version (SPI-CY)
Schultze-lutter F, Michel C, Schmidt SJ, et al. Eur Psychiatry. 2015;30(3):405-16.
Prodromal Phase
Premorbid Risk
Early Psychosis
Basic Symptoms Criteria
UHR Criteria: Genetic risk and
functional decline
UHR Criteria: Attenuated
psychotic symptoms (APS)
Psychotic symptoms that meet
the threshold for an ICD or
DSM diagnosis of psychosis
Symptom Severity
UHR Criteria: Brief limited
intermittent psychotic
symptoms (BLIPS)
Attenuated
psychotic
symptoms (APS)
Brief limited
intermittent psychotic
symptoms (BLIPS)
Basic
Symptoms
Indicated Prevention
Treatment
Fusar-poli P, Borgwardt S, Bechdolf A, et al. JAMA Psychiatry. 2013;70(1):107-20.
European Psychiatric Association (EPA)
Guidance on the Early Detection of High Risk
Recommendation 1: 3 clinically high-risk (CHR)
criteria should be alternatively used in the early
detection of psychosis
– At least 1 attenuated psychotic symptom that
meets the additional requirements of either SIPS or
early CAARMS
– At least 2 self-experienced and self-reported
cognitive basic symptoms according to the SPI-A
– At least 1 transient psychotic symptom that meets
the additional requirements of either SIPS or early
CAARMS
CAARMS: Comprehensive Assessment of At-Risk Mental State.
Question 2
After full assessment, you determine that Henry meets the
criteria for UHR of psychosis. Henry's parents are very
concerned and ask if this means that he is definitely going
to develop a psychotic disorder. What percentage of
individuals who meet the criteria for ultra high risk (UHR)
transition within 2 years of their first clinical presentation?
1. 5-10%
2. 15-20%
3. 25-35%
4. 40-50%
Speed of Psychosis Progression in UHR
Meta-analysis: 2% of UHR individuals are expected
to transition 1 month after presentation
y = 2.2[e−0.07x]
Kempton MJ, et al. Risk. JAMA Psychiatry 2015:622–622.
Risk Progressively Increases for
Patients at UHR
Meta-analysis suggests that the transition to psychosis in patients at
UHR is most likely to occur within the first 2 years, with half of patients
who progress doing so within the first 8 months
Kempton MJ, et al. JAMA Psychiatry 2015:622–622.
Other Early Detection Considerations
• It is not possible to predict with great accuracy who
will develop schizophrenia, but certain symptoms,
such as social withdrawal and cognitive decline, can
identify teenagers and young adults at high risk
• In the North American Prodrome Longitudinal Study
(NAPLS 2), those who transitioned to psychosis
differentiated from other groups on unusual thought
content, disorganized communication, and overall
ratings on disorganized symptoms
Addington J1, Liu L, Buchy L et al. J Nerv Ment Dis 2015;203(5):328-35.
What percentage of individuals who meet the criteria
of ultra high risk (UHR) transition within 2 years of
their first clinical presentation?
1. 5-10%: Too low
2. 15-22%: The average transition of 6 months to 1 year
3. 25-35%: On average, there is a 29% risk of developing
psychosis within 2 years
4. 40-50%: By year 3, transition risk plateaus at 36%
Transition risk varies with age of patient, nature of
treatment provided, and definitions of "syndrome" and
"transition to psychosis."
Fusar-poli P, Bonoldi I, Yung AR et al. Arch Gen Psychiatry. 2012;69(3):220-9.;
Kempton MJ et al. JAMA Psychiatry 2015:622–622.
Question 3
Henry's parents want to know if there are genetic tests or
biological markers available to help make the diagnosis of
eventual schizophrenia or if they must simply wait for a
first-break episode of psychosis. Would you refer him for
neuroimaging or genetic testing?
1. Yes
2. No
Genetic or Biological Predictors of
Schizophrenia Remain Research Tools
• Recent studies prove promising for the future
– Abnormalities of the N-methyl-D-aspartate (NMDA)
glutamate receptor and glutamate synapses in
schizophrenia
– Pro-inflammatory factors and pathways involved in
histone methylation
– New serum blood test for panel of 26 biomarkers?
Although Still a Research Tool, Steeper Rate of Gray
Matter Loss Is Seen in Patients at UHR Who Convert
to Psychosis
UHR Converter vs.
UHR Non-converter
UHR Converter
vs. Healthy Control
Expansion
Thinning
False Discovery Rate (FDR) Corrected P-Maps
Cannon TD, Chung Y, He G, et al.. Biol Psychiatry. 2015;77(2):147-57.
Youth and Young Adults at UHR Have
Shown Thalamic Dysconnectivity
Blue: reduced
Yellow: increased
1 Left cerebellum
2 Right lateral prefrontal
cortex
3 Left sensory/motor
cortex
4 Right sensory/motor
cortex
5 Anterior cingulate
Anticevic A, Haut K, Murray JD, et al. JAMA Psychiatry. 2015;72(9):882-91.
Identification of 26 Biomarkers That Best
Discriminated Patients and Controls
Stages
Analyte Panel
Discovery meta-cohorts
I. Discovery
n=331
5 independent cohorts
Validation cohorts
II. Validation
III. Predictive
Performance
Testing
n=181
2 independent cohorts
29 analyte panel
Refined to 26
analyte panel
22/26 analyte panel
26 analyte panel
Test cohorts
n=445
Pre-onset or at-risk
individuals
Chan MK et al. Transl Psychiatry. 2015;5:e601.
24/26 analyte panel
22/26 analyte panel
First-Onset Schizophrenia Biomarker
Angiotensin-converting enzyme (ACE)
Alpha-2 macroglobulin (A2M)
Apolipoprotein A1 (ApoA1)
Apolipoprotein H (ApoH)
AXL receptor tyrosine kinase (AXL)
Beta-2 microglobulin (B2M)
Carcinoembryonic antigen (CA)
Factor VII (FVII)
Follicle-Stimulating Hormone (FSH)
Haptoglobin (HAPT)
Immunoglobulin A (IgA)
Insulin-like Growth Factor-Binding Protein 2
(IGFBP-2)
Interleukin-10 (IL10)
Interleukin-13 (IL-13)
Interleukin-1 receptor antagonist (IL1ra)
Interleukin-8 (IL8)
Leptin
Macrophage migration inhibitory factor (MIF)
Pancreatic Polypeptide (PPP)
Receptor for advanced glycosylation end
products (RAGE)
Stem Cell Factor (SCF)
Serum glutamic oxaloacetic transaminase
(SGOT)
Tenascin C (TNC)
Testosterone, Total (TEST)
Thyroid-Stimulating Hormone (TSH)
von Willebrand factor (VWF)
Chan MK et al. Transl Psychiatry. 2015;5:e601.
Question 4
Henry's family wants to know if there is any treatment that
might protect him from developing a psychotic disorder. In
recent studies, interventions in patients at UHR have
demonstrated at least preliminary efficacy for:
1. Delaying or preventing onset of first episode
2. Treating current prodromal symptoms
3. Improving functional outcomes
4. 1 & 2
5. 1, 2, and 3
Delaying or Preventing
Onset of First Episode
Meta-Analysis of Psychological and/or Pharmacological Interventions
Conversion Rates
Experimental group
Control group
Risk ratio [95% CI]
At 6 months
(7 studies)
3.6%
10.4%
0.36 [0.21, 0.60]
P<0.001
NNT=15
At 12 months
(9 studies)
8.1%
17.8%
At 18 months
(4 studies)
5.4%
13.7%
0.41 [0.25, 0.69]
P<0.001
NNT=13
At 24–48 months
(5 studies
11.8%
19.0%
0.58 [0.40, 0.85]
P<0.01
NNT=13
0.44 [0.31, 0.61]
P<0.001
Schmidt et al., Eur Psychiatry. 2015;30:388-404
NNT=10
No difference between psychological vs. pharmacological approaches
Promising Results from a Follow-up
Study of Omega 3 Fatty Acids
12-week intervention with omega-3 polyunsaturated fatty acids
(PUFAs) reduced the risk of progression to psychotic disorders
in patients with subthreshold psychotic states (vs. placebo)
Treatment for
12-weeks
Rate of transition
to psychosis1
Rate of transition
to psychosis2
Omega-3
n=41
4.9%
9.8%
Placebo
n=40
27.5%
40%
0
1Amminger
1
2
3
4
Years
5
6
7
GP, Schäfer MR, Papageorgiou K, et al. Arch Gen Psychiatry. 2010;67(2):146-54.
GP, Mechelli A, Rice S, et al. Transl Psychiatry. 2015;5:e495.
2Amminger
Improving Functional Outcomes
Meta-Analysis of Psychological and/or Pharmacological Interventions
Experimental vs. Control
Risk ratio [95% CI]
At 2–6 months
(7 studies)*,**
0.05 [-0.22, 0.32]
P = 0.70
At 12 months
(8 studies)*
0.43 [-0.12, 0.97]
P = 0.13
At 18–48 months
(4 studies)
0.13 [-0.09, 0.34]
P = 0.25
No difference between psychological vs. pharmacological approaches
*Significant heterogeneity of studies.
**Heterogeneity mainly due to one study;
exclusion of that study led to significant difference (P=0.03).
Treating Current
Prodromal Symptoms
• Atypical antipsychotics have demonstrated symptom relief in
early trials of both pre-symptomatic schizophrenia and
prodromal schizophrenia
• Low dose, low side effect antipsychotic medications may be
justified in some cases to treat symptomatically if risks are
outweighed by the potential benefits, in recognizing that such
use of these medications is not approved
• Antidepressants, anxiolytics, and omega 3 fatty have also had
encouraging results in reducing current symptoms
Schmidt et al., Eur Psychiatry. 2015;30:388-404.;
Addington J1, Liu L, Buchy L et al. J Nerv Ment Dis 2015;203(5):328-35.
2015 EPA Guidance on Early
Intervention in Clinical High Risk Cases
1. Early intervention in patients at UHR should aim
not only to prevent first-episode psychosis but also
the development or persistence of functional
deficits
2. Any psychosis-preventive intervention should be in
accordance with EPA* guidance on early detection
of psychosis
3. Psychological, in particular CBT, as well as
pharmacological interventions are able to prevent
or at least postpone first-episode in high-risk
patients
*Or standard/accepted
ADULTS
4.
Staged intervention, with least restrictive service approach
(CBT) as first choice
– If psychological treatment is ineffective and symptoms are
severe and progressive: complement with low-dose
atypical antipsychotics
• APS with minimal/declining insight or BLIPS in
higher/increasing frequency
– Long-term antipsychotic treatment with primarily
prevention purpose is not recommended
5. Any intervention should also address current individual
needs and comorbidities, in particular depression and anxiety
CHILDREN/ADOLESCENTS
6. Evidence insufficient to justify primarily preventive
interventions (psychological or pharmacological)
7. Specific psychological interventions with the aim to
improve functioning should be part of the overall
treatment plan
Summary:
Ultra High Clinical Risk
• It is not possible to predict with great accuracy who will
develop schizophrenia or another psychotic disorder
• Certain symptoms such as social withdrawal and cognitive
decline can identify teenagers and young adults at high risk
• A recent meta-analysis suggests that the transition to
psychosis in patients at ultra-high risk is most likely to occur
within the first two years, with half of patients who progress
doing so within the first eight months
• Genetic and neuroimaging tests of high risk individuals remain
research tools
• No drug is approved for pre-symptomatic or prodromal
schizophrenia, but studies of different drug classes suggest
symptom relief and possibly even delay of onset
ALTERED BRAIN VOLUME:
THE DISORDER OR THE
TREATMENT?
Question 5
In medication-naïve patients with first-episode
schizophrenia, structural neuroimaging has shown:
1. Loss of brain volume
2. Cortical thinning
3. Altered functional connectivity
4. Disturbed white matter integrity
5. All the above
1. Loss of Brain Volume
Results from recent-onset antipsychoticnaïve patients
• Decrease in intracranial volume
• Decrease in total brain volume
• Decrease in total gray matter volume
• Decrease in total white matter volume
1Haijma
SV, Van haren N, Cahn W, et al. Schizophr Bull. 2013;39(5):1129-38..;
2. Cortical Thinning
1.
2.
3.
4.
5.
6.
7.
Insula
Superior temporal gyrus
Supramarginal area
Inferior parietal area
Superior frontal area
Lateral occipital area
Rostral middle frontal
(dorsolateral prefrontal)
area
Red to yellow clusters show decreased thickness
Blue to light blue clusters show increased thickness
Song X, Quan M, Lv L, et al. J Psychiatr Res. 2015;60:22-8.
3. Altered Functional Connectivity
Compared to healthy control, schizophrenia patients exhibited:
– Increased rsFCD in striatum and hippocampus
– Decreased rsFCD in sensorimotor regions
Red = increased rsFCD
Blue = decreased rsFCD
No linear correlation
between AP dose
and brain functional
activity disturbances
was found
Zhuo C, Zhu J, Qin W, et al. Front Behav Neurosci. 2014;8:404.
4. Disturbed White Matter Integrity
Two distinct patterns of white matter abnormalities
in medication-naïve first-episode schizophrenia
Widespread white matter abnormalities had more severe
negative symptoms
Sun H, et al. JAMA Psychiatry2015:678–678.
Question 6
With response to antipsychotics in patients with
chronic schizophrenia, structural neuroimaging has
shown:
1. Loss of brain volume
2. Cortical thinning
3. Altered functional connectivity
4. Disturbed white matter integrity
5. All the above
1. Loss of Brain Volume
Gray matter (Effect
Size)
Meta-Regression on Effects Sizes of Gray Matter and
Dose of Antipsychotic Medication
Results
Dose antipsychotic medication (CPZ-Eq)
Each circle
represents
a study
sample.
Total gray matter loss was more pronounced in patients using a higher dose of
antipsychotic medication at time of scanning
Haijma SV, Van haren N, Cahn W, et al. Schizophr Bull. 2013;39(5):1129-38.
However, Gray Matter Loss Is Worse in Patients
With a Longer Duration of Untreated Psychosis
Colored voxels depict brain areas of significantly greater gray matter
loss in patients with a long duration of untreated psychosis (>18 wks)
compared to those with a short duration (<18 wks)
Malla AK et al. Schizophr Res 2011;125(1):13-20.
2. Cortical Thinning
Antipsychotics effects on cortical thinning in first episode
schizophrenia patients
Unmedicated
< Control
Medicated
< Control
Medicated
< Unmedicated
Control n=37
Medicated n=23
Unmedicated n=22
No significant cortical
thickness differences
Significant cortical
thinning in prefrontal and
occipital region
Some cortical thinning in
dorsolateral prefrontal
cortex and temporal
cortex
Blue to light blue clusters show increased cortical thinning
Lesh TA, Tanase C, Geib BR, et al. JAMA Psychiatry 2015:226–226.
Although short-term treatment with antipsychotics was
associated with prefrontal cortical thinning, treatment
was also associated with better cognitive control and
increased prefrontal functional activity.
Between-Group results of Continuous
Performance Task (CPT)
Control > Unmedicated
Control group showed
significantly higher
activity compared with
the unmedicated patient
group
1.5
Medicated > Unmedicated
Medicated patient group
showed higher activity
compared with the
unmedicated patient group
Control n=37
Medicated n=23
Unmedicated n=22
Red clusters represent the higher activity
Right DLPFC
1.0
Β Value
Control > Medicated
Control group showed
higher activity compared
with the medicated
patient group
Left DLPFC
0.5
0.0
-0.5
-1.0
Control
Medicated
Patient
Group
Lesh TA, Tanase C, Geib BR, et al. JAMA Psychiatry 2015:226–226.
Unmedicated
Patient
3. Altered Functional Connectivity
Baseline untreated patients with first-episode
schizophrenia have decreased amplitude of
low-frequency fluctuations
Patients treated for 6 wks with antipsychotics
have increased amplitude of low-frequency
fluctuations compared to baseline
Patients treated for 6 wks with
antipsychotics have increased
amplitude of low-frequency
fluctuations compared to controls
Lui S et al. Arch Gen Psychiatry 2010;67(8):783-92.
4. Disturbed White Matter Integrity
Patients with chronic schizophrenia treated with
antipsychotics have decreased fractional anisotropy (FA)
within prefrontal and temporal lobes, as well as
abnormalities within the fiber bundles connecting these
regions.
View
Lateral (top)
Frontal (bottom)
White matter tracts most frequently identified as disrupted in
patients with chronic schizophrenia.
Wheeler AL, Voineskos AN. Front Hum Neurosci. 2014;8:653.
However, similar white matter abnormalities are also
seen in unaffected siblings of schizophrenia patients
Mean fractional anisotropy (FA) of the left cuneus
0.5
Mean FA
Disruptions
of white
matter
integrity
0.4
0.3
The fact that patients as well as
unmedicated siblings show deficits may
indicate that this represents a genetic
vulnerability for schizophrenia rather than
a medication effect.
0.2
Schizophrenia
(COS)
Healthy
Sibling
Healthy
Control
Groups
Leeuw MD, Bohlken MM, Mandl RCW, et al., NPJ Schizophr. 2015:15001–15001.;
Moran ME, Luscher ZI, Mcadams H, et al. Schizophr Bull. 2015;41(1):66-73.
Does the Antipsychotic Class Matter?
Research showed patients treated with FGAs had greater
gray matter loss compared with those who took SGAs.
Brain Region
Cortical Gray Matter Changes*
FGA or mixed
SGA only
Whole Brain (GM)
-0.27
-0.10
Frontal Lobe (GM)
-0.26
0.01
Temporal Lobe (GM)
-0.15
0.16
Parietal Lobe (GM)
-0.24
-0.14
*negative coefficient indicates loss over time of cortical gray matter
Vita A et al. Biol Psychiatry 2015;78(suppl):403-412
Correlation Between Dose Exposure to Individual
SGA's and Changes in Gray Matter (GM) Volume
Clozapine
0.80
Changes in Gray Matter
(Hedges' g)
0.66
Risperidone
0.52
Olanzapine
0.24
0.10
Quetiapine
-0.4
Ziprasidone
-0.32
-0.46
Multi SGAs
-0.60
164.50 187.90 211.30 234.70 258.10 281.50 304.50 328.30 351.70 375.10 398.50
Each circle represents
a study sample.
Mean Daily Dose (CPZ-Eq)
Vita A et al. Biol Psychiatry 2015;78:403-412
Multi SGAs
Muti SGAs
THE LATEST ADDITIONS TO THE
CLINICIAN'S "TOOLBOX" OF
ANTIPSYCHOTICS
Question 7
I am a D2 partial agonist, but I also have potent 5HT1A
partial agonism, alpha 1B antagonism, and 5HT2A
antagonism.
1. Aripiprazole
2. Brexpiprazole
3. Cariprazine
Question 8
I am a potent D2 and D3 partial agonist, but have
preferential binding to D3 receptors at low doses. I also
have potent 5HT2B antagonism, 5HT1A partial agonism,
and moderate 5HT2A antagonism.
1. Aripiprazole
2. Brexpiprazole
3. Cariprazine
Brexpiprazole
• Approved by FDA on July 10 2015
– Treatment of schizophrenia in adults
– Adjunct treatment for resistant depression in adults
• Most common side effects: weight gain, dosedependent akathisia
• Also being studied for ADHD, PTSD, and agitation
associated with Alzheimer dementia
Adapted from NEI Prescribe (2015)
Brexpiprazole:
Dosing Tips and Pearls
Formulation: Tablet 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg
Can be administered with or without food
Treatment for schizophrenia in adults
Recommended Dosage Range: 2–4 mg once daily
Day 1
Day 2
Day 3
Day 4 Day 5 Day 6
Day 7 Day 8 and beyond Maximum Dose
1 mg
1 mg
1 mg
1 mg 2 mg 2 mg
2 mg
1X/day 1X/day 1X/day 1X/day 1X/day 1X/day 1X/day
4 mg
1X/day
4 mg 1X/day
Treatment for major depressive disorder (adjunct)
Recommended Dose: 2 mg once daily
Initial Dose
Weekly intervals
Weekly intervals
Maximum Dose
0.5–1 mg 1X/day
Increase up to 1 mg
1X/day
Increase up to 2 mg
1X/day
3 mg 1X/day
Brexpiprazole: Pharmacokinetics
• Metabolized primarily by CYP450 2D6 and CYP450 3A4
• In presence of strong/moderate 3A4 inhibitor
• Use half the usual brexpiprazole dose
• In presence of strong 3A4 inducer
• Use double the usual brexpiprazole dose
• In presence of strong/moderate 2D6 inhibitor or 2D6 poor
metabolizer
• In schizophrenia: use half the usual brexpiprazole dose
• In depression: no dose adjustment
• In presence of both strong/moderate 3A4 inhibitor AND strong
2D6 inhibitor or poor 2D6 metabolizer
• Use one-quarter the usual brexpiprazole dose
Cariprazine
• Approved by FDA on September 17, 2015
– Treatment of schizophrenia in adults
– Treatment of manic or mixed episodes associated
with bipolar I disorder
• Most common side effects: EPS, akathisia, GI
distress, drowsiness, restlessness
• Also being studied for bipolar depression and
treatment-resistant unipolar depression (adjunct)
Cariprazine :
Dosing Tips and Pearls
Formulation: Capsule 1.5 mg, 3 mg, 4.5 mg, 6 mg
Can be administered with or without food
Treatment for schizophrenia in adults
Recommended Dosage Range: 1.5–6 mg once daily
Day 1
Day 2
Day 3 and beyond
1.5 mg
1X/day
3.0 mg
1X/day
Depending upon clinical response and tolerability, further
dose adjustments can be made in 1.5–3 mg increments
Treatment for bipolar mania in adults
Recommended Dosage Range: 3–6 mg once daily
Day 1
Day 2
Day 3 and beyond
1.5 mg
1X/day
3.0 mg
1X/day
Depending upon clinical response and tolerability, further
dose adjustments can be made in 1.5–3 mg increments
Due to cariprazine's long half-life, monitor for adverse effects and response for
several weeks after starting cariprazine and with each dosage change
Cariprazine: Pharmacokinetics
• Metabolized into two very long-lasting active metabolites by 3A4
• Monitor for adverse effects and response for several weeks after
initiation and with each dose change
• Initiating strong 3A4 inhibitor in patients on stable cariprazine dose
• Decrease cariprazine by half
• For patients taking 4.5 mg, reduce to either 1.5 mg or 3 mg;
for patients taking 1.5 mg, reduce to 1.5 mg every other day
• Initiating cariprazine in patients on strong 3A4 inhibitor
• Day 1: 1.5 mg
• Day 2: do not dose
• Day 3: 1.5 mg
• Day 4: 1.5 mg
• Maximum daily dose 3 mg
• Concomitant cariprazine and 3A4 inducer not recommended
Comparing D2 Partial Agonists
Receptor Binding
aripiprazole
brexpiprazole
cariprazine
More Potent than D2
Less Potent than D2
Key 5HT Receptor Binding
5HT1A
5HT7
5HT2A
aripiprazole
5HT1A
5HT2A
brexpiprazole
5HT7
5HT1A
5HT2A
5HT7
cariprazine
More Potent than D2
Less Potent than D2
Antihistamine/Anticholinergic Binding
H1
aripiprazole
H1
brexpiprazole
H1
cariprazine
More Potent than D2
Less Potent than D2
Alpha1 Receptor Binding
1A
1B
aripiprazole
1B
1D
brexpiprazole
1B
cariprazine
More Potent than D2
1D
1A
Less Potent than D2
1A
Alpha2 Receptor Binding
2C
aripiprazole
2C
brexpiprazole
2A
cariprazine
More Potent than D2
Less Potent than D2
2A
2B
POP QUIZ:
ARE YOU AWARE OF THE
LATEST FDA UPDATES?
The Latest FDA Updates
This antipsychotic received an FDA warning associated
with a rare but serious skin reaction, known as Drug
Reaction with Eosinophilia and Systemic Symptoms
(DRESS). Patients who have a fever with a rash and/or
swollen lymph nodes should stop treatment immediately.
1. Risperidone
2. Asenapine
3. Olanzapine
4. Ziprasidone
5. Quetiapine
http://www.fda.gov/Drugs/DrugSafety/ucm426391.htm
This antipsychotic received FDA approval to treat acute
manic/mixed manic episodes of bipolar I disorder in
pediatric patients ages 10 to 17.
1. Paliperidone
2. Asenapine
3. Clozapine
4. Aripiprazole
5. Quetiapine
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022117s017s018s019lbl.pdf
The FDA has approved this long-acting injectable
antipsychotic to treat schizoaffective disorder as either
monotherapy or adjunctive therapy.
1. Aripiprazole monohydrate (Maintena)
2. Paliperidne palmitate (Invega Sustenna)
3. Risperidone microspheres (Consta)
4. Olanzapine Pamoate (Relprevv)
This antipsychotic drug received FDA approval for
treating Tourette's disorder in children ages 6 to 18.
1. Clozapine
2. Asenapine
3. Olanzapine
4. Aripiprazole
5. Quetiapine
To address "continuing safety concerns" about severe
neutropenia associated with this atypical antipsychotic,
the FDA has "clarified and enhanced" it's prescribing
information to better explain how to monitor patients for
neutropenia and manage treatment, and the FDA has
approved a new, shared risk evaluation and mitigation
strategy (REMS).
1. Paliperidone
2. Asenapine
3. Clozapine
4. Aripiprazole
5. Quetiapine

2 - Neuroscience Education Institute

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