Transcript Atypical antipsychotic medications

Little Known Secrets of
Psychopharmacology
David Cutler, MD
Medical Director
Bentson McFarland MD PhD
Mental Health and Addiction Services
Multnomah County
Psychopharm (The Old and The New)
• Part I Antipsychotics
• Part II Antidepressants and Mood Stabilizers
Childhood and adolescent
depression.
• Bhatia SK, Bhatia SC.
Major depression affects 3 to 5 percent of children
and adolescents. Depression negatively impacts
growth and development, school performance, and
peer or family relationships and may lead to suicide.
Biomedical and psychosocial risk factors include a
family history of depression, female sex, childhood
abuse or neglect, stressful life events, and chronic
illness. Diagnostic criteria for depression in children
and adolescents are essentially the same as those for
adults; however, symptom expression may vary with
developmental stage, and some children and
adolescents may have difficulty identifying and
describing internal mood states.
• Safe and effective treatment requires accurate diagnosis, suicide risk
assessment, and use of evidence-based therapies. Current literature
supports use of cognitive behavior therapy for mild to moderate childhood
depression. If cognitive behavior therapy is unavailable, an antidepressant
may be considered. Antidepressants, preferably in conjunction with
cognitive behavior therapy, may be considered for severe depression.
Tricyclic antidepressants generally are ineffective and may have serious
adverse effects. Evidence for the effectiveness of selective serotonin
reuptake inhibitors is limited. Fluoxetine is approved for the treatment of
depression in children eight to 17 years of age. All antidepressants have a
black box warning because of the risk of suicidal behavior. If an
antidepressant is warranted, the risk/benefit ratio should be evaluated, the
parent or guardian should be educated about the risks, and the patient
should be monitored closely (i.e., weekly for the first month and every other
week during the second month) for treatment-emergent suicidality. Before
an antidepressant is initiated, a safety plan should be in place. This
includes an agreement with the patient and the family that the patient will
be kept safe and will contact a responsible adult if suicidal urges are too
strong, and assurance of the availability of the treating physician or proxy
24 hours a day to manage emergencies.
Major depressive disorder
• Low mood / loss of pleasure (anhedonia)
• Four or more of:
Sleep disturbance
Appetite disturbance
Agitation / retardation
Loss of energy
Worthlessness / guilt
Impaired concentration / decision-making
Suicidal ideation
Evidence- based treatments for people
with major depressive disorder
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Cognitive-behavioral therapy
Interpersonal therapy
Antidepressant medication
Electroshock treatment
Antidepressants
• Tricyclics
• MAOIs Monoamine Oxidase Inhibitors
• SSRIs Selective Serotonin Reuptake
Inhibitors
• Others: Trazodone, Nefazodone,
Bupropion, and Mirtazapine
Tricyclics
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Imipramine
Amitriptyline
Nortriptyline
Desipramine
Clomipramine
Doxepin
Maprotiline
Protriptyline
Doses
75-300Mg
50-300Mg
75-150Mg
100-300Mg
25-250Mg
75-350Mg
75-225Mg
15-60Mg
MAOIs
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Phenylzine (Nardil)
15-90Mg
Isocarboxazid (Marplan)
20-60Mg
Tranylcypromine (Parnate) 30-60MG
Selegiline Transdermal (EMSam) 20-40Mg
Food Restrictions: Cheese, Fava Beans,
Salami,Brewers Yeast, Red Wine, Chocolate,
and others may cause hypertensive crisis.
• Used for Atypical depression, Dysthymia,
Narcolepsy, Chronic Pain,
Headache,Bulimia,OCD, GAD
SSRIs
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Fluoxetine (Prozac)
20-80 Mg
Paroxetine (Paxil)
10-60Mg
Fluvoxamine (Luvox)
50-300Mg
Citalopram (Celexa)
20-60Mg
Escitalopram (Lexapro) 10-20Mg
Duloxetine (Cymbalta)
20-60Mg
Venlafaxine (Effexor)
75-375Mg
Others
• Trazodone (Desyrel) 150-600Mg
(used mostly for sleep)
• Nefazodone (Serzone) 200-600Mg
(liver problems)
• Bupropion (Wellbutrin) 200-450 Mg
(Less side effects)
• Mirtazapine (Remeron) 15-45Mg
(also used for sleep)
CNS Neurotransmitter Effects
Serotonin Norepinephrine Dopamine
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Amitriptyline ++++
Bupropion 0/+
Citalopram ++++
Fluoxetine ++++
Maprotiline 0
Paroxetine ++++
Venlafaxine ++++
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Antidepressant medications
• Effectiveness more or less same
– Roughly 60% of drug-naïve patients respond
(mostly in drug company studies but also in federally funded studies)
– Roughly 30% of patients respond to placebo
• Side effects different
• Prices different (but patents expiring rapidly)
Adverse Effects
• Tricyclics: Sedation, Risk of Death with
Overdose
• MAOI’s: Hypertensive Crisis, Serotonin
Syndrome
• SSRI’s: P450 Enzyme Drug interactions +
Wt Gain, Decreased Sex Drive, Serotonin
Syndrome.
• Venlafaxine can raise B/P
Cost of a Month’s
Antidepressant Treatment
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Nortriptiline
Fluoxetine
Citalopram
Mirtazapine
Paroxetine
Bupropion XR
Duloxetine (Cymbalta)
$ 6
$ 20
$ 20
$ 40
$ 60
$ 70
$120
$4 / month scripts at Target
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Amytriptyline 10,25,50,75,and 100Mg x30
Doxepin 10,25, 50, 75, 100 Mg x 30
Nortriptyline 10, and 20 Mg x 30
Citalopram 20, 40 Mg x 30
Fluoxetine 10 tbs + 10,20,40 Mg Cps x 30
Paroxetine 10,20 Mg x 30
Trazodone 50, 100, 150 Mg Tabs x 30
LI CO3 300 Mg x 90
Carbamezepine 200Mg x 60
Antidepressant medications
• What to do if patient fails to respond ?
– Switch (different drug)
– Augment (continue original drug and add another drug)
– Stop drug / start cognitive behavioral therapy
– Cognitive behavioral therapy with a drug
Mood Stabilizers For Bipolar
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Lithium Carbonate
900-1500Mg / Day
Anticonvulsants
Carbamazapine
400-1600Mg/Day
Valproic Acid
750-4200Mg/Day
Lamotrigine
50-200Mg/Day
Topiramate
50-400Mg/Day
Neurontin
1200-3600Mg/day
Adverse Effects of Mood
Stabilizers
• Lithium: Vomiting, Tremor, Polyuria,
Hypothyroidism, Confusion, Death
• Valproic Acid: Tremor, Wt Gain, Edema,
Thrombocytopenia, Diplopia, Sedation
• Carbamezapine: Leukopenia,Ataxia,
Sedation, Wt Gain
• Lamotragine: Dizzyness, Ataxia, Diplopia,
• Headaches, Rash (slow titration reduces
the chances of getting a rash)
Sequenced Treatment
Alternatives to Relieve
Depression (STAR*D)
• Funded by National Institute of Mental Health
• Drug companies provided medication
• What to do when depressed patient fails to
improve with medication?
STAR*D
• Level One = citalopram (Celexa)
• Level Two = switch drug or augment
– Switch drug = Level Two
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Bupropion (Wellbutrin) SR
Sertraline (Zoloft)
Venlafaxine XR (Effexor)
Cogntive Behavioral Therapy
– Augment = Level Two
• Celexa plus Bupropion
• Celexa plus Buspirone
• Celexa plus Cognitive Behavioral Therapy
• Level Three (switch again or more complex augmentation)
• Level Four (switch to Remeron plus Effexor = California Rocket Fuel)
Star*D Algorithm Levels 1&2
• Level 1 (twelve weeks more or less)
• Initial Treatment Citalopram (Celexa)
• Level 2 (twelve weeks more or less)
• Switch to: Bupropion SR, Cognitive
Therapy, Sertraline, Venlafaxine ER or
• Augment With: Bupropion SR, Buspirone,
Cognitive Therapy
STAR*D Algorithm Level 2A
• (Only for those receiving cognitive therapy
in level 2)
• Switch to : Bupropion SR (Sustained
release) or Venlafaxine ER (Extended
release)
STAR*D Algorithm Level 3 &4
• Level 3 (twelve weeks more or less)
• Switch to : Mirtazapine or Nortriptyline or
• Augment with: Lithium or Triiodothyronine
(T3) (only with Bupropion SR, Sertraline,
Venlafaxine ER)
• Level 4 (twelve weeks mor or less)
• Switch to: Mirtazapine combined with
Venlafaxine ER
STAR*D Treatment of
Depression
• The STAR*D study is the largest prospective study of a sequential
series of treatments for depression ever conducted. In this study,
3,671 patients entered treatment at 41 sites, 18 of which were
primary care facilities. The STAR*D study differs from typical clinical
trials. Subjects were identified as they came for treatment. Although
psychotic and bipolar patients were excluded, most other psychiatric
disorders were allowed. Most clinical trials in depression exclude
patients with recent active substance abuse. STAR*D only excluded
patients likely to need inpatient detoxification. Of the patients
entering the first treatment step, 61.5% had a concurrent psychiatric
disorder. As the result of broad inclusion criteria, the STAR*D study
is more representative of patients in clinical practice.
STAR*D Remission
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Level One (Celexa)
Level Two (switch or augment)
Level Three (switch or augment)
Level Four (rocket fuel)
37%
31%
14%
13%
STAR*D Remission
Are some drugs better than others?
• Switch to bupropion (Wellbutrin), sertraline (Zoloft), venlafaxine
(Effexor considered more potent):
– all the same
• Augment with bupropion (Wellbutrin) or buspirone (Buspar):
– bupropion (Wellbutrin) maybe a little more effective and better tolerated
Remission
• Remission rates were 36.8%, 30.6%, 13.7%,
and 13% after treatment steps 1 through 4.
Remission rates drop substantially after two
failed treatments.
• Higher remission rates during the initial trial
were seen in patients who were female,
Caucasian, employed, or had higher levels of
education and income. Patients who required
more treatments were more severely depressed
and had more concurrent psychiatric and
medical disorders.
Relapse
• Among those achieving remission, relapse rates were
33.5%, 47.4%, 42.9%, and 50.0% after the four
treatment steps. Relapse rates were even higher in
patients who improved but did not achieve remission
(range=59% to 83%). It is particularly worrisome that at
steps 3 and 4, in addition to low remission rates (13.7%
and 13.0%), nearly half of those remitting relapsed. From
step 2 on, less than half of those responding and
remitting remained well.
• The study also found that intolerance increased after
each treatment step: 16.3%, 19.5%, 25.6%, and 34.1%.
(the term "intolerance" includes dropouts for any reason
during the first 4 weeks, or side effects after that).
Perhaps patients that drop out are becoming
demoralized with each failure and are giving up.
STAR*D Relapse
within twelve weeks of remission
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Level 1 (Celexa)
34%
Level 2 (Switch or augment) 47%
Level 3 (Switch or augment) 43%
Level 4 (Rocket fuel)
50%
For STAR*D patients,
Maintaining Recovery is not Easy.
• This study paints a less hopeful picture for
the treatment of depression, but it may be
consistent with "real world" patients. More
than 75% of the STAR*D patients had
recurrent or chronic depression, 61.5%
had a concurrent psychiatric diagnosis,
and 83% had previous treatment for their
current episode (N=3,057 of 3,671).
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age
Behavior Suicidality
Psychosis /Positive Symptoms
• Hallucinations (false perceptions)
– hearing voices others do not hear
– Seeing,feeling,or smelling things other do not
• Delusions (false beliefs)
– Not believed by others in the culture
– Thoughts controlled by Martians
– Radios implanted in teeth
• Disordered Thought Processes
Loose associations, Word salad, Flight of Ideas
Diagnostic Criteria S/A 295.70
• A. An uninterrupted period of illness with
major depression or mania or mixed with
Schizophrenic Symptoms.
• B. During the same period delusions or
hallucinations without mood symptoms.
• C. Mood Symptoms are present for a
substantial portion of the illness period
• D. Not due to drugs
• Type: Bipolar (includes mania) Depressive
Biochemistry of psychosis
• Dopamine relative excess
• Causes
– Substance abuse (e.g., methamphetamine)
– Medications (e.g., prednisone)
– Heredity (e.g., Huntington’s disease)
– Functional disorder (e.g., schizophrenia)
People with schizophrenia
• Psychosis (“positive” symptoms)
• Decline in function (“negative” symptoms)
– Lack of ambition
– Social withdrawal
Medications
for people with schizophrenia
• Neuroleptics
– First generation antipsychotic drugs
– Typical antipsychotic drugs
• Atypical antipsychotic drugs
– Second generation antipsychotics
Neuroleptics
FGA’s First Generation Drugs
Chlorpromazine (Thorazine)
Perphenazine (Trilafon)
Trifluperazine (Stelazine)
Doses
30-800 mg / day
12-64 mg / day
2-40 mg / day
Fluphenazine (Prolixin also long acting injectable) 1-40 mg / day
Haloperidol (Haldol also long acting injectable)
1-100 mg / day
(many others not often used any longer)
Neuroleptic medications
• Block doparmine
• Reduce psychosis (positive symptoms)
• Extrapyramidal side effects
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Involuntary motor system
Stiffness
Tremors
Restlessness
Tardive dyskinesia
• May worsen negative symptoms
• Some weight gain
• Cheap (five to ten cents per day)
Tardive dyskinesia
• Abnormal involuntary movements
– Lip smacking
– Tongue thrusting
• Neuroleptic side effect
• May be permanent
Atypical Antipsychotic drugs
SGAs
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Clozapine (Clozaril) 12.5-900 Mg/Day
Risperidone (Risperdal) 2-16 Mg/Day
Olanzapine (Zyprexa)
5-20 Mg/Day
Ziprasidone (Geodon)
40-60 Mg/Day
Quetiapine (Seroquel) 50-750 Mg/Day
Aripiprazole (Abilify)
10-30 Mg/Day
Atypical antipsychotic drugs
• Block dopamine but also involve serotonin (and
maybe other neurotransmitters)
• Reduce psychosis (positive symptoms)
• May improve negative symptoms
• Few motor side effects
• Weight gain
• Diabetes
• Strokes in users over age 65
• Expensive (e.g., $5 to $10 per day)
Clozapine
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Clozaril (and generics)
Affects dopamine, serotonin, perhaps more
May improve positive and negative symptoms
Side effects include weight gain, seizures, sedation,
and salivation (but not tardive dyskinesia)
• Agranulocytosis (no white blood cells) possible
– Blood draws weekly or twice monthly
– National registry system
– Need to fail other antipsychotic drugs
• Works extremely well for a few people
Olanzapine
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Zyprexa
Improves positive symptoms
Might help negative symptoms
Weight gain in almost all users
Diabetes in many (perhaps most) users
Intramuscular (short acting) form available
• Used (at least once) by 20 million people worldwide
• Used annually by 2 million people worldwide
• $ 4 billion per year for manufacturer Eli Lilly
• Indicated for schizophrenia and bipolar mania
Disparity Emerges in Lilly Data
on Schizophrenia Drug
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By ALEX BERENSON
NY Times, December 21, 2006
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For at least a year, Eli Lilly provided information to doctors about
the blood-sugar risks of its drug Zyprexa that did not match data that
the company circulated internally when it first reviewed its clinical
trial results.
The original results showed that patients on Zyprexa, Lilly's pill for
schizophrenia, were 3.5 times more likely to experience high blood sugar
levels than those taking a placebo. But the results that Lilly
eventually provided to doctors indicated that patients taking Zyprexa
were only slightly more likely to suffer high blood sugar as those
taking a placebo, or an inactive pill.
Another Lilly report, from November 1999, shows that Lilly found after
examining 70 clinical trials that 16 percent of patients taking
Zyprexa for a year gained more than 66 pounds.
The company did not publicly disclose that figure, instead they showed
trials that showed about 30 percent of patients gained 22 pounds.
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Risperidone
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Risperdal (generic in 2007)
Risperdal Consta (long acting injection – two weeks or more)
Improves positive symptoms
Rare improvement of negative symptoms
Extra-pyramidal side effects not uncommon
Some weight gain
Indicated for autism irritability as well as
psychosis (schizophrenia and bipolar mania)
Quetiapine
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Seroquel
Some improvement in positive symptoms
Rare improvement in negative symptoms
Sedating
Twice a day dosage not uncommon
Indicated for bipolar depression as well as
schizophrenia and bipolar mania
Ziprasidone
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Geodon
Some impact on positive symptoms
Rare impact on negative symptoms
Usually taken twice a day
• Intra-muscular (short acting) form available
• Indicated for schizophrenia and bipolar mania
• Some weight gain
Aripiprazole
• Abilify
• Perhaps some impact on positive symptoms
• Rare (if ever) impact on negative symptoms
• No (or rare) weight gain
Research on
atypical antipsychotic medications
• Clozapine versus haloperidol (U.S. Veterans)
• Clinical antipsychotic trial of clinical
effectiveness (CATIE – United States)
• Cost Utility of Latest Antipsychotic Drugs
in Schizophrenia Study (CUtLASS – England)
Clozapine versus Haloperidol
• Supported by U.S. Department of Veterans Affairs
• 423 veterans at 15 veterans hospitals
• Refractory schizophrenia
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Clozapine versus haloperidol (plus benztropine = Cogentin)
• No difference in positive or negative symptoms
• More extra-pyramidal side effects in haloperidol group
• More weight gain in clozapine group
• Expenditures same
• Comments:
– Do veterans represent everyone with schizophrenia?
– Does the veterans health care system represent other systems?
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Rosenheck et al. New England Journal of Medicine 337:809, 1997
Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) – I
Study design
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Sponsored by National Institute of Mental Health (U.S. Public Health Service)
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1,493 patients with schizophrenia at 57 sites (2001 – 2004)
Average age 41
74% male
60% white
85% unemployed
Randomized to:
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Olanzapine (Zyprexa)
Risperidone (Risperdal)
Quetiapine (Seroquel)
Ziprasidone (Geodon)
Perphenazine (Trilafon = neuroleptic)
Outcome = discontinuation of medication assigned at baseline
Lierberman et al. (2005). New England Journal of Medicine 353:1209
Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE)-II
Baseline Psychotropic use Among Participants
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Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) – III
Main outcome
Discontinuation of assigned medication for any reason
Olanzapine (Zyprexa) *
Quetiapine (Seroquel)
Risperidone (Risperdal)
Ziprasidone (Geodon)
Perphenazine (Trilafon = neuroleptic)
Percent
Months on drug
64%
82%
74%
79%
75%
9.2
4.6
4.8
3.5
5.6
* Participants stayed on Zyprexa significantly longer than any other drug
Time on all other drugs the same (i.e., Trilafon same as atypicals)
Lierberman et al. (2005). New England Journal of Medicine 353:1209
Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) – IV
Secondary outcome
Hospitalization due to schizophrenia exacerbation
Olanzapine (Zyprexa) *
Quetiapine (Seroquel)
Risperidone (Risperdal)
Ziprasidone (Geodon)
Perphenazine (Trilafon = neuroleptic)
Percent
Admits per year
11%
20%
15%
18%
16%
0.29
0.66
0.45
0.51
0.57
* Participants on Zyprexa stayed out of hospital more than any other drug
Hospitalization rate on all other drugs the same (i.e., Trilafon same as atypicals)
Lierberman et al. (2005). New England Journal of Medicine 353:1209
Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) – V
Side effects
Pounds per month
Olanzapine (Zyprexa) *
Quetiapine (Seroquel)
Risperidone (Risperdal)
Ziprasidone (Geodon)
Perphenazine (Trilafon = neuroleptic)@
+ 2.0
+ 0.5
+ 0.4
- 0.2
- 0.3
Extra-pyramidal side effects
2%
3%
3%
4%
8%
* Weight gain significantly more on Zyprexa than other drugs
@ More participants on Trilafon stopped due to extra-pyramidal side effects
than did users of other drugs
Lierberman et al. (2005). New England Journal of Medicine 353:1209
Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) – VI
Phase Two: clozapine
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99 Phase One participants who discontinued first drug due to lack of efficacy
Randomized to clozapine versus atypical not received in Phase One
Months to discontinuation in phase two
Clozapine *
Olanzapine
Quetiapine
Risperidone
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10.5
2.7
3.3
2.8
Time on clozapine significantly longer than time on other drugs
No differences among drugs other than clozapine
Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) – VII
Comments
• More reports coming (e.g. cost-effectiveness)
• Do participants represent everyone with schizophrenia?
(if you were doing well, would you volunteer?)
Cost Utility of the Latest Antipsychotic Drugs
in Schizophrenia (CUtLASS)
• Supported by United Kingdom Ministry of Health
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227 participants with schizophrenia at 14 community clinics in England
Randomized to first generation versus second generation antipsychotic
Psychiatrists chose drug in each class before randomization
Average age 40
68% female
75% white
40% inpatients at randomization
Primary outcome = quality of life
Quality of life same at one year after randomization
Cost studies forthcoming
Jones et al. (2006). Archives of General Psychiatry 63:1079