Little Known Secrets of Psychopharmacology

1
Little Known Secrets of Psychopharmacology

• David Cutler, MD
• Medical Director
• Bentson McFarland MD PhD
• Mental Health and Addiction Services
• Multnomah County

2
(No Transcript)
3
Psychopharm (The Old and The New)

• Part I Antipsychotics
• Part II Antidepressants and Mood Stabilizers

4
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.

5

• 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.

6
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

7
Evidence- based treatments for people with major
depressive disorder

• Cognitive-behavioral therapy
• Interpersonal therapy
• Antidepressant medication
• Electroshock treatment

8
Antidepressants

• Tricyclics
• MAOIs Monoamine Oxidase Inhibitors
• SSRIs Selective Serotonin Reuptake Inhibitors
• Others Trazodone, Nefazodone, Bupropion, and
  Mirtazapine

9
Tricyclics Doses

• Imipramine 75-300Mg
• Amitriptyline 50-300Mg
• Nortriptyline 75-150Mg
• Desipramine 100-300Mg
• Clomipramine 25-250Mg
• Doxepin 75-350Mg
• Maprotiline 75-225Mg
• Protriptyline 15-60Mg

10
MAOIs

• 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

11
SSRIs

• 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

12
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)

13
CNS Neurotransmitter Effects
Serotonin Norepinephrine Dopamine

• Amitriptyline 0
• Bupropion 0/
• Citalopram 0 0
• Fluoxetine 0
  0/
• Maprotiline 0 0
• Paroxetine 0/ 0/
• Venlafaxine 0/

14
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)

15
Adverse Effects

• Tricyclics Sedation, Risk of Death with Overdose
• MAOIs Hypertensive Crisis, Serotonin Syndrome
• SSRIs P450 Enzyme Drug interactions Wt Gain,
  Decreased Sex Drive, Serotonin Syndrome.
• Venlafaxine can raise B/P

16
Cost of a Months Antidepressant Treatment

• Nortriptiline 6
• Fluoxetine 20
• Citalopram 20
• Mirtazapine 40
• Paroxetine 60
• Bupropion XR 70
• Duloxetine (Cymbalta) 120

17
4 / month scripts at Target

• 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

18
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

19
Mood Stabilizers For Bipolar

• 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

20
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)

21
Sequenced Treatment Alternatives to Relieve
Depression (STARD)

• Funded by National Institute of Mental Health
• Drug companies provided medication
• What to do when depressed patient fails to
  improve with medication?

22
STARD

• Level One citalopram (Celexa)
• Level Two switch drug or augment
• Switch drug Level Two
• 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)

23
StarD Algorithm Levels 12

• 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

24
STARD Algorithm Level 2A

• (Only for those receiving cognitive therapy in
  level 2)
• Switch to Bupropion SR (Sustained release) or
  Venlafaxine ER (Extended release)

25
STARD 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

26
STARD Treatment of Depression

• The STARD 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 STARD
  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. STARD 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 STARD
  study is more representative of patients in
  clinical practice.

27
STARD Remission

• Level One (Celexa) 37
• Level Two (switch or augment) 31
• Level Three (switch or augment) 14
• Level Four (rocket fuel) 13

28
STARD RemissionAre 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

29
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.

30
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 (range59 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.

31
STARD Relapsewithin twelve weeks of remission

• Level 1 (Celexa) 34
• Level 2 (Switch or augment) 47
• Level 3 (Switch or augment) 43
• Level 4 (Rocket fuel) 50

32
For STARD 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
  STARD patients had recurrent or chronic
  depression, 61.5 had a concurrent psychiatric
  diagnosis, and 83 had previous treatment for
  their current episode (N3,057 of 3,671).

33

• 0 1 2 3
• 0 20 40 60 80 100
• age
• Behavior Suicidality

34
(No Transcript)
35
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

36
(No Transcript)
37
Biochemistry of psychosis

• Dopamine relative excess
• Causes
• Substance abuse (e.g., methamphetamine)
• Medications (e.g., prednisone)
• Heredity (e.g., Huntingtons disease)
• Functional disorder (e.g., schizophrenia)

38
People with schizophrenia

• Psychosis (positive symptoms)
• Decline in function (negative symptoms)
• Lack of ambition
• Social withdrawal

39
Medicationsfor people with schizophrenia

• Neuroleptics
• First generation antipsychotic drugs
• Typical antipsychotic drugs
• Atypical antipsychotic drugs
• Second generation antipsychotics

40
Neuroleptics

• FGAs First Generation Drugs Doses
• Chlorpromazine (Thorazine) 30-800 mg / day
• Perphenazine (Trilafon) 12-64 mg / day
• Trifluperazine (Stelazine) 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)

41
Neuroleptic medications

• Block doparmine
• Reduce psychosis (positive symptoms)
• Extrapyramidal side effects
• Involuntary motor system
• Stiffness
• Tremors
• Restlessness
• Tardive dyskinesia
• May worsen negative symptoms
• Some weight gain
• Cheap (five to ten cents per day)

42
Tardive dyskinesia

• Abnormal involuntary movements
• Lip smacking
• Tongue thrusting
• Neuroleptic side effect
• May be permanent

43
Atypical Antipsychotic drugs SGAs

• 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

44
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)

45
Clozapine

• 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

46
Olanzapine

• 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

47
Disparity Emerges in Lilly Data on Schizophrenia
Drug

• By ALEX BERENSON
• NY Times, December 21, 2006
• 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.

48
Risperidone

• 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)

49
Quetiapine

• 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

50
Ziprasidone

• 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

51
Aripiprazole

• Abilify
• Perhaps some impact on positive symptoms
• Rare (if ever) impact on negative symptoms
• No (or rare) weight gain

52
Research onatypical 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)

53
Clozapine versus Haloperidol

• Supported by U.S. Department of Veterans Affairs
• 423 veterans at 15 veterans hospitals
• Refractory schizophrenia
• 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?
• Rosenheck et al. New England Journal of Medicine
  337809, 1997

54
Clinical Antipsychotic Trialsof Intervention
Effectiveness (CATIE) IStudy design

• Sponsored by National Institute of Mental Health
  (U.S. Public Health Service)
• 1,493 patients with schizophrenia at 57 sites
  (2001 2004)
• Average age 41
• 74 male
• 60 white
• 85 unemployed
• Randomized to
• 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 3531209

55
Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE)-IIBaseline Psychotropic
use Among Participants

56
Clinical Antipsychotic Trialsof Intervention
Effectiveness (CATIE) IIIMain outcome

• Discontinuation of assigned medication for any
  reason
• Percent Months on drug
• Olanzapine (Zyprexa) 64 9.2
• Quetiapine (Seroquel) 82 4.6
• Risperidone (Risperdal) 74 4.8
• Ziprasidone (Geodon) 79 3.5
• Perphenazine (Trilafon neuroleptic) 75 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 3531209

57
Clinical Antipsychotic Trialsof Intervention
Effectiveness (CATIE) IVSecondary outcome

• Hospitalization due to schizophrenia exacerbation
• Percent Admits per year
• Olanzapine (Zyprexa) 11 0.29
• Quetiapine (Seroquel) 20 0.66
• Risperidone (Risperdal) 15 0.45
• Ziprasidone (Geodon) 18 0.51
• Perphenazine (Trilafon neuroleptic) 16 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 3531209

58
Clinical Antipsychotic Trialsof Intervention
Effectiveness (CATIE) VSide effects

• Pounds per month Extra-pyramidal side effects
• Olanzapine (Zyprexa) 2.0 2
• Quetiapine (Seroquel) 0.5 3
• Risperidone (Risperdal) 0.4 3
• Ziprasidone (Geodon) - 0.2 4
• Perphenazine (Trilafon neuroleptic)_at_ - 0.3 8
• Weight gain significantly more on Zyprexa
  than other drugs
• _at_ 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 3531209

59
Clinical Antipsychotic Trialsof Intervention
Effectiveness (CATIE) VIPhase Two clozapine

• 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 10.5
• Olanzapine 2.7
• Quetiapine 3.3
• Risperidone 2.8
• Time on clozapine significantly longer than
  time on other drugs
• No differences among drugs other than clozapine

60
Clinical Antipsychotic Trialsof Intervention
Effectiveness (CATIE) VIIComments

• More reports coming (e.g. cost-effectiveness)
• Do participants represent everyone with
  schizophrenia? (if you were doing well, would
  you volunteer?)

61
Cost Utility of the Latest Antipsychotic Drugs in
Schizophrenia (CUtLASS)

• Supported by United Kingdom Ministry of Health
• 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 631079