1. Chris Pelic M.D.
Associate Dean for Students
Assistant Professor of Psychiatry
Medical University of South Carolina
2. Learn the dopamine hypothesis of
schizophrenia
Learn basic proposed mechanism of
antipsychotics
Understand the difference between first
generation and second generation
antipsychotics
Learn common side effects of antipsychotics
3. Early 1950’s accidental discovery
Found antihistamine chlorpromazine
(phenothiazine) exerted antipsychotic effects.
Was used as anxiolytic before surgery
Through side chain substitutions, more drugs
developed
?13 first generation antipsychotics are still
available
Atypical second generation drugs - 1989
4. 1959 serendipitous discovery of Clozaril
Used in 1972 in Europe but withdrawn 3
years later after several cases of
agranulocytosis and death
Re-introduced in 1988 after trial
demonstrated its clinical superiority but
required monitoring
Other atypical agents soon followed
Most consider atypical agents first line tx
5. Clozapine
1950 1960 1970 1980 1990 2000 2002 2006
Reserpine
Chlorpromazine
Fluphenazine
Thioridazine
Haloperidol
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Kaplan HI et al. Kaplan and Sadock’s Synopsis of Psychiatry. 7th ed.1994.
Black DW et al. Introductory Textbook of Psychiatry. 2001.
Palidperidone
6. **from Michael D. Jibson, M.D., Ph.D.
Ira D. Glick, M.D ASCP CURRICULUM edition 4
7. 1. Nigrostriatal tract-
(extrapyramidal pathway) begins
in the substantia nigra and ends
in the caudate nucleus and
putamen
2. Mesolimbic tract - originates in
the midbrain tegmentum and
innervates the nucleus
accumbens and adjacent limbic
structures
3. Mesocortical tract - originates in
the midbrain tegmentum and
innervates anterior cortical areas
4. Tuberoinfundibular tract -
projects from the arcuate and
periventricular nuclei of the
hypothalamus to the pituitary
9. Clinical efficacy of antipsychotics
correlates with dopamine D2 blockade
Psychotic symptoms can be induced by
dopamine agonists
**from Michael D. Jibson, M.D., Ph.D., Ira D. Glick, M.D ASCP
CURRICULUM edition 4
Carlsson A, Am J Psychiatry 1978;135:164; Seeman P, Synapse 1987:1:133
10. Normal subjects have 10% of dopamine
receptors occupied at baseline
Schizophrenic subjects have 20% of
dopamine receptors occupied at baseline
**from Michael D. Jibson, M.D., Ph.D., Ira D. Glick, M.D ASCP CURRICULUM
edition 4
Laruelle M, Quart J Nuc Med 1998;42:211
11. 65% D2 receptor occupancy is required for
efficacy
80% D2 receptor occupancy is correlated with
EPS
Shorter time of D2 receptor occupancy is
correlated with lower EPS
**from Michael D. Jibson, M.D., Ph.D., Ira D. Glick, M.D ASCP CURRICULUM edition 4
Kapur S & Remington G, Biol Psychiatry 2001;50:873
12. Atypical antipsychotics are high in
serotonin activity
Serotonin agonists (e.g., LSD) produce
psychotic symptoms
Dopaminergic activity is modulated by
serotonin
13. Active psychosis
◦ most common reason for hospitalization
◦ most responsive to medications
◦ Hallucinations, delusions, paranoid, disorganization
Negative symptoms
◦ poor response to medication
◦ progress most rapidly during early acute phases of
illness
◦ alogia, poor grooming, flat affect, poor motivation
14.
15. FDA indications; schizophrenia,
schizoaffective d/o, bipolar disorder,
irritability associated with autism, tourette’s
OFF LABEL: PTSD, MR, ODD, ADHD,
Personality disorders
Hiccups, motion sickness, pruritus
Delirium, aggression, agitation, anxiety
*Many of the above uses are off label but
accepted. Inform pt and family *
16. Dopamine receptor blocking in the brain
(5 receptor subtypes with D1, D2, D3, D4 playing most
significant role)
1. Full antagonist – most agents
2. Partial agonist – aripiprazole
Serotonin receptor blocking in the brain
(5HT2a, 1a, or 5HT2c appears to play a role)
1. Full antagonist – most atypical agents with
different ratios
2. Partial agonist - aripiprazole
**Other receptors: acetylcholine, histamine, NE,
alpha receptors, and glutamate
17. Different meds work on a different
combination of receptors
In general, atypical agents work at D1, D2,
D4, 5HT2a or 5HT2c, receptors as an
antagonist or partial agonist (aripiprazole)
Typical agents mostly work as D2 antagonists
non-selectively
18. Reduce hallucinations
Reduce delusions?? Probably not much.
Reduce paranoia
Calm patient and reduce agitation
PRODUCE SIDE EFFECTS (e.g. sedation, weight
gain, orthostatic hypotension, EPS, etc)
20. Typical agents=1st generation
1. Older
2. Cheaper
3. Work more on positive symptoms
4. Primarily D2 blockade and anticholinergic
activity
5. High potency vs Medium vs Low potency
21. Possible Benefit
Antipsychotic effect
Possible Side Effects
EPS
dystonia
parkinsonism
akathisia
tardive dyskinesia
Endocrine changes:
prolactin elevation
galactorrhea
gynecomastia
menstrual changes
sexual dysfunction
22. Parkinsonian effects – changes balance between
cholinergic and dopaminergic neurons (dopamine
blockade leads to excess of cholinergic influence)
Tardive dyskinesia
Akathisia/akinesia
Orthostatic hypotension
Constipation/Urinary retention
Weight gain
Confusion
Sexual dysfunction
Seizures
NMS
Metabolic problems (glucose, lipids)
23. Akinesia (lack of movement, Parkinson-like)
Dystonic Reaction (muscle spasms of face,
neck, back)
Dyskinesia (Blinking or twitches)
Akathisia (Inability to sit still)
24. Tardive Dyskinesia
◦ Hyperkinesia (lingual or facial)
Blinking
Lip smacking
Sucking or chewing
Rolls or protrudes tongue
Grimaces
◦ Choreathetoid extremity movement
Clonic jerking fingers, ankles, toes
◦ Tonic contractions of neck or back
25. Anticholinergic meds - benztropine,
diphenhydramine for EPS
Dopamine agonists – amantadine for EPS
Beta-blockers - propranolol for akathisia
Reduce the dose
Change meds
Stop the neuroleptic (NMS, ?TD)
You don’t – use them to the patient’s benefit
(e.g. sedation, weight gain)
26. Medical emergency
¼ cases culminate in coma, stupor, and
death
Unexplained hyperthermia with an increase
in muscle tone
Usually after med increase or initiation
Elevated CK, elevated WBC, stiffness, fever,
autonomic instability, confusion
Treat with dantrolene, bromocryptine fluids,
benzos, and maybe ECT
Don’t rechallenge before 2 weeks
27. Phenothiazines
1. Aliphatic, e.g. chlorpromazine (thorazine) and
trifluopromazine (vesprin).
2. Piperazine, e.g. perphenazine (trilafon),
trifluoperazine (stelazine), fluphenazine
(prolixin), acetophenazine (tindal)
3. Piperidine, e.g. thioridazine (mellaril),
mesoridazine (serentil)
33. MOST antipsychotics can prolong the Qtc
interval of the heart (avoid if >500msec)
MOST antipsychotics lower seizure threshold
Typical antipsychotics – more problems with
EPS, anticholinergic effect
Atypical antipsychotics – more problems with
metabolic side effects
35. Butyrophenone
EPS common but sedation, hypotension not
Comes in tabs, elixir, shot (IM or IV)
Has depot form q4weeks
High potency
Most commonly used 1st generation
antipsychotic
36. Piperazine
Most potent
High potential for EPS
Has IM and IM 2 week depot shot
Low potential for sedation
37. Sedating/low EPS risk
Potential for severe hypotension (be very
careful with IV use)
Low potency
Very anticholinergic
Used for intractible hiccups
38. Piperidine
Low potency – high anticholinergic activity
High likelihood of QTc prolongation
Associated with retinitis pigmentosa
Not used clinically much
39. Atypical agents
1. Newer
2. More expensive
3. May work on both positive and negative
symptoms
4. Lower incidence of EPS, TD, NMS
5. Act on D1, D2, D4, serotonin receptors (as
well as NE, glutamate, histamine)
43. Dibenzodiazepine class (CAT B)
(D1, D2, D4, 5HT2 activity)
Gold standard - more selective D blockade & serotonin
activity
Reserved for more refractory cases
High metabolic risk
Low EPS, may help TD
Risk for seizures (dose dep), hypotension, weight gain,
sialorrhea
Risk of agranulocytosis is 1%
Requires weekly WBC count – looking at WBC/ANC
44. D2 – blocker, 5 HT2a blocker
Above 6mg - EPS more likely (acts more like
haldol)
Potential for weight gain, sedation,
orthostatic hypotension, sexual dysfunction
Comes in tabs, dissolvable tabs (mtab),
elixir, LONG ACTING (Consta)
Known to increase prolactin levels
Metabolic risk
45. Partial agonist of dopamine and serotonin
Usual effective dose is starting dose of 15mg
High potential for akathisia
Dosed in am with food
Has IM form for acute agitation
Little metabolic risk
? About efficacy or speed of action
46. Major active metabolite of risperidone
FDA approved for schizophrenia
OROS delivery system (like concerta)
Works similarly to risperdal. Marketed as
having less side effects?
47. Thienobenzodiazepine class (similar to clozaril)
Very sedating and high likelihood of significant
weight gain 10-100lbs
Monitor lipids, glucose
Comes in tab, dissolvable Zydis form, IM
Very effective
48. Sedating, potential for orthostatic
hypotension, and weight gain
Very low EPS/TD risk
Often used off label
49. Benzothiazolyl - piperazine class
?Potential for QTc prolongation but not
necessary to do EKG if no h/o cardiac disease
Low side effects/Take with food (will lower
blood levels if you don’t). Food=400+calories
Low doses you see activation, high doses you
get dopamine blockade
53. Some slides adapted from:
David N. Osser, M.D.
Harvard Medical School
ASCP Model Curriculum
December, 2007 Version
54. Introduction to anxiety
Understand mechanism, effect, and side
effects of barbiturates, benzodiazepines,
buspirone, propranolol, hydroxyzine, and
other antianxiety agents
Learn basic agents for sleep disorders (e.g.
zolpidem)
55. Anxiety – feeling of apprehension
and fear
25% lifetime prevalence of any
anxiety disorder (Nat. Co-morbidity
Survey 1994)
Many more have situational anxiety
related to “normal” fears and use of
medication for short term relief can
be appealing. (Pomerantz JM, 2007)
56. Alcohol, bromide, and paraldehye
preparations were initially used
1903 barbital was first barbiturate used but
toxicity and dependency issues developed
1950 meprobamate was developed (non-
barbiturate) but highly addicting
57. Late 1950’s Librium (chlordiazepoxide) – first
benzodiazepine
Few years later Valium (diazepam) was
developed with 3-10 X potency
Early 1960’s Imipramine (TCA) was found to
be useful for panic disorder
MAOIs began being looked at for anxiety
SSRI and Buspirone used in late 80s and 90s
58. Due to stigmatization, patients often seek
a quick, private remedy.
Self-medication with alcohol and drugs of
abuse is common, and reinforced by social
acceptance – and even by psychiatric
clinicians
59. Used early in 20th century for anxiety and
sedative hypnotic
Now rarely used as anticonvulsant and
anesthetic
Steep drug response curve – dangerous
Induces liver enzymes (e.g. other drugs)
Potential for dependence/withdrawal
Withdrawal can be life threatening
Work on GABAa receptor – Increases Cl-
Phenobarbital, thiopental
63. Highly lipid soluble
Rapid onset
Short duration of action
IV general anesthetic
64. Work on GABA a – specific benzo. site on this
receptor
Leads to hyper-polarization
BZ1 receptor (w1) – sedation and hypnosis
BZ1 receptor (w2) – cognition, motor functioning
-
Replaced barbiturates
CLINICAL USES: anxiety, muscle relaxation,
hypnosis, anticonvulsant, catatonia, preop, sleep
69. Inhibition of polysynaptic transmission at
spinal and suprasinal locations
Diazepam used most often in this capacity for
back spasms
70. Used in preventing or abolishing seizures
Often used for status
IM (lorazepam) or IV (diazepam) preferred
71. Used before procedures
Facilitates anesthesia
Conscious sedation
Can produce anterograde amnesia
72. Lipid solubility
Half life
Short half life/High Lipid solubility=Good PRN
but more addicting
Long half life/Less Lipid solubility=less
addicting and worse PRN
73. Long half life/highly lipid solubility
Used for withdrawal
Used for PRN anxiety
Can accumulate secondary to redistribution
Used IV for seizures
Used for back/muscle spasms
74. Drug of choice for status epilepticus (IM)
Highly lipid solubility but short half life
Used PRN anxiety
Used a lot for alcohol withdrawal
75. High potential for addiction
High lipid solubility/short acting
Requires frequent dosing
Used mainly for PRN uses (e.g. panic attacks)
76. More selective anticonvulsant activity
Used for longer term management of anxiety,
mania, restless leg syndrome
77. Quick onset
Mid acting benzodiazepine
Used most for sleep
78. Used most perioperatively
More rapid elimination
Quick onset and more potent than diazepam
79. Benzodiazepine antagonist
Used to reverse overdose or anesthesia
Can precipitate seizures/acute withdrawal
Rarely used
80. Glucuronidation:
lorazepam oxazepam, temazepam, alprazolam,
triazolam (used in pts with liver disease)
Nitroreduction:
clonazepam
Demethylation and oxidation:
diazepam, chlordiazepoxide, chlorazepate
81. Cytochrome inhibitors: metoprolol,
propranolol, disulfiram, omeprazole,
erythromycin, fluoxetine.
Anticholinergics: additive cognitive
impairment especially in the elderly
Additive CNS depression with other
sedatives
Clozapine added to ongoing BZ may rarely
give severe sedation, delirium, respiratory
depression/death
84. Dependence, addiction, abuse – by far most
common in alcoholics and other drug abusers
Elderly – watch for increased fall risk with long
half-life drugs
Memory impairment
Impaired motor coordination, auto driving in
simulated driving tests
Disinhibition/violence – more uncommon than
presumed
Depression
85. Pregnancy risk “D” level due to oral cleft,
except clonazepam C
Most recent studies show they are fairly
safe but old studies suggested cleft palate
86. 5HT1a partial agonist
No sedating, muscle-relaxant, sexual,
or anticonvulsant effects
No abuse potential
Used mainly for generalized anxiety
disorder
Does not suppress respiration so is
useful for anxiety in COPD patients
No impairment of cognition or motor
coordination
87. Has some efficacy in depression at 40
mg/d (STAR*D)
Side effects: headache, insomnia,
jitteriness, and nausea.
88. Propranolol 30 minutes prior to the event.
Try test doses before
Side effects: hypotension, bradycardia,
dizziness, asthma, fatigue. Evidence
contradicts idea that betablockers mask
hypoglycemia symptoms. (Chalon, 1999)
Half-life 3-6 hours
Lipophilic so crosses into brain
Not useful for social phobia, generalized type
89. Anticonvulsants e.g. gabapentin, valproate,
lamotrigine, topiramate
Pregabalin (Lyrica) – got “non-approvable”
letter from FDA in 2004 for GAD but
approved in Europe in 2006.
Tiagabine (Gabatril)– didn’t separate from
placebo in unpublished studies.
MAOIs
Antihistamines e.g. hydroxyzine,
diphenhydramine
Prazosin and terazosin (Alpha-1 antagonists)
91. Chemically unrelated to benzodiazepines
Zolpidem - Works on BZ1 receptor
Eszopiclone – works on GABA a receptor
Used for insomnia
Intended for short term use or PRN
92. Works as “melatonin” for sleep
Does not work immediately
