Psychopharmacology and
Psychiatric Disorders
• Pharmacology basics
• Psychiatric disorders
– Their etiologies
– The molecular action of therapeutic drugs
Psychopharmacology
• The treatment of psychiatric disorders
through drugs (better living through
chemistry).
• The understanding of the biological origins
of most psychiatric illnesses has been
driven by the pharmacology.
Pharmacology Basics
• Drugs have several names:
– Chemical name
• Ex. 7-chloro-1,3-dihydro-1-methyl-5phenyl-2H-1,3-benzodiazepin-2-one
– Generic name
• Ex. diazapam (non-capitalized)
• By type: -pam (benzodiazapine), -al
(barbituate), -caine (local anesthetics)
– Trade or brand name
• Ex. Valium (capitalized)
Pharmacology Basics
• Kinetics
– Metabolism
• The breakdown of a drug, by liver or other means.
• Some metabolites are as or more active than the
original drug.
• Some genetic variability in drug metabolism.
(cytochrome enzymes, e.g. CYP450 1A2)
– Elimination
• Removal of the drug by the kidneys.
Pharmacology Basics
• Kinetics
– Half-life
• Time required to eliminate half of the maximum
concentration of drug in the blood.
• Long half-lives require infrequent dosing, and blood
levels remain relatively more constant.
• Short half-lives require frequent dosing, or timerelease dosing. Blood levels vary significantly.
Pharmacology Basics
Pharmacology Basics
•
Drug actions
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Alter availability of neurotransmitter
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Alter availability of precursor
Alter enzymatic processes on precursor
Alter neurotransmitter synthesis
Alter release of neurotransmitter
Block reuptake of neurotransmitter
Alter autoregulation
Pharmacology Basics
• Drug actions
– Alter synaptic neurotransmitter
• Enhance or inhibit enzymatic activity which breaks
down the neurotransmitter in the synapse.
– Alter postsynaptic receptors
• Upregulation/Downregulation – more receptors
synthesized/destroyed.
• Typically takes 2-3 weeks, hence therapeutic delays.
Psychiatric Disorders
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Diathesis-Stress model
Widely held belief that psychological
disorders are caused by the interaction of:
1. A genetic propensity or predisposition (diathesis)
2. Environmental triggers (stress)
Psychiatric Disorders
• All have some biological underpinnings
• Neurotransmitter anomalies
• Polygenetic
– Multiple propensity and protection factors
• More infectious causes constantly being found
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Some autoimmune involvement
Rubella, HSV1, etc. tied to schizophrenia
Streptococcus associated with some OCD cases
HIV known to cause cognitive impairments
Psychiatric Disorders
• 3 Major classes of disorders:
– Anxiety disorders
– Affective disorders
– Schizophrenia
often comorbid
Anxiety/Affective Disorders
Anxiety/Affective Disorders
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They are often comorbid.
They share some pharmacology.
They both activate the SNS and HPA axis.
Current interpretation is moving towards a
shared etiology.
Anxiety Disorders
• Chronic fears that persist in the absence of
any direct threat.
• Can include physiological responses to the
imaginary fears.
• Most prevalent of psychiatric disorders.
• Most easily treated with therapy.
Anxiety Disorders
• Five major classes:
– Generalized anxiety disorders
• No obvious cause
– Phobic anxiety disorders
• Specific fear
– Panic disorders
• Rapid onset of extreme fear and anxiety
– Obsessive-compulsive disorders
• Recurring, uncontrollable thoughts or actions
– Post-Traumatic Stress Disorder (PTSD)
Anxiety Disorders
• Symptoms identical to stress:
– SNS activation, increased cortisol and
adrenaline (“fight”).
– Avoidance (“flight”).
– Hypervigilance
• Produce a variety of physiological
stress reactions:
– Tachycardia, hypertension, nausea,
sleep disturbances, etc.
Senses
Amygdala
HPA
Cortisol
Epinephrine
Anxiety Disorders
• Stress response is mediated by the HPA axis
(hypothalamus, pituitary, adrenal glands)
• Increased amygdala activation increases the stress response.
• Increasing hippocampus activation decreases it.
Senses
+
Amygdala
Hippocampus
Cortisol
HPA
+
-
Anxiety Disorders
• The cortex can cause or inhibit fears. Inhibition is learned.
• High density of GABA receptors in amygdala.
• 5-HT increases hippocampal suppression of HPA.
Therap
y
Therapy = learned
compensatory/
inhibitory process
5-HT
Fear
s
Senses
+
Amygdala +
* 5-HT ↑ GCRs
* Excessive cortisol
kills GCRs
Hippocampus
Cortisol
+
HPA
-
Anxiety Disorders
• Etiology
– Because of the effective drugs, GABAA and
serotonin are both implicated. Both inhibit
anxious behaviors.
– Amygdala (high concentration of GABAA
receptors) seems to be involved, as would be
expected for a “fear” response.
– Anxious persons have too little inhibition.
– Anxiolytics increase inhibition.
Anxiety Disorders
• Benzodiazapines
bind to GABA
receptors.
• Radioactive
benzodiazapine
uptake sites.
Normal
Anxious
Anxiety Disorders
• Pharmacology
– GABAA agonists
• Benzodiazapines (Valium, Xanax, etc.)
• Increase Cl- flow thru GABAA receptors and
immediately increase inhibition.
• Ataxia, muscle relaxation, sedation side effects.
– Serotonin agonists
• Buspirone (Buspar) selectively blocks 5HT1A
receptors – anxiolytic w/o side effects.
• Up- or down-regulation – takes weeks.
Anxiety Disorders
• Pharmacology
– GABA agonists
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diazepam (Valium)
alprazolam (Xanax).
lorazepam (Ativan)
oxazepam (Serax)
chlordiazepoxide (Librium)
clorazepate (Tranxene)
– SSRIs
• buspirone (Buspar)
• paroxetine (Paxil)
– [CRH antagonists]
Anxiety Disorders
• Obsessive-Compulsive Disorder
– Swedo (1989) identified a link between OCD and
Sydenham’s chorea, a basal ganglia disorder that
often follows streptococcal infections.
– Certain streptococcal infections cause an
autoimmune response which attacks the basal
ganglia in susceptible patients.
– PANDAS (Pediatric Autoimmune Neuropsychiatric
Disorders Associated with Streptococcal infections)
Affective Disorders
Affective Disorders
• Depression (unipolar)
– Reactive or endogenous
– 6% incidence, F = 2xM (non-western cultures higher)
– MZ: 60%, DZ: 15% reared together or apart
• Mania (bipolar)
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Bipolar I: manic-depressive
Bipolar II: hypomanic-depressive
1% incidence, F = M
MZ: 80%, DZ: 16%
Affective Disorders
• Course
– Chronic
• Relation to stress
– Brown (1993) found:
• 84% of patients seeking help for depression had
a severe stressor in the last year compared to
32% of controls.
– Early life stress is hypothesized to contribute
to adult depression, but proof is difficult.
Affective Disorders
• Depression pharmacology
– Iproniazid, 1st commercial antidepressant was
developed for TB, but improved patient moods.
– Tested on mixed psychiatric patients, it was
found effective against depression.
– Iproniazid is a monoamine oxidase inhibitor –
it keeps monoamine oxidase from breaking
down monoamines.
Affective Disorders
• Etiology
– Monoamine theory of affective disorders:
• Excess monoamines (D, NE, 5-HT) cause mania.
• Monoamine depletion causes depression.
• Many receptor types involved.
Dopamine (tyrosine)
Serotonin (tryptophan)
Affective Disorders
Affective Disorders
• Monoamine oxidase inhibitors (MAOIs)
– Inhibit monoamine oxidases, which normally
break down monoamines, allowing more
monoamine to remain in the synapse.
– The postsynaptic neuron downregulates.
– Dietary restrictions (“cheese effect”) required
to prevent severe hypertension problems.
Dietary monoamines build up and cause
hypertension.
Affective Disorders
• Major classes of affective pharmacology
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Monoamine oxidase inhibitors (MAOIs)
Tricyclic & tetracyclic antidepressants (TCAs)
Selective serotonin reuptake inhibitors (SSRIs)
Others
Affective Disorders
• Tricyclic antidepressants
– Named for their 3 ringed structures
(tetracyclic = 4 rings).
– Nonspecifically blocks reuptake of
serotonin and norepinephrine.
– Since neurotransmitter cannot be
reuptaken, more remains in the
synapse.
– Downregulation also occurs.
– Safer than MAOIs.
Affective Disorders
• Selective serotonin reuptake inhibitors (SSRIs)
– Only block serotonin reuptake.
– Leaves more serotonin in synapse.
– Various SSRIs affect different serotonin receptors (at
least 16 known!).
• Selective norepinephrine reuptake inhibitors
– NE and 5-HT have reciprocal control pathways.
– Same idea, but only block NE reuptake.
– Can be as effective as SSRIs.
Affective Disorders
• MAOIs
– iproniazid (), phenelzine (Nardil) and tranylcypromine (Parnate).
• Tricyclics
– amitriptyline (Elavil), imipramine (Tofranil), desipramine (Norpramin),
doxepin (Sinequan), clomipramine (Anafranil), nortriptyline (Pamelor).
• Tetracyclic
– maprotiline (Ludiomil)
• SSRIs
– fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft)
• Other
– trazodone (Desyrel), nefazodone (Serzone), bupropion (Wellbutrin)
Bipolar Disorder
• 1. Mania (I) or hypomania (II) (key factor)
– Loss of inhibition, cognition, rational thinking.
• 2. Major depression
– No depressive episodes required for diagnosis!
• Often comorbid with psychotic features.
• Perhaps a different mechanism than normal
depression – like negative schizophrenia
symptoms.
Bipolar Disorder
• Pharmacology
– Lithium
• No effect in 1/3 of the population.
• Action unknown
– Agonizes 5-HT system
– Possibly modulates inositol-type second messenger
systems.
• Low therapeutic index, caution required.
– (therapeutic index = lethal dose / effective dose)
Bipolar Disorder
• Pharmacology
– Anticonvulsants
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Seizures have (temporary) antidepressive effects.
Course of bipolar disorder mimics epilepsy.
Sometimes work when lithium doesn’t.
valproate (Depakote)
carbamazapine (Tegretol)
oxcarbazapine (Trileptal)
topiramate (Topamax)
risperidone (Risperidal)
Schizophrenia
Schizophrenia
• “Split mind” - breakdown of integration between
emotion, thought and action – “going mad.”
• Incidence
– 1% of general population
• No race, sex or cultural differences.
– MZ: 48%, DZ: 17%, Family 10%, GP 1%
• Course
– Symptoms appear in adolescence or early adulthood
(somewhat later in females).
– Chronic, with possible remissions.
Schizophrenia
• Subtypes include paranoid (most treatable),
disorganized, catatonic and residual types.
• Two classes of symptoms:
– Positive Symptoms
• Abnormal behaviors and thoughts – delusions,
hallucinations, disorganization.
– Negative Symptoms
• Lack of appropriate responses – reduced motivation,
decreased affect, etc.
• Physical changes noted
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Abnormally small cortex
Abnormally large ventricles
Prefrontal cortex, amygdala abnormalities
Smaller hippocampus
No ongoing deterioration
Abnormalities seem to be in place before
symptoms (i.e. seems to be a developmental
disorder).
Schizophrenia
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Relation to maternal factors
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Prenatal stresses increase risk.
Rh incompatibility
(Hollister, Laing and Mednick (1996)
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Incompatible Rh factor increases risk in males.
Late male birth order increases risk in males.
Maternal stress
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Quebec Ice Storm of 1998 -> brain differences
(King, LaPlant, Joober (2005)
Dutch Winter Famine (1944-1945) (Hoek, etc.)
Chinese famine of 1959-1961 (St. Clair, et al, 2005)
Schizophrenia
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Relation to infections
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Late winter babies have a higher incidence rate
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Assumed to be from autumn (2nd trimester) infection
Brown, et al. prospectively collected blood serum
samples from mothers during 1959-1967 and
tracked their offspring.
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(2002) 2nd semester in utero rubella and respiratory
infections are significantly linked to schizophrenic
offspring.
(2004) found elevated 2nd trimester IL-8 levels in mothers
of those who later developed schizophrenia.
Schizophrenia
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Relation to stress
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Several studies have found:
1. Exposure to severe stress is common before onset.
2. Symptom severity is proportional to stress severity.
3. Maternal stress exposure may be correlated.
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Susceptibility seems to be strongly genetic, but
environmental factors, especially stress, can
trigger disorder in susceptible individuals.
Schizophrenia
• Pharmacology
– 1950 Dr. Henri Laborit used the new antihistamine,
chlorpromazine (Thorazine), to prevent surgical
shock, and found it lessened surgical anxiety. It was
tried on various mental patients and was found to be
effective with schizophrenics.
– An American psychiatrist got interested in the
traditional Indian snakeroot treatment and
confirmed the anti-psychotic effects of reserpine,
the active agent in snakeroot.
Schizophrenia
• Pharmacology
– Chlorpromazine and reserpine
• Dissimilar chemical structures
• 2-3 week period before effective
• Comorbid Parkinson-like effects
– Parkinson’s research, ca. 1960
• Found depleted dopamine in striatum
– Amphetamines & cocaine, which cause psychotic
effects, both elevate dopamine levels.
Schizophrenia
• Dopamine (primary) theory of schizophrenia
• Positive symptoms
– Increased dopamine in mesolimbic pathway (D2) is
responsible for positive symptoms.
• Phenothiazines (incl. chlorpromazine): Bind to and block
both D1 and D2 receptors.
• Reserpine: Destroys monoamine vesicles.
• Seeman (1976) anti-psychotic effects proportional to
dopamine receptor D2 affinity.
• Butyrophenones (haloperidol) bind only to D2.
Schizophrenia
• Negative symptoms
– Decreased dopamine in mesocortical pathway causes
negative symptoms (few D2 receptors in PFC).
– Structural pathologies thought to be responsible (also
related to bipolar/autism).
– BDNF, dysbindin, etc. abnormalities during
development lead to oddly wired brains.
– Cell bodies are smaller.
– Nerve connections are not normal.
Schizophrenia
• Glutamate theory of schizophrenia
– Phenylcyclidine (PCP), originally an anesthetic, is
hallucinogenic, but affects glutamate, not dopamine,
receptors.
– This lead to a glutamate theory of schizophrenia,
with diminished NMDA receptor activation.
– NMDA-receptor knockout mouse experiments
confirm schizophrenia-like symptoms including
altered social interactions and repetitive movements.
Both conventional and atypical antipsychotics restore
normal behavior.
Schizophrenia
• Mesocortical D system in
prefrontal cortex normally
inhibits (via glutamate) the
mesolimbic D system in
brainstem.
• Deficient D in mesocortical
system causes negative
symptoms.
• Excess D release in the
mesolimbic areas from underinhibition cause the positive
symptoms.
Schizophrenia
• Pharmacology
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chlorpromazine (Thorazine, Ormazine, Largactil)
trifluoperazine (Stelazine)
pimozide (Orap)
flupenthixol (Fluanxol)
thioidazine (Mellaril)
mesoridazine (Serentil)
haloperidol (Haldol)
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clozapine (Clozaril)
risperidone (Risperidal)
olanzapine (Zyprexa)
quetiapine (Seroquel)
ziprosidone (Geodon)