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-5-phenyl-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 time-release dosing. Blood levels vary significantly.

Pharmacology Basics

Pharmacology Basics

• Drug actions– Alter availability of neurotransmitter

• 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

• 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– 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

• 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.

Amygdala

HPA

Senses

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.

Amygdala Hippocampus

HPA

Cortisol

-+

+

Senses

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.

Amygdala Hippocampus

HPACortisol

Therapy

Fears

+

-

-

* 5-HT ↑ GCRs

* Excessive cortisol kills GCRs+

Therapy = learned compensatory/ inhibitory process

5-HTSenses

+

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• 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)– 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– 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

• 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– 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• Relation to maternal factors

– Prenatal stresses increase risk.– Rh incompatibility

(Hollister, Laing and Mednick (1996)• Incompatible Rh factor increases risk in males.

• Late male birth order increases risk in males.

– Maternal stress• 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

• Relation to infections– Late winter babies have a higher incidence rate

• 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.

• (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

• Relation to stress– 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.

– 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 under-inhibition cause the positive symptoms.

Schizophrenia• Pharmacology

– chlorpromazine (Thorazine, Ormazine, Largactil)– trifluoperazine (Stelazine)– pimozide (Orap)– flupenthixol (Fluanxol)– thioidazine (Mellaril)– mesoridazine (Serentil)– haloperidol (Haldol)

– clozapine (Clozaril)– risperidone (Risperidal)– olanzapine (Zyprexa)– quetiapine (Seroquel)– ziprosidone (Geodon)