Psychobiology and Psychopharmacology Flashcards
Psychosis Psychobiology
- Elevated dopamine in basal ganglia
- Change is medolimbic-mesocortical circuits
- Decreased serotonin 5-HT receptor activity contributes to negative symptoms
Depressive and Manic Symptoms Psychobiology
- Decreased levels of 5-HT and/or norepinephrine
- Most involved circuit is the locus coeruleus
- Bipolar disorder may be due to interactions between NE, DA, 5-HT, acetylcholine, GABA, and peptides
Anxiety Disorders Psychobiology
- Elevated levels of 5-HT and NE; and decreased levels of GABA
- Raphe nucleus is the most involved circuit
Cognitive/Attention Disorders Psychobiology
- Circuits involved: dorsal anterior cingulate cortex, dorsal lateral prefrontal cortex, orbital frontal cortex
- Dysregulation of dopamine, norepinephrine, and other neurotransmitters
Dementia/Neurocognitive Psychobiology
*Multifactorial including amyloid plaques, tau protein tangles, metabolic and oxygenation issues
Dopamine: D2 and D4 receptors
- Excitatory NT controls thoughts and emotions in frontal cortex; mesocortical tract involved in attention, focus, and depression
- Controls complex movement in nigrostriatal dopamine pathway
- Elevated dopamine in the mesolimbic dopamine pathway that projects into the nucleus accumbens (pleasure pathway) is associated with psychosis
- Influences in the tuberoinfundibular pathways controls prolactin secretion
- D2 receptors stimulated by dopaminergic agonists for Parkinsons treatment and blocked by dopamine agonists in treatment of psychosis
Norepinephrine
*Excitatory NT elevates mood, modulates attention and fatigue; may contribute to anxiety
Located predominantly in the brainstem in the locus coeruleus
*Noradrenergic projections from the locus coeruleus to frontal cortex regulate mood (beta-1 receptors)
*Frontal cortex projections influence attention/concentration (alha-2 receptors)
*Projections in the limbic cortex influence emotions/energy; projections into the cerebellum mediate tremors
*Brain stem projections affect blood pressure and innervate heart via beta-1 receptors
*Innervation of the urinary tract via sympathetic neurons affect bladder emptying via alpha-1 receptors
Serotonin 5-HT
- Located primarily in the raphe nucleus with projections ……
- Frontal lobe: affects mood and depression
- Basal ganglia: (5HT2A) control of movements and obsessions/compulsions
- Limbic: (5HT2A & 5HT2C) related to anxiety and panic
- Hypothalamus: (5HT3) appetite and sleep
- Brainstem: (5HT2A) sleep centers
- Spinal cord: sexual response and gut
- Peripheral: (5HT3 & 5HT4) receptors in gut regulate appetite and GI mobility
GABA (gamma-amino-butyric acid)
- Inhibitory
* Works to sedate and calm
Acetycholine (ACh)
- Play a role in memory and cognition
* Held in balance with dopamine in the substantia nigra
Glutamate
*Excitatory
Hypothalamus-Pituitary_Adrenal Axis (HPA)
- Hypothalamus releases corticotropin releasing hormone (CRH)
- CRH stimulates release of adrenocorticotropic hormone from the anterior pituitary
- Adrenocorticotropic stimulates release of cortisol from adrenals
- Cortisol: elevates blood glucose/fats; elevates BP; Suppresses immune response
- HPA axis may be abnormal in individuals with disorders of: circadian rhythm, stress disorders, depression, diabetes/hyperlipidemia
Hypothalamus-Pituitary-Thyroid Axis
- Hypothalamus releases thyrotropin releasing hormone (TRH)
- TRH acts on the anterior pituitary to secrete thyroid stimulating hormone (TSH)
- TSH stimulates the thyroid to secrete T4
- T4 is converted to T3 through hepatic pathways: regulates basal metabolic rate, neurological function
- Deficiencies: Weight gain, depression, slow mentation
- Excess: Anxiety, Stress, Hypermetabolic state (Graves)
Hypothalamus-Pituitary-Gonadal Axis (HPG)
- Hypothalamus releases gonadotropin releasing hormone (GnRH)
- GnRH acts on the pituitary to cause secretion of FSH & LH
- FSH stimulates: Ovarian follicle development, estrogen secretion, sperm production
- LH stimulates: estrogen and progesterone in females; testosterone in males
CYP450 Enzymes
- Inducers: When used with another medication increases metabolism and reduces therapeutic effect
- Inhibitors: When used with another medication decreases metabolism and causes drug levels to rise
CYP450 1A2
1A2 is inhibited by SSRIs. Increased levels of theophylline (e.g. smoking) induces 1A2, increasing the elimination of olanzepine.
CYP450 2D6
2D6 is most strongly inhibited by fluoxetine, paroxetine, and bupropion; If switching from a TCA to a serotonin agent, will have elevated levels of TCA. Affects metabolism of hydrocodone, morphine, and tramadol
CYP450 3A4
- Inhibited by some SSRIs, nefazodone, and grapefruit juice; some benzo levels will rise when given with fluoxetine.
- Inhibited by erythromycin and will affect carbamazspine level or increase BZD levels. Use azithromycin instead of EES.
- Induced by carbamazepine affecting oral contraceptives, carbamazepine itself, and fluticasone.
- Induction greatly affects methadone, certain HIV meds will induce methadone, increase dose required
- Induced by St. John’s Wort, decreases cyclosporin levels
- Citalopram is a substrate for CYP 450 2C19 and 3A4, and therefore, poor metabolizer status could result in higher than predicted levels for the dosage
Glucuronidation enzyme 1A4
Oral contraceptives in combination with lamotrigine induces the production of glucuronidation enzyme 1A4 increasing metabolism of lamotrigine by as much as 50%, leading to mood destablization
Lithium levels
- Therapeutic level: .8 - 1.2
- Lithium levels increase the inhibition of prostglandins so common NSAID (ibuprofen) can lead to lithium toxicity; exceptions are ASA, Sulindac and tylenol
CATIE Trial: Clinical Antipsychotic Trials of Intervention Effectiveness
- Olanzapine had the least amount of discontinuation; associated with weight gain, increase blood glucose, lipid metabolism
- Typical anti-psychotics are equally effective to atypical but more likely to be discontinued because of extrapyramidal symptoms
STEP-BD Trial: Systematic Treatment Enhancement Program for Bipolar Disorder
In conjunction with mood stabilizing agents, intensive psychotherapy is more effective for depression than collaborative care treatment
STAR-D Trial: Sequenced Treatment Alternatives to Relieve Depression
- Citalopram to another randomly selected SSRI/SNRI to TCA or MIrtazepine
- Pts with hard to treat depression can get better with step treatment but chance of recovery diminish with each step
Typical Anitpsychotics (first generation)
- Phenothiazines: Chlorpromazine/Thorazine; Fluphebazine/Prolixin; *Trifluoperazine/Stelazine
- Butyrophenones: Halperidol/Haldol; Droperidol/Inaspine
- Thioxanthenes: Thiothixene/Navane
- Dihydroindolenes: Molindine/Moban
- Dibenzoazopines: Amoxapine/Asendin
Typical Antipsychotics Effect
Bocks D2 receptors in the mesolimbic and mesocortical tract
Typical Antipsychotics Side Effects
- Sedation/weight gain from H1 blockade
- Orthostatic hypotension and drowsiness from alpha-1 adrenergic receptro blockade
- Increased prolactin from D2 blockade in the tuberoinfundibular tract
- Anticholinergic effects from Muscarinic blockade
- Extrapyramidal side effects from De blockade in the nigrostriatal tract
- Neuroleptic Malignant Syndrome
