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
Extrapyramidal Side Effects and Treatment
- Pseudoparkinsonism, dystonias, akathesia
- Change medication
- Lower dose
- Benzoptropine (Cogentin)
Atypical Antipsychotics
- Dibenzodiazepines: Clozapine/Clozaril
- Benzisoxazoles: Risperidone/Risperdal
- Thienobenzodiazepines: Olanzepine/Zyprexa
- Dibenzothiazepine: Quetiapine/Seroquel
- Benzisothiazolyl piperazines: Ziprasidne/Geodone
- Aripiprazole/Abilify
- Lurasidone/Latuda
- Asenapine/Saphis
Atypical Antipsychotics Mechanism of Action
- Block D2 and 5HT receptors
- Relieves negative symptoms not seen with typical antipsychotics
- Decreased risk of extrapyramidal symptoms and tardive dyskinesias
Side Effects of Atypical Antipsychotics
Orthostatic hypotension Dizziness Weight gain Tachycardia Sleep disturbance Constipation Neuromalignant Syndrome Agranulocytosis EPS, TD
Clozapine/Clozaril
- May cause agranulocytosis
- 12.5 mg first dose, increase by 25-50 mg /day to 330-400 mg/ day
- 900 mg max per day; 450 mg max per dose
- CBC/Diff?ANC every week X 6 months then every 2 weeks x 6 months, then every 4 weeks
Risperidone/Risperdal
- May cause seizures
- Contraindicated in pregnancy
- Increased prolactin
Long Acting Injectable Antipsychotics
- Older: Fluphenazine/prollixin; Haloperidol
- Respiridone: q 2 weeks
- Paliperidone/Invega: q 4 weeks
- Olanzipine/Zyprexa: q 2-4 weeks; post injection delirium and extreme sedation
- Aripiprazole/Abilify: q 4 weeks
Neuroleptic Malignant Syndrome
- 0.2% - 2.4% incidence
Usually develops in first 2 weeks - HOT, DTIFF and OUT OF IT: Mental status change, muscle rigidity, extreme autonomic instability/hyperthermia
- 10-20% mortality; Death from cardiac, respiratory, or renal failure
- Treatment with dopamine agonists: Amantadine, bromocriptine; Muscle relaxant: Dantrolene
Neuroleptic Syndrome Associated Symptoms
- Hyperthermia, confusion, muscle rigidity
- Diaphoresis, hypertension, tachycardia, irregular pulse, fasiculations
- elevated creatine kinase, elevated myoglobin, elevated WBC, Elevated AST/ALT, iron deficiency, proteinuria/myoglobinuria
Main medications for Bipolar Affective DIsorder
- Lithium
- Depakote
- Other agents include: antiepileptics, antipsychotics, sedatives
Lithium
- May work by affecting NE and DA but exact mechanism unknown
- Therapeutic levels .5 - 1.2 mmol/L
- Acute treatment: blood levels twice a week
- Chronic treatment: blood levels every 2-6 months
- Check serum levels 12 hours after last dose and after five days of steady dosing
Lithium Side Effects
- Muscle weakness
- Tiredness
- Slurred speech
- Fine hand tremor
- Thirst
- Nausea
- Diarrhea
- Vomiting
Lithium Cautions
- Concomitant use of haloperidol linked to encephalopathy
- IBU can increase serum lithium levels
- Calcium channel blockers are contraindicated
- Use diuretics with caution
Antiepileptics in Psychiatry
- Carbamazepine (Tegretol)
- Divalproex sodium (Depakote)
- Topiramate (Topamax): chronic headaches, alcohol craving
- Lamotrigine (Lamictal)
- Gabapentin (Neurontin)
- Pregabalin (Lyrica): alpha 2 delta ligands block voltage sensitive Ca channels, decreasing release of calcium, decreasing release of glutamate, decreasing AMPA activation, decreasing release of NE & Substance P
Antiepileptics in Psychiatry
- Decreases the firing of CNS nerves
* Potentiating the effects of GABA in certain parts of the brain, reducing the number of action potentials
Antiepileptics Adverse Effects
- Sedation
- Fatigue
- Dizziness
- GI upset
- Phenobarbital: Induction of liver enzymes
- Phenytoin: Gingival hyperplasia
- Carbamazepine: Hepatitis and liver failure
- Divalproex sodium: Pancreatitis, hepatitis; MONITOR LIVER
- Lamotrigine: Serious skin rash
Tricyclic Antidepressants
- Amitriptyline (Elavil)
- Nortriptyline (Aventyl, Pamelor)
- Desipramine (Norpramine, Pertofrane)
- Imipramine (Tofranil)
- Doxepin (Sinequan)
- Protriptyline ( Vivactil)
- Amoxapine (Asendin)
- Trimipramine (Surmontil)
- Clomipramine (Anafranil)
Tetracycline Antidepressants
- Maprotiline (Ludiomil)
* Mirtazapine (Remeron)
Tricyclic & Tetracyclic Antidepressants Side Effects
- Sedation
- Anticholinergic effects: dry mouth, mydriasis, hyperthermia, tachycardia
- Cognitive impairment
- Memory loss
- Weight gain
- Tetracyclic: Agranulocytosis
** Possible QT prolongation; baseline EKG
Tricyclic Antidepressant Pharmacokinetics
- Eliminated by 2D6
- If elimination is blocked by inhibition of 2D6 agents such as fluoxetine, risk of widening QTc interval allowing for Torsade de points arrhythmia/sudden death.
- Can lower seizure threshold
Monoamine Oxidase Inhibitors (MAOI)
- Phenelzine (Nardil)
- Tranylcypromine (Parnate)
- Isocarboxazid (Marplan)
- Selegiline (patch Emsam, buccal Zelapar, capsule Eldepryl)
MAOI Side Effects
- Dizziness
- Vertigo
- Headache
- Insomnia
- Memory impairment
- Hypertensive crisis: precipitated by tyramine rich foods, sympathomimetic drugs, meperidine
Norepinephrine-Dopamine Reuptake Inhibitor (NDRI) Antidepressants
- Buproprion (Wellbutrin)
Selective Reuptake Inhibitor Antidepressants
- Nefazodone (Serzone)
* Trazodone (Desyrel)
Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants
- Fluoxetine (Prozac)
- Paroxetine (Paxil): known for withdrawal symptoms
- Citalopram (Celexa): cardiac effects may require decreased doses
- Sertraline (Zoloft)
- Escitalopram (Lexapro)
- Vilazodone (Viibryd): 5HT1A partial agonism
- Vortioxetine (Brintellix): 5HT1A partial agonism
Serotonin Norepinephrine Reuptake Inhibitor (SNRI) Antidepressants
- Venlafaxine (Effexor) : increased BP
- Duloxetine (Cymbalta)
- Desvenlaxafine (Pristiq)
SRI and SSRI Side Effects
- Nervousness
- Insomnia
- Sedation (Paroxetine)
- Headache
- Sweating
- Dry mouth
- Teeth clenching
- Sexual dysfunction
- Initially: Nausea, weight loss
- Prolonged use: weight gain
Antidepressants which cause lower sexual dysfunction
- Bupropion (Wellbutrin)
- Mirtazapine (Remeron)
- Vilazodone (Viibryd)
- Virtioxetine (Trintellix)
- Erectile dysfunction caused by inhibition of alpha 1 adrenergic receptors
Pediatric Antidepressants
- Fluoxetine (Prozac): FDA indicated for MDD 6+; OCD & PTSD 7+; cataplexy ages 7+
- Escitalopram (Lexapro): FDA indicated for MDD 7+; autism 6+
Serotonin Syndrome Symptoms
- Agitation
- Confusion
- Hallucinations
- Tachycardia
- Fever
- Muscle rigidity
- Hyperrelexia
- Tremors
- Diarrhea
- Hypo/hypertension
- Myoclonus
Serotonin Syndrome cause/treatment
- Use of more than one SSRI or St. John’s Wort
- Withdraw from SSRI
- Stabilize temperature with antipyretics
- Benzodiazepine, dantrolene for muscle relaxation
- Beta blocker for tachycardia
- Cyproheptadine (Periactin): Binds to serotonin (5HT1A & 5HT2A) and histamine receptors
Discontinuation of SSRIs: FINISH
- Flue like symptoms
- Insomnia
- Nausea
- Imbalance (dizziness)
- Sensory disturbance
- Hyperarousal (anxiety); Headache
Anxiolytic Side Effects
- lethargy
- sedation
- depression
- dizziness
- lightheadedness
- anticholinergic effects
- addiction
** Avoid in acute narrow angle glaucoma
Side Effects of ADHD Medications
- Weight loss
- Hypertension
- Insomnia
- Irritability
- Nervousness
- Palpitations
- Tachycardia
- Monitor growth
- Pros and cons of drug holidays
Anxiolytics/Hypnotics
- Diazepam (Valium)
- Lorazepam (Ativan)
- Alprazolam (Xanax)
- Clonazepam (Klonopin)
- Chlordiazepoxide (Librium)
- Buspirone (Buspar): Nonbenzo
- Zaleplon (Sonata): Nonbenzo
- Zolpidem (Ambien): Nonbenzo
Anxiolytic withdrawal
- withdraw slowly
- irritability
- anxiety
- insomnia
- depression
- seizures
Stimulant Medications
- Accelerate “slow rate” behaviors; Suppress “fast rate” behaviors
- Blockade of DA
Contraindications: glaucoma, motor tics, tourette’s syndrome, caution with seizure disorder
ADHD Medications
- Methylphenidate: Ritalin, Concerta, Focalin
- Dextroamphetamine: Adderall, Vyvanse
- Non-stimulant
* * Atomoxetine (Strattera): Blocks reuptake of NE
* * Guanfacine (Intuniv)
* * Catapres (Clonidine)
Anti-Parkinsonian Drugs
- Parkinson’s is the result of loss of dopaminergic neurons in the substantia nigra and cholinergic deficits
- Levodopa is the gold standard
- Acetylcholine antagonists (first line therapy): Benzotropin (Cogentin); Trihexyphenidyl (Artane); Amantadine (Symmetrel); Selegine (Eldepryl): MAOI
- Dopamine agonists added: pramipexole, ropinirole, pergolide
Side Effects of Anti-Cholinergic anti-Parkinsons Drugs
- Tachycardia
- Confusion
- Agitation
- Constipation
- Urinary Retention
- Blurred Vision
- Dry mouth; Dry skin
**Tolcapone (Tasmar) and Entacapone (Comtan); Catechol-)-methyl (COMT) enzyme inhibitors help reduce levodopa drug induced dyskinesias
