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Amine
Hypothesis
Depression is caused by a functional in activity of the CNS amine neurotransmitters NE, serotonin, and
DA.
Amine
Hypothesis
Problems
Neurotrophic
Hypothesis
Antidepressant drugs cause changes in amine activity within hours, but weeks may be required to achieve
clinical effects
At least one antidepressant, Bupropion, has minimal effects on brain NE or 5-HT
Brain-derived neurotrophic factor (BDNF)
Depression is associated with the loss of neurotrophic support.
Antidepressants increase neurogenesis and synaptic connectivity
Changes in trophic factors (especially brain-derived neurotrophic factor, BDNF) and
hormones appear to play a major role in the development of major depression
(A). Successful treatment results in changes in these factors
(B). CREB, cAMP response element-binding (protein).
BDNF, brain-derived neurotrophic factor.
Neuroendocrin
e
Factors
Cortisol levels
Corticotropin-releasing Hormone
Dexamethasone suppression test
25% depressed pts have abnormal thyroid function
Estrogen
Testosterone
Tricyclics
TCAs
Amitriptyline
Classification
Tricyclics
Heterocyclics
Selective serotonin reuptake inhibitors
Serotonin-norepinephrine reuptake inhibitors
5HT2 antagonists
Monoamine oxidase inhibitors
SE:
Sedation (Antihistamine
Actn)
Fatigue
Confusion
Muscarinic Rc Blockade
Orthostatic hTN (Alpha
Block)
Seizure Threshold
Sympathomimetic Effects
- Tachycardia
- Agitation
- Sweating
- Insomnia
Atropine-like Effects
Cardiomyopathy (EtOH)
Heterocyclics
Amoxapine
Tremor
Paresthesia
Weight Gain
Antipsychotic &
Antidepress
Properties
Dopamine Antagonism
Akathisia
Parkinsonism
AmenorrheaGalactorrhea Syndrome
Autonomic Effects
Nicotine Withdrawal
Dizziness
Seizures
Psychosis Aggravation
Low Incidence Sexual SE
Sometimes in Unrspnsve
TCA
SE:
Sedation
Less Antimuscaric Than
TCA
Less CV Effects
Cardiotoxicity
Conduction/Arrhythmi
a
Circulatory Collapse
Respiratory
Depression
Hyperpyrexia
Formerly Called
2nd/3rd
Generation
Antidepress
Like Phenothiazine
Buproprion
Unknown
Structurally Like
Amphetamine
CNS Activating Effects
Maprotiline
Inhibit NE Reuptake
Seizure in Overdose
Autonomic Effects
Mirtazapine
Presynaptic Alpha 2 Rc
Antagonism
Sedative Effects
Autonomic Effects
5HT2
Antagonist
Trazadone
5HT2 Rc Antagonist
Nefazodone
SE:
Priapism
Interactions:
Inhibits p450
Inhibit Metabolism of:
- Alprazolam
- Triazolam
SNRIs
Venlafaxine
Desvenlafaxine
Duloxetine
Milnacipran
Serotonin-Norepi Reuptake
Inhibitor
SSRIs
Selectively Inhibit
Serotonin
Transporters/ Reuptake of
the
Nerve-Ending Membrane
Depression
Chronic Pain
Endogenous Depression
- DOC
Panic Attack
OCD
Bulimia
PMS
EtOH Dependence
Lack Potent
Antihisatmine,
-Adrenergic Blocking,
Anticholinergic Effects of
TCA
SE:
Withdrawal Reaction
Interactions:
Venlafaxamine Inhibits
Halperidol Metabolism
CNS Stimulating, Not
Sedating
Minimal Atropine-Like
Effects
Minimal CV Effects
SE:
HA
Nausea
Anxiety
Agitation
Insomnia
Libido
Retarded Ejaculation
Seizures from Overdose
Extrapyramidal Effect
Early Tx
- Akathisia
- Dyskinesia
- Dystonic Rxns
Withdrawal Syndrome
- Nausea
- Dizziness
- Anxiety
- Tremor
- Palpitations
Bleed Risk
- Platelet 5HT Uptake
Non-Vertebral Fracture
Risk
- Older Females
Hepatic Metabolism
Interactions:
Inhibit p450=
Potentiate:
- TCAs
- Warfarin
Less Interactions w/
Citalopram
Serotonin
Syndrome
When Combo
w/Drugs
Serotonergic
Function
- MOAIs
- Triptans
- TCAs
- Meperidine
Muscle Rigidity
Myoclonus
Hyperthermia
CV Instability
Seizures
Wet Dog Shakes
Tx:
Seizure Control
Muscle Relaxants
Cyproheptadine
Fluoxetine
Bulimia
Paroxetine
Citalopram
Escitalopram
Fluvoxamine
MAOIs
Category D
- Fetal Cardiac
Malformations
Prolong QT
OCD ONLY
Atypical Depression
Phenelzine
Tranylcypromin
e
Isocarboxazide
Significant:
- Anxiety
- Phobia
- Hypochondriasis
Structure Like
Amphetamine
Selegliline
Emsam
Active Metabolite w/
7-9 day Half-Life
Once Daily Dosing
No Need to Taper
MAO-B Inhibitor
SE:
BP First THEN BP
CNS Stimulation
Serotonin Syndrome
Interactions:
Many 2/2 P450 Inhibition
HTN Crisis w/ Indirect
Sympathomimetics
- Tyramine
Fastest Onset
Shortest HL
Transdermal Patch
- Once Daily
Serotonin
Schizophre
nia
Hypothesis
Dopamine
Dopamine
Schizophre
nia
Hypothesis
Dopamine is a major CNS neurotransmitter that binds to five types of dopamine receptors.
D1 and D5 receptors activate adenylyl cyclase and thereby cAMP levels.
D2, D3, and D4 receptors inhibit adenylyl cyclase and cAMP levels
Plays a significant role in behavioral and drug reinforcement
Regulates emesis (vomiting), prolactin release, mood states, motor coordination, and olfaction.
Degradation results in the formation of homovanillic acid (HVA), a metabolite that is subsequently excreted
in the urine.
Glutamate
Schizophrenia
Hypothesis
Positive Symptoms
Excessive DA activity in
mesolimbic neuronal
pathways
Agitation
Delusions
Disorganized Speech
Disorganized Thought
Hallucinations
Insomnia
Dopamine D2 receptor
blockers
alleviate the positive
symptoms
Phenothiazines
Chlorpromazi
ne
Thioridazine
Negative Symptoms
Insufficient DA activity in
cortical &
hippocampal neuronal
pathways.
Apathy (avolition)
Affective flattening
Lack of motivation
Lack of pleasure
(anhedonia)
Poverty of speech (alogia)
Social isolation
Serotonin 5-HT2A Rc
blockers
alleviate the negative
symptoms
Thioxanthenes
Aliphatic Derivative
Thiothixene
Prototypical
Butyrophenon
es
Haloperidol
Protoypical
Piperidine
Slightly Less Potent Than Phenothiazines
These Agents More Potent & Fewer SE but
Derivative
More Extrapyramidal SE
- Retinal Deposit SE
Perphenazine Piperazine
Derivative
- Most Potent
Highly lipid soluble
Highly protein
Pharmacokinetics Significant first pass metabolism
Metabolized in the liver to inactive metabolites
bound
Renal excretion of inactive polar metabolites
Large volume of distribution
Long duration of action when compared to plasma HL
Antipsychotic activity produced (at least in part) by dopaminergic blockade in the mesolimbic and
Pharmacological
mesofrontal systems
Effects
Parkinsonian effects are produced by dopamine antagonism in the nigro-striatal system
Hyperprolactinemia caused by blockade of dopamines tonic inhibitory effect on prolactin release from the
pituitary
Changes in eating behavior caused by dopamine blockade in the medullary-periventricular pathway
Psychologic effects Nonpsychotic pts, neuroleptics cause combo of sleepiness, restlessness, and
autonomic effects
May precipitate seizures
Amenorrhea-galactorrhea, decreased libido, gynecomastia,
Orthostatic hTN more likely with low potency drugs such as Chlorpromazine
Atypical Antipsychotics
2nd Generation
Clozapine
Tx Failure ONLY
Clozaril
Olanzapine
Zyprexa
Risperidone
Risperdal
Asenapine
Saphris
Quetiapine
Seroquel
Sig QT Prolongation
Ziprasidone
Geodon
Aripiprazole
Abilify
Lurasidone
Latuda
Paliperidone
Invega
Iloperidone
Fanapt
Indications:
Typical & Atypical
Sedation
Toxicity
Schizophrenia
Schizoaffective disorder
Mania
Tourettes
Extrapyramidal
Dose Dependent
Tardive Dyskinesia
- Choreoathetoid Movements of Lips and Buccal Cavity
- Late Onset
Alzheimer's
Psychotic depression
Poikilothermy
Neuroleptic Malignant Syndrome:
- Hyper-thermia
- Muscle rigidity
- Impairment of sweating
- Autonomic instability
- Leukocytosis
Antiemetic
- Worse w/ Antimuscarinics
Muscarinic Blockade
- Atropine-like Effect
Lithium
Alternative
Bipolar
Drugs
Carbamazepine
Clonazepam
Olanzapine
SE:
Tremor
Sedation
Ataxia
Aphasia
Thyroid Enlargement
Nephrogenic DI
Edema
Acne
Leukocytosis
Congenital Cardiac
Anomolies
Contra:
Nursing Mothers
Interactions:
Thiazides Renal Clearance
25%
- Dose Needs Reduction
NSAIDs Also Clearance
Extrapyramidal Sx w/
Antipsychotics
Valproic Acid
Aripiprazole Abilify
Lamotrigine - Lamictal