Antidepressants, Antipsychotics, and Antimanic Medications

Terms in this set (52)

Patho:
monamine hypothesis- repletion of monamine neurotransmitters lead to symptom resolution
chronic stress- leads to secretion of glucocorticoids which delete neurons of brain-derived neurotrophic factor, which leads to decrease in neurogenesis in the hippocampus
depression is heritable
environmental stress (life stressors)- death of a family member

Symptoms:
characterized by sign changes in behavior, physical functioning, cognition leading to the inability to function
sadness and despair
mental slowing
loss of concentration
weight gain or loss
dec energy
inability to feel pleasure
agitation

Depression
Tx, Assessment and expectations

Tx:
inc the amount of neurotransmitter available at the synaptic cleft
dec the rate at which the neurotransmitter is taken back up into presynaptic neuron
inhibiting the neurotransmitter's metabolic degradation

Assessment and Expectations:
weekly or biweekly for at least 8 wks
adherence, medication tolerability and effectiveness
week 1: sleep, appetite disturbances and executive functioning should improve
week 3: positive changes in memory, energy and self-care
week 4 or greater: depressed mood and suicidality will begin to decrease

Guidelines for Tx of Depression
Acute phase

Treatment choice
mild-moderate: pharmacotherapy, psychotherapy or combo
severe: pharmacotherapy with or without psychotherapy
pts with psychotic features: antidepressant and antipsychotic or ECT

Goals: complete remission of depressive symptoms

Choice of initial tx
pt preference, prior response, safety, tolerability, comorbid disorders, potential drug interactions, pharmacokinetics and cost
no agent has shown superiority
tricyclics and MAOIs usually reserved for refractory cases bc of tolerability issues and lower safety profile in overdose situations
monotherapy is generally recommended

Guidelines for Tx of Depression
Continuation Phase and Maintenance Phase

Continuation Phase
once clinically sig improvement, continue therapy for 4-9 months to prevent relapse
risk of relapse without continuations is about 85%- potential causes: dose reduction, dec adherence, drug interactions, psychosocial stressors

Maintenance Phase
pts with chronic depressive symptoms or hx of > 3 depressive episodes

Tx for Depression

tricyclic antidepressants
SSRI
MAOI
Others:
Bupropion (Wellbutrin)
Mirtazapine (Remeron)
Trazodone (Desyrel)
Venifaxine (Effexor)
Desveniafaxine (Pristiq)
Duloxetine (Cymbalta)
Vilazodone (Vilbryd)

Tricyclic Antidepressants (TCA)
MOA, Agents

MOA:
non-selective inhibition of norepinephrine (NE) and serotonin (5-HT) reuptake
tertiary amines are frequently metabolized to secondary amines that are active and genreally more potent for NE reuptake
Other receptor effects: a1 adrenderic blockade, antihistamine, anticholinergic, sodium channel blockade

Agents
Tertiary amines:
Amitriptyline (Elavil)
Clomipramine (Anafranil)
Doxepin (Sinequan)
Imipramine (Tofranil)
Trimipramine (Surmontil)

Secondary amines:
Desipramine (Norpramine)
Nortriptyline (Pamelor)
Protriptyline (Pamelor)

Were the first class of antidepressant meds available, however, side effects have limited their use

TCA
Availability, Withdrawal

Rapidly absorbed after oral admin
bioavailablity is variable (30-70%)
widely distributed (large Vd)- higher concentrations in the CNS and cardiac tissues
extensively bound to plasma proteins (>90%)
primarily metabolized through the liver

a withdrawl syndrome that includes GI complaints, dizziness, insomnia, and restlessness occurs if these agents are DC bvaqtoo quickly- gradual dose reductions of 25-50 mg/day per week helps reduce these symptoms

therapeutic plasma concentration monitoring available- usually used in overdose situations

SSRI
MOA, Agents

MAO- preferentially inhibits the reuptake of serotonin by selectively blocking presynaptic neuron receptors responsible for the reuptake of serotonin back into the neuron

Agents-
Fluoxetine (Prozac, Prozac weekly)
Paroxetine (Paxil, Paxil CR)
Sertraline (Zoloft)
Fluvoxamine (Luvox)
Citalopram (Celexa)
Escitalopram (Lexapro)

The efficacy of the different SSRIs is not that different
It appears that some pts may respond to one but not another SSRI

SSRI
Availability, Interactions

Good oral bioavailability
highly protein bound (94-99%)
widely distributed
extensively metabolized by the liver through CYP450

Interactions
MAOIs
Linezolid (has MAOI inhibition)

Wait 5 wks after stopping SSRI before starting a MAOI
Wait 2 wks after stopping a MAOI before starting a SSRI

SSRI AE

GI- N/V/D- inc risk of GI hemorrhage, esp with asprin, NSAIDs and anticoagulants
sexual dysfunction- this class has highest %
weight gain - paroxetine > all others
cardio (bradycardia)- QT prolongation with citalopram (max dose 40mg/day)
hyponatremia (Na < 135)
weithdrawal syndrome- manifested by GI complaints, flu-like symptoms, anxiety and insomnia. most notable with paroxetine. restart medication and gradually taper
dec bone mineral density with prolonged exposure

incidence of orthostatic hypotension, sedation, anticholinergic SE, and cardio effects are significantly less than TCAs

Serotonin syndrome

central excitatory syndrome related to excess serotonin
manifested as confusion, restlessness, autonmic dysregulation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, and diarrhea
tx includes stopping the offending agent and supportive care

Non-antidepressant medication with associated serotonin syndrome

antiemetics (metoclopramide, ondansetron, granisetron)
dextromethorphan
fentanyl
meperidine
ritonavir
serotonin 1D agonists (sumatriptan and others)
tramadol
valproic acid

SSRI vs TCA

equally effective
SSRI have fewer SE
SSRI are safer

Vilazodone (Viibryd)

MOA- serotonin reuptake inhibitor and partial 5-HT1a agonists
oral formula only
pharmacokinetics- hepatically metabolized through CYP450, 3A4 (major), 2D6, and 2C19 )minor)
sign AE- LESS sexual dysfunction than SSRI

MAOI

MAO- irreversible inhibition of the intercellular enxyme monoamine oxidase- responsible for metabolism of NE, 5-HT, and dopamine within the neuronal synapses

Agents- Tranycypromine (Pamate), Selegiline (Esam) transdermal, Phenelzine (Nardil), Isocarboxazid (Marplan)
Due to potentially serious AD, generally NOT used as first line therapy

AE- hypotension, hypertensive crisis, sedation with pheneizine, insominia with tranycypromine, weight gain (less with selegiline)

sing drug interactions- TCAs, SSRI, Sympathomimetics
drug food interactions- tyramine content (aged cheeses, yeast extract, wine esp chianti and sherry)

Bupropion (Wellbutrin)

MOA- potent blockade of dopamine and norepinephrine reuptake
Oral formulation (immediate or sustained release)
also used in the mngmnt of smoking cessation
pharmacokinetics- hepatically metabolized though CYP450 to three active metabolites. active metabolites excreted unchanged by the kidney
AE- seizure (associated with high doses and abrupt withdrawal)

Mirtazepine (Remeron)

MOA- blockade of 5-HT2 and 5-HT3 receptors
oral formulation only
pharmacokinetics- hepatically metabolized through CYP450
AE- less sedation, weight gain (higher than other options), low incidence of sexual dysfunction

Triazolopyridines

Trazodone (Desyrel)
Nefazodone (Serzone)
MOA- blocks 5-HT2 receptor and 5-HT reuptake inhibitor
Pharmacokinetics- hepatically metabolized through CYP450 to active metabolized
AE- sedation (more with trazadone), hypotension, weight gain (less with nefazodone), sexual dysfunction, nefazodone: hepatic toxicity

Norepinephrine/Serotonin Reuptake Inhibitors

Available Agents (all oral)
Venlafaxine (Effexor)- immediate and extended release
Desvenlafaxine (Pristiq)
Duloxetine (Cymbalta)
Milnacipran (Savella)

MOA- as the dose inc more profound effect on norepinephrine. Desvenlafaxine is active metabolite of veniafaxine
Pharmacokinetics- hepatically metabolized through CYP450 to an active metabolite
AE- HTN, sexual dysfunction, drowsiness, GI distress

Black Box Warning for All Antidepressants

associated with an inc risk of suicidal thinking and behaviors

impt to monitor pts for failure to respond or worsening sympt of depression when these drugs are started or the dose is inc

Second-Generation Antipsychotics (SGA) in Combination with Antidepressants

Indicated for major depressive disorder with psychotic features

uses in nonpsychotic depression
antidepressant actions of SGA- serotonin 2A receptor antagonism, 1A receptor agonists, indirect effect on norepinephrine transmission
FDA labeling- Aripiprazole and ER Quetiapine
Risperidone and Olanzapine may be effective
may reduce the acute severity of depression
pts more liekly to dc therapy secondary to adverse effects- sedation, akathisia, and weight gain

Augmentation Strategies
SGA with AD

Add treatment- Buspirone, Triiodothyroinine, Lithium
Add antidepressant with a diff MOA- Buproprion, Mirtazapine
No data to support combining agents with same MOA

Schizophrenia

heterogeneous syndrome
disorganized and bizarre thoughts
delusions
hallucinations
inappropriate affect
impaired psychosocial functioning

typical onset late adolescence, early adulthood

Schizophrenia Positive Symptoms

delusions
hallucinations
disorganized speech
unusual behavior

Schizophrenia Negative Symptoms

blunted affect
lack of motivation and pleasure
poverty of speech

Schizophrenia Neurotransmitters

dopamine receptor defect-
dopamine hyperactivity (caudate nucleus)- positive symptoms
dopamine hypoactivity (frontotemporal regions)- negative symptoms and cognitive dysfunction

serotonin receptors-
present on dopaminergic axons
higher 5HT concentrations found in schizophrenics

Antipsychotic Drugs

MOA-
Dopamine (D2) receptor blockers inhibit the release of DA and thereby alleviate the positive symptoms of schizophrenia
Serotonin (5HT2) receptor blockers inc the release of DA and thereby alleviate the neg symptoms of schizophrenia

Clinical implications of blockade of various receptors:
Dopaminergic- emotions (pos sympt), thinking/memory, movements
Serotonergic- mood stabalization, weight gain

Typical drugs:
D2 >> 5HT2
pos sympt gen respond well
neg symp generally DONT respond well
Phenothiazines, Thiozanthenes, Butyrophenones

Atypical Drugs:
5HT2 >> D2
efficacy against both pos and neg sympt
Azepines, Others

Antipsychotic Drugs AE

Dopaminergic blockade-
parkinsonism: bradykinesia, rigidity, tremor
akathisia: somatic restlessness and inability to stay still
tardive dyskinesia: usually seen after 6mo of tx

alpha receptor antagonism- a1 blockage- hypotension

cardiovascular- direct cardiac depression, prolongation of QT

neurologic effects- seizures, sedation
anticholinergic effects- dry mouth, urinary retention, constipation
weight gain
impaired glucose tolerance
sexual dysfunction
clear risk of DM in pts treated with ATYPICAL antipsychotics (although data is conflicting, clozapine and olanxapine may have higher risk), monitor serum glucose

Bipolar Disorder Tx

Lithium
anticonvulsants
antipsychotics
benzodiazepines

Lithium

MOA- dec the reuptake of serotonin and norepinephrine

Pharmacokinetcs- rapid absorption, extensively cleared unchanged through the kidneys

Therapeutic level .4-1 mEq/L
Narrow range between therapeutic and toxic levels
frequent need for blood levels

contraindications- renal insufficiency, dehydration, sodium depletion

sign drug interactions- NSAIDs, ACEI and ARBs, Diuretics

AE- tremor, cognitive effects, hypothyroidism, weight gain, seizures

Selected Drugs that may precipitate Delirium

Sedative/Hypnotics- Benzos, Barbiturates, Alcohol
Antidepressants- TCAs, SSRIs (less common)
Anticholinergic Agents- Diphenhydramine, Atropine, Scopolamine
Opiates- especially meperidine
Anticonvulsants
Antiparkinsonian agents
Histamine-2 receptor blockers
Digoxin
Corticosteroids
Lithium

Legal and Illegal Drug Induced Delirium

Ethanol
Marajuana
Lysergic acid diethylamide
Amphetamines
Cocaine
Heroin
Phencyclidine

Tx of Delirium

Benzodiazepines
ineffective when used alone for general causes of delirium
may exacerbate delirium
may be effective in certain types of delirium (alcohol or benzo withdrawal)

Alzheimer's Dx
Epidemiology and Patho

Currently affects an estimated 4.5 million Americans
the most common form of dementia
Primary risk factors are age and family hx
cerebral atrophy
three histophathologic hallmarks that can impair neurotransmitter function and lead to memory deficits- Beta-amyloid-rich senile plaques, neuofibriliary tangles, neuronal degeneration

Alzheimer's Dx
Goals of Therapy

improve QOL
improve or slow the loss of memory and cognition
maintain and maximize independent function
minimize adverse effects of drug therapy

Alzheimer's Dx
Medications to Treat

Cholinesterase inhibitors-
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Razadyne)

NMDA Receptor antagonist-
Memantine (Namenda)

Cholinesterase Inhibitors

selectively inhibit cholinesterase in the CNS and inc acetylcholine levels in the cerebral cortex

these agents may slow deterioration of cognitive function, but they do NOT affects the underlying neurodegenerative process

AE- bradycardia, N/V/D, hepatotoxicity (tacrine, rivastigmine), GI bleeding

Sig Drug Interactions- anticholinergic drugs will inhibit the effects

Memantine

noncompetitive antagonist at the NMDA receptor
attenuates the excitotoxic effects of glutamate
AE- constipation, insomnia, HA, over excitation

Other Alzheimer's Therapies

Vitamin E- may be considered to slow decline
Insufficient evidence to use other antioxidants or other anti-inflammatory agents
use of atypical antipsychotics for psychosis and agitation remains controversial- short term use may be considered for individual situations

Parkinson's Dx
Epidemiology

Affects 160/100,000 people
onset is usually between the ages of 40 and 70
slightly more common in men

Parkinson's Dx
Signs and Symptoms, Goals of Therapy

Cardinal signs- akinesia or hypokinesia, rigidity, tremor, posture or gait abnormalities
secondary signs- cognitive function, autonomic dysfunction, speech disturbances

goals of therapy-
improve symptoms and QOL
slow dx progression
max drug therapy and min AE

Parkinson's Dx
Medications

Dopaminergic agents-
Leovodopa (L-DOPA)
Carbidopa/Levidopa (Sinemet)
Amantadine (Symmetrel)

MOA-B Inhibitors- Selegiline (Eldepryl)

COMT Inhibitors-
Tolcapone (Tasmar)
Entacopone (Comtan)

Dopamine receptor agonists-
Bromocriptine (Pariodel)
Pramipexole (Mirapex)
Ropinirole (Requip)
Apomorphine (Apokyn)

Acetylcholine receptor antagonists-
Benztropine (Cogentin)
Trihexyphenidyl (Artane)

Levodopa

MOA-biosynthetic precursor of dopamine
inc the conc of dopamine in the brain
Metabolized-peripheral tissue by two enzymes (Decarboxalase, COMT)
Large first pass metabolism- 1% of administered drug reached the brain
AE-dose related. N/V, orthostatic hypotention, depression, delirium, paranoia, delusions, hallucination
(CNS effects associated with long term use)

Carbidopa/Levodopa

Carbidopa inhibits the conversion of levodopa in peripheral tissues through inhibition of decarboxalase
inc amt of levodopa that enters the brain
dec GI and CV adverse effects because less levodopa in the peripheral tissue
wearing off phenomenon- loss of efficacy over time (proven effective for 2-5 yrs) or fluctuation in responses to the medication occurs. when this happens levodopa is needed in higher doses

Amantadine

MOA-inc the release of dopamine from neurons in the brain. inhibits the reuptake of dopamine by neurons
AE-confusion, hallucinations, insomnia, nightmares, peripheral edema

Selegiline

MOA- irreversibly inhibits MAO-B which degrades dopamine.
neuroprotective (blocks formation of free radicals released with dopamine degradation that contribute to neuronal degeneration)
AE-nausea, dizziness, orthostatic hypotension, hallucination, insomnia

Tolcaprone

MOA- inhibits peripheral metabolism of levodopa through inhibition of COMT
Used to enhance the effectiveness of levodopa
AE-hepatotoxicity, orthostatic hypotension, diarrhea, hallucinations

Entacapone

no reports of hepatotoxicity

Dopamine Receptor Agonists

MOA-directly activate the dopamine receptors (D2) in the brain
Agents- Bromocriptine, Pramipexole, Ropinirole, Apomorphine SC
AE-nausea, hypotension, sedation, hallucinations
Advantages over levodopa therapy-
direct action on receptor (no conversion of dopamine means less free radicals released).
longer half-life (not dosed as often)
Given with or without food (no absorption delay)

Acetylcholine Receptor Antagonists

MOA-help reduce tremor more than other manifestations of the dx. may also inhibit the uptake of dopamine into the neutron of the brain
Agents- Benxtropine, Trihexyphenidyl
AE-sedation, depression, confusion, dry mouth, blurred vision, constipation, urinary retention

Depression Treatment Approach

interview thoroughly to obtain complete medical, family, and psych hx, including previous hospitalization and suicide attempts
obtain list of current meds (prescription, herbal, dietary, OTC, previous and current psychotropic medication an response to each)
physical exam to rule out medical causes (CBC, serum chemistries, thyroid)
psychiatric eval
target symptoms and goals of therapy
safety plan: appropriate intervention for suicidal ideation or behaviors

TCA
AE,

AE
Antihistamine- sedation, weakness, fatigue
anticholinergic- dry mouth, blurred vision, constipation, urinary retention (red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare)
a1 blocking- hypotension
sodium channel blockade- arrhythmias
sexual dysfuncion, seizure potential, weight gain, rash, photosensitivity, hepatotoxicity

Sign drug interactions
MAOI- inc risk for HTN, tachy, confusion, and seizures
alcohol and other CNS depressants- additive effects

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