drug induced depression
reserpine, methyldopa, propranolol, metoprolol, prazosin, clonidine, digitalis, alcohol, benzos, barbituates, meprobamate, indomethacin, phenylbutazone, opiates, pentazocine, corticosteroids, OCs, estrogen withdrawal, anti-parkinson, anti-neoplastic, neuroleptics
neuroendocrine hypothesis of depression
changes in hypothalamic-pituitar-adrenal axis
stress causes release of CRF, CRF promotes release of ACTH from pituitary, ACTH promotes release of cortisol from adrenal
overactivity of HPA desensitizes feedback response in hypothalamus and pituitary
elevated CRF causes insomnia, anxiety, dec appetite and libido
neurotrophic hypothesis of depression
brain-derived neurotrophic factor (BDNF) is critical in neural plasticity, resilience, neurogenesis
stress and pain decrease BDNF levels
BDNF has antidepressant activity
neuroadaptive response
antidepressants cause the amount of NT in the intrasynaptic space to increase
delay of effect due to… activation of presynaptic receptors? presynaptic adaptation? postsynaptic adaptation?
MAOIs MOA
MAO-A degrades NE and 5HT, inhibiting MAO increases the amount of NE and 5HT, more NE and 5HT released from vesicles into the synapse
MAOIs
tranylcypromine, isocarboxazid, phenelzine, selegiline
SE: HA, drowsiness, dry mouth, weight gain, orthostatic hypotension, sexual dysfunction
Generally restricted to 3rd or 4th line use after failure of trials of newer agents and polypharmacy
Avoid drugs that contribute to hypertensive crisis risk or serotonin syndrome: decongestants, dextromethorphan, amphetamines, methylphenidate, linezolid, meperidine, other antidepressants, cyclobenzaprine, asthma inhalers
Tyramine diet required to avoid hypertensive crisis: Avoid smoked, aged, pickled meat or fish, sauerkraut, aged cheeses, yeast extracts, fava beans, beer/wine
TCAs
indications: depression, panic disorder, chronic pain, enuresis
3rd line
overdose/toxicity: exremely dangerous, depressed patients are more likely to be suicidal
tertiary amines
third line; TCA
imipramine, amitriptyline (metabolized to secondary amines - more selective for NE), trimipramine, clomipramine, doxepin
inhibit both NE and 5HT via NET and SERT, also antagonize antihistamine
sedation, weight gain, autonomic SE
secondary amines
TCA - secoNdary (NET)
desipramine, nortriptyline, protriptyline, maprotiline
SE: less sedation, less anticholenergic, less autonomic, less weight gain, less CV than tertiary
SSRI MOA
increased 5HT in synapse, stays in synapse longer and remains active longer
SSRIs
fluoxetive, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram
uses: depression, alcoholism, OCD, enuresis, PTSD, eating disorders, social phobias, panic anxiety, PMDD, GAD
SE: NV, HA, sexual dysfunction, anxiety, insomnia, tremor
SSRI discontinuation syndrome: “brain zaps”, dizziness, sweating, nausea, insomnia, tremor, confusion, vertigo
P450 interactions for fluoxetine, paroxetine, fluvoxamine
Onset of action in 1-2 weeks -> 4-6 weeks until benefit can be seen
serotonin syndrome
Clinically considered a drug interaction between 2 or more serotonergic drugs
Similar symptoms to neuroleptic malignant syndrome
Symptoms include: diarrhea, mental status changes, hyperpyrexia, anxiety/confusion, myoclonus/tremor, diaphoresis, agitation, labile blood pressure, tachycardia, restlessness
Associated with: amphetamines, fentanyl, buspirone, linezolid, cocaine, lithium, tramadol**, dextromethorphan, LSD, serotonergic antidepressants
Treatment includes: d/c offending agent, supportive care, serotonin blockers
SSRI + 5HT1A partial agonists
vialzodone
vortioxetine
bupropion inhibits…
DAT, NET, SERT
SNRIs
venlafaxine
desvenlafaxine
duloxetine - treats GAD and diabetic neuropathy
milnacipran - approved for fibromyalgia
levomilnacipran
Class side effects similar to SSRIs, addition of increased blood pressure d/t norepinephrine effects
Can also be used for pain syndrome, musculoskeletal pain, fibromyalgia, neuropathic pain
non-pharm considerations
Vagus Nerve Stimulation and Transcranial Magnetic Stimulation; VNS: first approved for epilepsy; most studies show no benefit over placebo; FDA-approved; TMS: pulsing magnetic fields stimulating left front cortex; studies don’t show robust response
electroconvulsive therapy
Advantages: efficacy in treatment resistance, can continue drug therapy, age is not a factor, safe in pregnancy; Disadvantages: temporary memory loss, stigma; Contraindicated: recent MI or stroke; or if loose teeth
psychotherapy
hospitalization
etiology
Depressed mood OR loss of interest or pleasure in previously pleasurable activities for > 2 weeks plus at least 4 of the following for > 2 weeks: Suicidal ideation, insomnia, guilt, energy loss, concentration difficulties, appetite (weight gain/loss), psychomotor agitation
risk factors
female gender, lack of social support, stressful life or events, prior episodes or suicide attempts, co-morbid medical disorder, co-morbid substance use/abuse
TCAs
amitriptyline, nortriptyline
Use for neuropathic pain syndromes more often than for depression
Side effects often limit the higher doses needed for the treatment of depression
Plasma concentrations can be done, but not often routinely
Can be fatal in overdose with death due to cardiac arrhythmia
novel antidepressants
Bupropion, Mirtazpine, Trazodone, Vilazodone, Vortioxetine
bupropion
dopamine/NE reuptake inhibitor: negligible effects on serotonin
Contraindicated in active seizure disorder or eating disorders
2D6 inhibitor
Stimulating antidepressant
mirtazapine
clinically used for sedation and weight gain
No significant P450 interactions
Can be used in combination with SSRI/SNRI antidepressants
trazodone
Very sedating drug, used clinically more often for insomnia Higher doses required for depression, but not tolerated due to sedation Priapism risk (painful and extended erection): medical emergency – counsel patients about this, especially in doses over 150mg/day
vilazodone
Primary mechanism of efficacy is SSRI
**Counsel patients to take with food, as it causes significant nausea (reason for initial titration)
AEs: insomnia, diarrhea, nausea
