Antidepressants And Treatment Of Bipolar Disorder Flashcards
Cyproheptadine
Serotonin (5-HT2) antagonist used in emergency maintenance of serotonin syndrome
Side effects: “Atropine-like” side effects - sedation - blurred vision - orthostatic hypotension - urinary retention - tachycardia
5-HT(2) receptor modulators
Trazodone, Nefazodone
Atypical antidepressant:
5-HT(2a), a(1) and H(1) antagonists
- also blocks SERT receptors
Indications:
- major depression (MDD)
- very good with MDD + insomnia patients, but not 1st line due to ADRs*
- anxiety
- hypnotic agent (most common prescribed reason for trazodone)
ADRs:
- extreme sedation
- nausea
- orthostatic hypotension (trazadone only)
- priapism (trazadone only)
- hepatotoxicity (Nefazodone only)
Contraindications:
- liver failure/disease (Nefazodone only)
- use with MAOIs (ALL)
5-HT receptor modulators
Vilazodone and vortioxetine
Atypical antidepressant:
5-HT reputable inhibitors (SERT)
5-HT(1a) agonists (vortioxetine > vilazodone)
5-HT(3a) antagonists (vortioxetine only)
Indications:
- MDD
- anxiety
ADRs:
- weight gain (vilazodone only)
- sleep disturbances (vortioxetine only)
- sexual dysfunction (vortioxetine only)
- nausea
- anticholinergic effects
- *serotonin syndrome (if combined with other serotonergic drugs)
Contraindications:
- use with MAOIs (BOTH)
Mirtazapine
Atypical antidepressant
- 5-HT(2/3a) antagonist
- H1- antagonist
- a2 antagonist
Indications
- refractory MDD
- first line in patients with insomnia and MDD due to more favorable ADR profile*
ADRs:
- extreme sedation
- increased appetite and weight gain (most reported)
- reduced nausea and vomiting
- dry mouth
- somnolence
- Very rare agranulocytosis (more rare than clozapine)
Bupropion
Blocks NET and DAT
(NE and dopamine reuptake receptors)
- increases levels of NE and dopamine in presynaptic cleft
- *also blocks nicotinic receptors
Indications:
- MDD
- prophylaxis for seasonal depressive disorder
- smoking cessation*
- ADHD
- neuropathic pain and weight loss (off-label)
ADRs:
- anxiety
- mild tachycardia
- HTN
- irritability
- tremors
- anticholinergic effects
- *increases odds of seizures (especially in bulemic/ anorexia patients)
Contraindications:
- patients who have seizures and general bulimic or anorexia patients (regardless of whether they have had seizures or not)
while not contraindicated, should use hesitantly with SSRIs due to possible DDIs
MDD epidemiology
17% lifetime prevalence in the US
- women are more likely, but not by much
- increases risk of coronary artery disease, diabetes and stroke
MDD decreases quality of life and prognosis of another illness if both are present
Antidepressant possible indications
MDD
Panic disorder
Generalized anxiety disorder
PTSD
Obsessive-compulsive disorder
Neuropathic pain
Fibromyalgia
Urinary symptoms
General principles of treatment with antidepressants
before beginning therapy, rule out drug induced or medical causes of depression.
most antidepressants have similar efficacy, therefore patient factors and ADR profile is generally what is looked at for treatment choice
Goals of treatment: (remission)
1) acute phase
- resolution of current symptoms
- 6-12 weeks
2) continuation phase (prevent relapse)
- elimination of residual symptoms
- 4-9 months
3) maintenance phase (prevent recurrence)
- stopping another depressive episode
- 12-36 months
- may be lifetime
What is the #1 risk with taking antidepressants?
All antidepressants carry increased risk of suicidal behavior
- especially in adolescences
Generally, what antidepressants are used the most?
SSRIs and SNRIs
Mirtazapine
Bupropion
Monoamine hypothesis
Is a hypothesis associated behind the pathophysiology behind MDD
A deficiency in monoamine signaling in the cortical-limbic regions
- reserpine use in antipsychotic cases causes depression as a symptom (reserpine depletes monoamine neurotransmitters)
- antidepressants increases levels of monoamines
Glutamatergic hypothesis
Is a hypothesis associated behind the pathophysiology behind MDD
A deficiency in glutamine signaling in the cortical-limbic regions
- esketamine (NMDAR antagonist) is very good at treating depression (bad ADRs thou)
How long does it usually take for antidepressant action to take place?
Full antidepressant effects usually take 4-6 weeks or longer.
This often caused due to paradoxical mechanisms involving autoreceptors
- 5-HT(1a/b) and a2-adrenergic
- treatment acutely ACTIVATES these autoreceptors, reducing levels of these amines
- *hypothesized to potentially be the cause of increased suicidal ideology when on antidepressants
chronic treatment down regulates inhibitory autoreceptors (due to habituation), so as long as the patient can adhere, the treatment usually works after 6 weeks
General differences between typical and antidepressants
Typical
- increase monoamine levels by inhibiting uptake or degradation of monoamines
Atypical
- increase monoamine levels by either inhibiting reuptake of monoamines or targeting the receptors themselves as agonists/antagonists
SSRIs
Fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram, citalopram
Target only the SERT receptors
- causes excessive stimulation of 5-HT receptors
Take 4-8 weeks usually to show improvement
Become prominent in the 1980s and are now the first line therapy for MDD
Relatively tolerable and cost is low. Also PO and either daily or weekly (fluoxetine only)
Indications:
- anxiety
- PTSD
- OCD
- panic
- PMDD
- bulimia
- Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (super rare)
common ADRs:
- anxiety/nervousness
- insomnia
- nausea
- serotonin syndrome (high levels of coadministration with other serotonergic drugs)
- sexual dysfunction/decreased libido
- emesis
SSRI-specifically ADRs
QT prolongation = citalopram
Anorexia = fluoxetine
Somnolence = fluvoxamine
Anticholinergic effects = paroxetine
Serotonin syndrome
A life-threatening ADR associated with overload of serotonin
Symptoms
- hyperthermia
- hyperreflexia*
- generalized muscle rigidity*
- myoclonus
- tremors
- autonomic instability (sweating/hyperthermia/increases HR/BP/mydriasis*)
- irritability
- agitation
- coma and death (if not treated)
- respiratory failure (if taken with alcohol or benzos)
- usually occur only in coadminstration of other serotonergic drugs or if taking CYP2D6/ 3A4 inhibitors*
How to tell serotonin syndrome from NMS based on symptoms?
SS = hyperreflexia, mydriasis, generalized muscle rigidity
NMS = hyporeflexia, normal pupils, “lead pipe rigidity” (legs and arms specific)
SSRI discontinuation syndrome
most intense for paroxetine due to bioavailability being the lowest
Occurs when SSRI is suddenly discontinued without weening off
Symptoms:
- dizziness
- headache
- nervousness
- Nausea
- insomnia
SNRIs
Venlafaxine, desvenlafaxine, levomilnacipran, Duloxetine, milnacipran
Block both SERT and NET receptors
- causes excessive activation of 5-HT and NE receptors
Indications
- MDD
- anxiety
- diabetic neuropathy
- fibromyalgia (Duloxetine/milnacipran)
- PTSD (venalfaxine)
- OCD (Venalfaxine)
ADRs:
- same as SSRIs
- orthostatic hypotension (Duloxetine only)
- HTN (venlafaxine)
Which SNRI has a serious withdrawal syndrome if stopped abruptly?
Venlafaxine
- lowest bioavailability
Tricyclic antidepressants (TCAs)
Amitriptyline, nortriptyline, imipramine, clomipramine, desipramine,doxepin
Were the 1st gen antidepressants
- not 1st line anymore due to ADR profile
- target Muscarinic receptors, a1 receptors and H1 receptors ontop of SERT and NET
PO once daily
Indications:
- MDD
- peripheral neuropathy
- chronic neuropathy
- migraine prophylaxis
- OCD (clomipramine only)
- nocturnal emesis (imipramine only)
ADRs:
- anticholinergic effects (M1)
- orthostatic hypotension (a1/2)
- sedation/weight gain (H1)
- prolonged QT interval and cardiac events ( #1 cause of death in OD)
- decreased lowered thresholds For seizures (#2 Reason for cause of death in OD)
- generally high chance of causing de novo serotonin syndrome
What cases are TCAs contraindicated?
Bulemia patients
Patients with seizure history’s
WPW patients our patients who are taking other QT elongation medications
Overdose with TCAs
Very common and reason why its not first line any more
Symptoms:
- Lethal arrhythmias (tx = sodium bicarbonate)
- BP changes/AMS and violent convulsions
- lethal respiratory depression (if combined with benzos/alcohol)
Why should you not increase frequency of dosing in patients taking SSRIs or SNRIs unless you must?
Causes stacking effects. Will not cause the desired effect and often will increase suicidal ideology and increase risk for serotonin syndrome.
Could consider increasing after 6-8 weeks on drug, especially if patient is handling the ADRs well so far
- *if swapping drug, should wait until 6-8 weeks (to see if drug actually works)**
- must allow a “wash out” period if switching.
MAOi’s
Tranylcypromnine, phenelzine, isocarboxazid, selegiline
Irereversibly inhibit MAO(a) and (b)
- exception is selegiline (only inhibits MAO(b))
- takes 2 weeks for MAO activity to recover (must wait 2 weeks before starting a different serotonergic drug)
Purpose in depression is to inhibits metabolism of NE and 5HT by inhibiting tyramine precursors
Not first line due to unfavorable ADR profile and increased OD effects as well as difficulty to adhere
Indications
- atypical depression
- anxiety
- Parkinson disease (selegiline only)
ADRs:
- *HTN crisis (especially if ingestion of tyramine containing foods)
- serotonin syndrome
OD symptoms
- seizures
- fever
- psychosis
- hyper adrenergic symptoms
- autonomic stability
What must patients avoid when on MAOIs
Foods containing high amounts of tyramine
Sympthomimetics
Contraindications of MAOIs
Patients taking any of the following
- SSRIs
- TCAs
- St. John’s wort
- meperidine
- dextromethoprim
- linezolid (antibiotic that has off-target effects of a serotonin agonist)
- any of these can cause serotonin syndrome if mixed with MAOIs*
**must wait 2 weeks after last MAOI dose, if needing to put a patient on any of these agents
What should you do if a side effect occurs on a treatment?
Lower dose or different antidepressant
- unless for some reason they cant
Goals of bipolar treatment
1) acute treatment:
- Eliminate mood episode with complete remission of symptoms
2) continuation treatment
- prevent recurrences or relapses of mood episodes
remember that baseline psychosocial functioning is the goal, cant get above it
also make sure to treat comorbid substance abuse/use and avoid stressors that are known to precipitate an acute episode
What group of antipsychotics can be used in treatment of bipolar disorder?
Atypical ONLY
- higher doses = acute mania
- lower doses = depressive episodes
almost never use clozapine unless its refractory mania
What is the worry of using antidepressant in bipolar episodes
Can precipitate manic episodes if not given with a mood-stabilizers
- never give as a monotherapy unless you are sure it is MDD and not bipolar disorder
- to be safe, you should just give with mood stabilizers
Mood stabilizers include what?
Lithium
- all three stages
Valproate
- acute mania and prophylaxis only
Carbamazepine
- acute mania and prophylaxis only
Lamotrigine
- prophylaxis and depression only
all of these are clinical efficacy
** in general, lower doses for depression and prophylaxis, higher doses for acute mania**
What are the three stages for treatment of bipolar?
Acute mania
Bipolar depression
Prophylaxis against recurrent episodes
Lithium ADRs
very pronounced and 80% of patients will show with ADRs
Common:
- headache
- dry mouth
- fatigue
- weight gain/fluid retentions
- derm reactions
GI specific:
- diarrhea
CNS specific:
- transient muscle weakness
- lethargy
- tremor
- sedation
- tremor (toxic levels only)
- ataxia (toxic levels only)
- seizures (toxic levels only)
Thyroid/endocrine specifc:
- hypothyroidism
- hyperparathyrodism
- adenoma
Renal
- nephrogenic diabetes insipidous (most common and 50% show this after treatment)
Cardiac:
- QT elongation
- inverted T waves
Contraindications:
- renal disease/failure
- pregnant patients (ebstein anomaly)
Why is pharmacokinetics of lithium importaint?
It is only eliminated renally (100%)
Can’t use in renal diseased patients or patients using thiazides diuretics, NSAID (aspirin specifically) and ACEIs
- increases odds of OD
caffeine enhances renal excretion of lithium
also shows neurotoxicity more commonly if missed with antipsychotics, Methyldopa, phenytoin and verapamil
Factors the predispose patients to lithium toxicity due to decreased extracellular fluid volume
Sodium restriction diets
Dehydration/vomiting disorders
Being older then 50
Has heart failure or liver cirrhosis
Very active in heavy exercise, saunas or hot weather
- must avoid excessive use of caffeinated beverages and alcohol*
Lithium toxicity symptoms
- Ataxia
- Slurred speech
- coarse tremors
- Confusion
- Convulsions
Treatment:
- monitor with IV fluids and sodium supplements in ER
- gastric lavage is indicated if acute OD
hemodialysis is indicated if any of the following occur:
- 2.5m/L and severe neurologic toxicity acute symptoms (any of the above symptoms with abrupt onset)
- > 4m/L and renally impaired
- > 5 m/L period
- *any concentration where a patient experiences LOC and you believe they have lithium toxicity
goal = get this plasma concentration below 1m/L
Valproate Acid/valproate
Anticonvulsant that can be used for bipolar mania and prophylaxis
- used in bipolar disorders with rapid mixed features and comorbid substance abuse
ADRs:
- alopecia
- CNS depression
- thrombocytopenia
- hepatotoxicty
- pancreatitis
- teratogenic
- GI distress
Carbamazepine
Anticonvulsant that is useful for acute mania in bipolar only
- is combined with lithium for resistant bipolar sometimes
- not first line due to very long DDI list
- also INDUCES CYP3A4
Inhibitors sodium channels on glutamate neurons, slowing their action
ADRs:
- fatigue nausea
- skin rashes
- aplastic anemia
- thrombocytopenia
- hepatic failure
- Steven Johnson’s syndrome (must screen for B*1502 polymorphisms if Asian (very high chance if has this))
- agranulocytosis (must monitor blood levels on this)
- teratogenic (cleft lip and neural tube defects and vitamin K deficiencies)
Toxic ADRs: 15 mcg/L only (toxic levels)
- ataxia
- diplopia
- nystagmus
- cardiac changes
- seizures and coma
is also a great agent for trigeminal neuralgia
Lamotrigine
Anticonvulsant indicated for prophylaxis and depression in bipolar 1/2
Inhibits sodium in glutamate neurons
- the only anticonvulsant agent used in bipolar that can be used in pregnant populations
Does show a DDI with valproate
- can be beneficial but must monitor
ADRs:
- Steven Johnson syndrome (missing does skyrockets this chance, very important to adhere!)
- rashes (greater in peds pateints)
- headaches
- nausea
- dry mouth
why does fluoxetine have the lowest risk of withdrawal syndrome?
Has the highest plasma half-life.
Side effects from excessive stimulating 5-HT2 receptors
Anxiety
Nervousness
Insomnia
Irritability
Decreased libido
Sexual dysfunction
Side effects from excessive stimulation of 5-HT3 receptors
GI distress
Nausea
Emesis
Diarrhea
Which SNRI cant be used in renal failure?
Duloxetine
What cytochromes (CYPs) are each antidepressant class metabolized by
SSRIs = 3A4 and 2D6
SNRIs = 2D6 (venlafaxine) and 1A2
TCAs = 2D6
MAOIs = acetylation specifically (no CYPs)
Trazodone/Nefazodone = 3A4
Mirtazapine = 2D6, 1A2 and 3A4
Bupropion = 2B6. INHIBTS 2D6
What SSRI should never be given in anorexia patients?
Fluoxetine
- ADR = anorexia/decreased hunger
instead use mirtazapine as first line
