660 exam 2 Flashcards
Medications with the strongest evidence of efficacy in bipolar depression with mania:
Quetiapine, olanzapine-fluoxetine, lurasidone
Gina is a 24-year-old patient with no psychiatric history. She gave birth to her first child 2 weeks ago and now presents with symptoms of depression. She scores a 20 on the Edinburgh Postnatal Depression Scale (EPDS; possible depression). Which of the following courses of action should be the next step?
Administer a (hypo)mania screening tool such as the Mood Disorders Questionnaire (MDQ)
MADRS Scoring
0-6 Normal
7-19 Mild depression
20-34 Moderate Depression
>/= 35 severe depression
Bipolar presentation
– + family Hx
– Early onset of first depressive episode (<25)
– Post partum depression x
– Rapid onset of depressive episodes
– Antidepressant induced hypomania
- -Psychotic features
– Impulsivity
– Aggression
– Hostility
– Comorbid substance use disorder
Which drugs would theoretically reduce glutamate release by blocking voltage-sensitive sodium channels?
Valproate and lamotrigine
Lithium MOA
DOWNSTREAM
Inhibition of glycogen synthase kinase 3ß (GSK-3ß) and inositol monophosphatase (IMPase)
Jimmy is a 20-year-old man recently diagnosed with major depressive disorder (MDD) with mixed features. Approximately what percentage of patients with MDD exhibit subthreshold symptoms of (hypo)mania during a major depressive episode?
26%
A 24-year-old man with bipolar disorder is being initiated on lithium, with monitoring of his levels until a therapeutic serum concentration is achieved. Once the patient is stabilized, how often should his serum lithium levels be monitored (excluding one-off situations such as dose or illness change)?
Every 6-12 months.
Blockade of which two receptors was most likely responsible for this weight gain induced by quetiapine?
Serotonin 2C and H1
According to data from the Stanley Foundation Bipolar Network, how many patients with bipolar disorder exhibit subsyndromal hypomanic symptoms during a major depressive episode in at least one single visit?
65%
Fluoxetine/Prozac MOA
5HT2C antagonism (only SSRI that does)
- enhances release of NE and DA
Halflife of Fluoxetine/prozac
Very long - 5 weeks
good for non compliant patients
Sertraline MOA
Sigma 1 receptor and DA transporter binding:
– Sigma 1 may help with anxiety and delusional/psychotic depression
Sertraline dosing above 150mg causes what?
Moderate CYP2D6
Which antidepressant for pregnancy
Sertraline
Paroxetine/Paxil MOA
Weak NET inhibition
Inhibits nitric oxide: Weight gain, sexual SE
Anticholinergic (M1):
calming, sedation
Which SSRI is notorious for withdrawal reactions?
Paroxetine/Paxil
Which SSRI is a potent CYP2D6 inhibitor
Paroxetine/Paxil
Fluvoxamine MOA
Sigma 1 receptor - more potent than sertraline
- good for anxiety and psychotic/delusion depression
Fluvoxamine Indications
OCD, social anxiety
Fluvoxamine CYP activity
1A2 & 3A4
decreases metabolism of caffeine
Citalopram/Celexa MOA
2 enantiomer: two molecules that are mirror images of each other (R&S)
Mild histamine (H1) - a little sedating
Citalopram BB Warning
higher doses (40mg) associated with QTc prolongation
Escitalopram MOA
S enantiomer of citalopram
PURELY ON SERT
Which SSRI is usually best tolerated
Escitalopram
Medication Names - serotonin partial agonist/reuptake inhibitor (SPARI)
Vilazodone (Vibrid)
Vilazodone MOA
Blocks SERT
5HT1A partial agonism is unique to vilazodone
– 5HT1A action can be achieved by adding buspirone or aripiprazole to SSRI/SNRI
Theoretically helps speed up the process because it helps down regulate the 5HT1A receptors faster
Vilazodone SE compared to SSRI
Lower incidence of wt gain
Lower incidence of sexual SE
Tends to have more GI SE due to rapid elevation of 5HT
Medication names: SNRIs
Venlafaxine
Desvenlafaxine
Duloxetine
Levomilnacipran
SNRI MOA
Block SERT
Blocks NET
Increases DA in PFC without blocking DAT
SSRI MOA
blocks SERT
Venlafaxine SERT vs NET dosing
low dosing - SERT (<200mg)
high dosing - NET (>200)
which SNRI is notorious for withdrawal reactions?
Venlafaxine
Desvenlafaxine MOA
More NET vs SERT
active metabolite of venlafaxine
Duloxetine MOA
Slightly more SERT vs NET
Levomilnacipran MOA
S enantiomer of milnacipran
NET>SERT
May be better for cognitive symptoms, fatigue, anergia, anhedonia
Levomilnacipran SE
sweating, urinary hesitancy, hypertension
Which SNRI should you avoid with liver issues?
Duloxetine
Trazodone
Serotonin antagonist and reuptake inhibitors (SARIs) - MOA
Block 5HT2A & 5HT2C
Behaves differently depending on dose
Higher doses (150-600) - antidepressant
Lower doses (25-150) - Sedative/Hypnotic
– 5HT2a antagonism, H1, alpha 1/2
Trazodone SE
PRIAPISM
too sedating to use as an antidepressant
NO wt gain or sexual SE
Nefazodone MOA
Blocks 5HT2A, HT2C, and SERT
also works on NET – differentiates from Trazadone
Nefazodone SE
Less sedating than Trazadone
1 concern with Nefazodone
Rare: Spontaneous liver failure
Medication names: Serotonin antagonist and reuptake inhibitors (SARIs) are
Trazadone
Nefazodone
Mirtazapine MOA
A2 antagonism
– increases NE release by blocking its ability to turn itself off
– enhances serotonin release by blocking norepinephrine’s ability to block serotonins release
Stimulates serotonin release via a2 receptor
– Essentially a2 antagonism cuts the breaks and steps on the gas
DOES NOT BLOCK ANY TRANSPORTER
5HT2C activity - increase NE and DA
H1 activity - sedating
5HT2C antagonism +H1 action = weight gain
5HT2C on suprachiasmatic nucleus in hypothalamus (brains pacemaker - helps manage sleep/wake cycle) - interact with melatonin receptors there. Can resync circadian rhythms
5HT3 localized in the chemoreceptor trigger zone (don’t see N/V/D)
Why might you give mirtazapine with an SSRI or an SNRI
When given with SNRI or SSRI it enhances the 5HT receptor response
Norepinephrine and dopamine reuptake inhibitors (NDRIs): Med name and MOA
Wellbutrin
Inhibits both NE and DA
Lacks SERT activity
BB Warning for Bupropion
BLACK BW: Increased seizure risk - especially with IR formulation)
– IR has higher risk
– increased risk with – pts going through drug withdrawal, bulimia/anorexia due to electrolyte imbalance
MAOI drug names
Nardil
Parnate
Marplan
(No Popular Meds)
MAOI MOA
Inhibit both MAO-A and MAO-B IRREVERSIBLY
→ increase in all three monamines (5HT, NE, DA)
(only antidepressant that directly increase neurotrasmission of all three)
MOAI SE
OH WISE:
- Orthostatic Hypotension
- Weight gain
- Insomnia
- Sexual Dysfunction
- Edema
MAOI drug interactions
Barbiturates
Tricyclic Antidepressants
Antihistamines
CNS Depressants
Antihypertensives
OTC Cold meds
MAOI - avoid what
No foods with tyramine: If it’s stinky or old.
- dried, aged, smoked, fermented, spoiled meat
- Aged cheese
- Tap & unpasteurized beer
- Marmite
- Sauerkrout, kimchee, soy
- Banana peel
TCA MOA
H1 blockade:
Sedation and wt gain
M1 blockade:
anticholiergic SEs -
dry mouth/blurred vision/urinary retention, constipation
Alpha1 blockade:
orthostatic hypotension and dizziness
Voltage-sensitive Na+ channel blockade:
coma, seizure, cardiac arrhythmias, cardiac arrest/death
TERTIARY AMINES:
block serotonin reuptake more potently than norepinephrine
SECONDARY AMINES:
block nerepinephrine more than serotonin reuptake
Some secondary amines metabolize into secondary amines so they have strong 5HT and NE
TCAs SE
Tertiary:
more anticholinergic SE and are more sedating
Hypotension, tachy, cardiac arrhythmias, cardiac arrest, death
dizziness, lethargy, confusion, agitation
coma, seizures
sedtaion, wt gain
dry mouth, burred vision, urinary retention, constipation
WIDENING QRS - hallmark, diagnostic value for seizures and ventricular arrhythmias
TCA initial monitoring
ECG if >50 yo
BMI, fasting glucose, A1C, Triglycerides, LDL
K+ and Mag+ if on diuretics
Nortriptyline (TCA): drug level and when to monitor
Drug lvl: 50-100
Check when you get to 100mg around 5-7 days
Glutamate receptor modulator medication names
Ketamine, Esketamine, Auvelity
Ketamine MOA
R&S ketamine
- binding on NMDA for glutamate (on GABA neuron)
Mu opiod receptor activity - if on naloxone it won’t work
Increases growth factors
Immediate glutamate burst – increased dendridic spine density and neuroplasticity
- stimulates AMPA, blocks NMDA
Esketamine MOA
S (only)
Inhibits NDMA on GABA – decreased stimulation of GABA neuron
Dextromethorphan/buproprion MOA
NMDA antagonist – reduces glutamate transmission
— increases glutamate
Blocks SERT - increases serotonin
Sigma 1 agonist - increases serotonin
Dextromethorphan is rapidly metabolized by CYP2D6
Buproprion inhibits CYP2D6
–Maintains dextromethorphan concentrations
Esketamine contraindications
Aneurysm, brain bleed, risk for stroke, uncontrolled HTN
Driving after treatments
Pregnancy
Esketamine SE
HTN, tachycardia
temporary cognitive impairment: attention, judgement, reactions
Dissociative, dizzy, sedation
Esketamine - what do we monitor
BP
Esketamine BB Warning
BLACK BW: risk of sedation and dissociation
MUST MONITOR FOR 2 HRS
all providers/patients have to enroll in program
Ketamine r/t suicide
suicide protective for a few days
When is ketamine given
treatment resistant depression or persistent suicidal thoughts
Lithium SE
Tremor
increased urination
acne, psoriasis, hair loss
decreased thyroid function
Stomach upset
Lithium initial labs
Serum Creatinine, UA
– to screen for renal function
– to avoid lithium toxicity
– chronic use can affect kidney fx
T4, TSH
– attacks thyroid
Pregnancy test
– teratogenic
ECG
- if >40 or clinically indicated
Electrolytes
– because lithium is a salt
– Na+ competes for reabsorption in renal tubule
CBC
– if indicated by patient’s risk factors
– lithium increases WBC
Lithium toxicity S/S
Lithium toxicity
– Early:
N/V/D
Dry Mouth
Ataxia, Dizziness, Slurred Speech, Nystagmus, Muscle weekness
Moderate - severe:
Anorexia, n/v/d
muscle fasiculations, clonic limb movements
hyperactive deep tendon reflexes
convulsions
delirium
syncope
stupor, coma
circulatory failure: low BP, arrhythmias
Lithium drug interactions
Renally excreted so minial dru-drug interactions
Diuretics:
Loop: increase or decrease lithium lvl
Thiazide: Increase lithium lvl - reduce lithium by 50%
NSAIDS
Reduces kidney’s ability to clear lithium: Lithium lvl increases
Carbamazepine
Inhances neurological effects of lithium even without incresaed lithium lvls
dizziness, tremor, confusion, hyperreflexia
SSRIs
Increases serotonergic SEs = incresed chance of serotonin syndrome
ACE I
Increases risk of lithium toxicity and may increase lithium lvls
- possibly due to increased Na+ and H2O excretion
Iodides
Increse in the hypothyroid properties of lithium
Valproate MOA
Voltage sensitive sodium channels
Lithium and pregnancy -
Teratogenic - Ebstein’s anomaly
3 antisuicidal medications
Clozapine, Ketamine, Lithium
Therapeutic Lvl of Lithium
0.6-1.2
How often to get lithium level
Lithium LVL every 3-6 months or if clinical indicated
Checking to make sure patient isn’t toxic
Lithium ongoing monitoring
Lithium LVL every 3-6 months or if clinical indicated
Checking to make sure patient isn’t toxic
BUN/Creatinine & TSH every 3 months intially then every 6-12 months
Valproate and pregnancy
BIG contraindication –
Teratogenic: neural tube defects = cleft palate, cleft lip
CONTRAINDICATED IN PREGO
Valproate lvl monitoring
Depakote:
3 days after initial dose
12 hrs after last dose
Depakote ER:
8-9 days after initial dose
15 hrs after last dose
Valproate lvls
Acute Mania: 45-125
Maintenance: 75-100
Initial monitoring for Valproate
Pregnancy Test
LFT:
hepatically clear - can dmg
CBC:
can affect decrease platelets/RBCs
Valproate r/t Lamictal
Increases lamictal levels by 50%
Valproate SE
N/V, tremor, hair loss, sedation
wt gain
Carbamazepine/Tegratol MOA
Blocks voltage sensitive sodium channels
Carbamazepine/Tegratol Indications
Bipolar
– better for mania - less so for depressive phase
Carbamazepine/Tegratol SE
Tremor
Confusion, Ataxia, Rash
Blurred vision, aplastic anemia, bone marrow suppression
eosinophelia
Agranulocytosis, ADH release
Neutropenia
Carbamazepine/Tegratol Drug interactions
POTENT CYP3A4 inducer
– increases metabolizer
Lamictal: Will decrease the lamictal lvl by 1/2
Carbamazepine/Tegratol Serious ADR
SJS & TEN - certain Asian population higher risk
Carbamazepine/Tegratol Initial Labs
CBC
- can cause neutropenia, decreased RBCs, and agranulocytosis
LFT
- Hepatic clearance
Na+ level
Carbamazepine/Tegratol: Continued Labs
Carbamazepine lvl:
Two lvls to establish dose – 4 weeks apart to account for autoinduction
CBC, LFT, Electrolytes, BUN/Creat monthly for 3 months then annually
Carbamazepine/Tegratol: Important Testing for specific group of people
Genetic testing for Asian decent - HLA - B 1502
BEFORE YOU START THEM ON TEGRATOL
Lamictal MOA
Blocks Na+ channels
Reduces the release of glutamate
Lamictal MOA
Blocks Na+ channels
Reduces the release of glutamate
Lamictal Indications
Prevent recurrence of manic and depressive bipolar
Good for depressive phase - not for acute
Lamictal SE
infection
HA, Nausea, dry mouth
Lamictal Drug interactions
Carbamazepine, Phenytoin, Phenobarbital, Primidone, Rifampin, Rifampin
– DECREASES LAMICTAL
Oral estrogen BC
– DECREASES LAMICTAL and possibly BC efficacy
Valproic Acid
– INCREASES VALPROIC ACID
Major ADR r/t Lamictal
SJS
Lamictal Standard Dosing
SLOW TITRATION
Start at 25mg for 2 weeks
50mg for 2 weeks
100mg for 2 weeks
Then 200mg
Lamictal Dosing with Depakote
Half the dose
Lamictal dosing with Tegratol/Carbamazapine
Double the dose
Which psychotropic treatment(s) can be considered as ALTERNATIVE maintenance treatments to antidepressants?
Atypical antipsychotic such as quietiapine and mood stabilizers such as Lamictal
Both atypical antipsychotics with mood stabilizing properties and mood stabilizers have shown some efficacy in the treatment of major depressive episodes with mixed features and are therefore recommended as first- or second-line treatments.
How long does it take for withdrawal dyskinesias to resolve?
Weeks to months
Of the following, the agent with the lowest risk of cardiometabolic side effects is:
– Lithium
– Lumateperone
– Olanzapine
– Valproate
Lumateperone
Both lithium and valproate are associated with a relatively high risk of significant weight gain. Among the atypical antipsychotics, olanzapine carries with it one of the highest risks for cardiometabolic side effects, including weight gain.
Lumateperone has been shown to be neutral for weight gain in long-term studies and in early clinical practice, and has a favorable metabolic profile that is similar to placebo for changes in triglycerides, fasting glucose, and cholesterol.
Patricia is a 31-year-old patient with bipolar I disorder who frequently exhibits impulsive symptoms of mania, including risk taking and pressured speech, during her manic episodes. Compared to a healthy brain, neuroimaging of this patient’s brain during a no-go task (designed to test response inhibition) would likely show:
– Increased activity in the orbitofrontal cortex
– Decreased activity in the orbitofrontal cortex
– Increased activity in the dorsolateral prefrontal cortex
Decreased activity in the orbitofrontal cortex
Neuroimaging of the orbitofrontal cortex of manic patients during a no-go task (a task that required the patient to suppress a response) shows that they fail to appropriately activate this brain region. This neuroimaging anomaly suggests that patients with bipolar disorder have problems with impulsivity associated with mania and with the orbitofrontal cortex.
Katherine is a 24-year-old patient who presents with symptoms of depression (including sadness, feelings of worthlessness, and suicidal ideation) occurring every day for the past month. Clinical interview with Katherine reveals that she has a maternal aunt with bipolar disorder I. Further assessment reveals that this patient also feels distracted and as though her thoughts are racing. Upon speaking with the patient’s mother, it is discovered that Katherine has been, at times, more talkative than usual and irritable with her friends and family. Which class of medication would NOT be recommended as monotherapy for this patient?
– A mood stabilizer
– An antipsychotic
– An antidepressant
– All of the above would be recommended as monotherapy
Antidepressant
Expert consensus and published guidelines recommend that antidepressant monotherapy NOT be used (and is contraindicated) in patients with depression who exhibit mixed features and a positive family history of bipolar disorder.
Of the following symptoms, which is the most common subsyndromal mania symptom in patients during a major depressive episode with mixed features?
– Decreased need for sleep
– Inflated self-esteem
– Psychomotor agitation
– Elevated mood
– High-risk behavior
Psychomotor agitation
During a major depressive episode with mixed features (concomitant subthreshold levels of mania or hypomania), the most common manic/hypomanic symptom exhibited is psychomotor agitation.
Approximately what percentage of patients with bipolar disorder have comorbid ADHD?
20-25%
A 26-year-old woman began treatment for a major depressive episode 8 months ago. Two months into her treatment she began to experience noticeable symptom improvement, and for the last 5 months she has been mostly symptom free, except for persistent cognitive dysfunction. Which of the following statements regarding cognitive dysfunction in depression is most accurate?
- Cognitive dysfunction is one of the most common residual symptoms following recovery
- Cognitive dysfunction can be treated with serotonergic modulation of glutamate transmission
- Both
BOTH
Cognitive dysfunction is one of the most common residual symptoms of major depressive disorder and can endure longer than mood symptoms following recovery. Moreover, cognitive dysfunction is strongly correlated with physical, mental, and functional disability. Pharmacotherapies used to treat depression that have action on glutamate signaling via serotonergic modulation also show pro-cognitive effects. The prime example is vortioxetine, which has agonist action at 5HT1A, weak partial agonist action at 5HT1B/D, and antagonist action at 5HT3, 5HT1D, 5HT7, and the serotonin transporter. Antagonism of 5HT3 disinhibits glutamate release, while antagonism of 5HT7 enhances release of glutamate release in the prefrontal cortex. In addition, agonism of 5HT1A (full) and 5HT1B (partial) may enhance or suppress glutamate transmission based on neuronal localization.
Theoretically, what is the therapeutic advantage of a SNRI over a SSRI?
– Increased norepinephrine via norepinephrine transporter inhibition
– Increased dopamine via norepinephrine transporter inhibition
– Increased norepinephrine and dopamine via norepinephrine transporter inhibition
Increased norepinephrine and dopamine via norepinephrine transporter inhibition
In addition to boosting serotonin like SSRIs (via inhibition of serotonin reuptake by the serotonin transporter [SERT]), SNRIs can boost norepinephrine by inhibiting reuptake by the norepinephrine transporter (NET). Additionally, in the prefrontal cortex, SNRIs can boost dopamine levels. In prefrontal cortex, SERTs and NETs are present in abundance on serotonin and norepinephrine nerve terminals, respectively, but there are very few dopamine transporters (DATs) on dopamine nerve terminals. Therefore, dopamine action is terminated either by enzymatic degradation or NET. If NET is inhibited by an SNRI then it cannot terminate the action of dopamine and dopamine levels increase in this brain region.
A 36-year-old man with major depressive disorder is having lab work done to assess his levels of inflammatory markers. Based on the current evidence regarding inflammation in depression, which of the following results would you most likely suspect for this patient?
– Elevated lvls of tumor necrosis factor-alpha
– Reduced levels of interleukin 6 (IL-6)
– Reduced C-reactive protein (CRP)
– Elevated interferon gamma (IFN?)
Elevated levels of tumor necrosis factor-alpha (TNF-alpha)
There is growing evidence that inflammation may play an important role in the pathophysiology of major depression. Clinical studies have shown that depressed patients have significantly higher concentrations of several inflammatory central and peripheral markers, including the pro-inflammatory cytokines TNF-alpha and interleukin-6. Patients with depression also have higher concentrations of C-reactive protein, which is synthesized by the liver in response to pro-inflammatory cytokines, and reduced interferon gamma, which is a pro-inflammatory cytokine. Furthermore, both cytokines and cytokine inducers can cause symptoms of depression. For example, as many as 50% of patients receiving chronic therapy with the cytokine interferon develop symptoms consistent with idiopathic depression.
A 28-year-old man with moderate depression achieves remission after 16 weeks on a therapeutic dose of an antidepressant. According to the neurotrophic hypothesis of depression, what is most likely true of his brain-derived neurotrophic (BDNF) expression before and after his successful treatment?
BDNF expression was abnormally low while he was depressed, and increased during antidepressant treatment
The neurotrophic hypothesis of depression posits that depression results from decreased neurotrophic support, leading to neuronal atrophy, decreased hippocampal neurogenesis, and that antidepressant treatment blocks or reverses this deficit, thereby reversing atrophy and cell loss. Several meta-analyses have reported deficient BDNF levels in patients with major depressive disorder and an elevation in BDNF following antidepressant treatment.
Which of the following antidepressant treatments is associated with the greatest risk of weight gain?
– Escitalopram
– Fluoxetine
– Mirtazapine
– Vilazodone
Mirtazapine
Which of the patient’s current medications MUST you discontinue BEFORE initiating tranylcypromine?
– Duloxetine
– Trazodone for insomnia
– Both
– Neither
Duloxetine
Although trazodone does have serotonin reuptake inhibition at antidepressant doses (150 mg or higher), this property is not clinically relevant at the low doses used for insomnia. In fact, because there is a required gap in antidepressant treatment when switching to or from an MAO inhibitor, low-dose trazodone can be useful as a bridging agent when switching.
A 56-year-old male patient with major depression is brought to the ER with cardiac arrhythmia and possible cardiac arrest. While at the hospital, he suffers a seizure. His wife states that he may have ingested an increased dose of his medication. Which of the following is most likely responsible for this apparent overdose reaction?
– Atomoxetine
– Clomipramine
– Fluvoxamine
– Venlafaxine
Clomipramine
lomipramine, a tricyclic antidepressant (TCA), may be most likely to cause these effects in overdose. TCAs block voltage-sensitive sodium channels (VSSCs) in both the brain and the heart. This action is weak at therapeutic doses, but in overdose may lead to coma, seizures, and cardiac arrhythmia, and may even prove fatal.
A 65-year-old patient on theophylline for chronic obstructive pulmonary disease (COPD) and fluvoxamine for recurring depressive episodes required a decreased dose of theophylline due to increased blood levels of the drug. Which of the following pharmacokinetic properties may be responsible for this?
Inhibition of CYP450 1A2 by fluvoxamine
Fluvoxamine is a strong inhibitor of CYP450 1A2. Theophylline is metabolized in part by CYP450 1A2, and thus strong inhibition of this enzyme by fluvoxamine may require a dose reduction of theophylline if the two are given concomitantly, so as to avoid increased blood levels of the drug.
Mike is a 31-year-old patient with major depressive disorder (MDD) has experienced some response with the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine XR (150 mg/day). However, the patient acknowledges that he and his wife have been having relationship problems because of his poor libido. The patient experienced this problem prior to being diagnosed and treated for MDD, but he has found that the venlafaxine has worsened this troubling symptom despite the fact that his mood has improved. He asks if there is a way to both prevent worsening of his mood and avoid this side effect. Which class of depressant should he be switched to?
Switch to a norepinephrine and dopamine reuptake inhibitor (NDRI) – Wellbutrin
Pharmacological agents that increase dopaminergic neurotransmission and/or decrease serotonergic neurotransmission (e.g., serotonin 1A agonists or serotonin 2 antagonists) are often effective in ameliorating sexual dysfunction. Switching to an NDRI such as bupropion would be expected to increase dopaminergic neurotransmission and improve sexual function. Given that the patient experienced libido problems prior to treatment with the SNRI, and that the problem has worsened on treatment with the SNRI, it makes sense to switch to bupropion. Augmentation with bupropion to address sexual dysfunction, although commonly done in clinical practice, is not actually supported by randomized controlled studies.
In addition to treating depressed mood, preclinical data indicate that serotonin 5HT3 receptor antagonists may have clinical utility as adjunct treatment for which symptoms?
Cognitive symptoms
Serotonergic neurons synapse with noradrenergic neurons, cholinergic neurons, and GABAergic interneurons, all of which contain serotonin 5HT3 receptors. When serotonin is released, it binds to 5HT3 receptors on GABAergic neurons, which release GABA onto noradrenergic, glutamatergic, and cholinergic neurons, thus reducing release of norepinephrine, glutamate, and acetylcholine, respectively. In addition, serotonin may bind to 5HT3 receptors on noradrenergic and cholinergic neurons, further reducing release of those neurotransmitters. This may theoretically contribute to symptoms of depressed mood and impaired cognition. Therefore, treatment with 5HT3 receptor antagonists improve depressed mood and cognitive problems.
A 36-year-old patient has only partially responded to his second monotherapy with a first-line antidepressant. Which of the following has the best evidence of efficacy for augmenting antidepressants in patients with inadequate response?
– atypical antipsychotic
– buspirone
– stimulant
atypical antipsychotic
Atypical antipsychotics have been studied as adjuncts to selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitor (SNRIs), with approvals for aripiprazole, brexpiprazole, quetiapine XR, and olanzapine (in combination with fluoxetine). Overall, most studies of atypical antipsychotics show a benefit of combination treatment over monotherapy, although effect sizes have been modest. Although atypical antipsychotics have the best evidence of efficacy for augmenting antidepressants in patients with inadequate response, their adverse event profiles may still put them later in the treatment algorithm.
Miryam is a 24-year-old woman with a major depressive episode that is only partially responding to treatment with a selective serotonin reuptake inhibitor. In particular, she continues to display reduced positive affect. She is prescribed adjunctive bupropion to manage this symptom. Through which mechanism(s) does bupropion theoretically ameliorate reduced positive affect?
Inhibition of dopamine and norepinephrine transporters
Which of the following statements about ketamine treatment is true?
– The strongest evidence for the efficacy of ketamine is in bipolar depression
– Repeated dosing extends the duration of ketamine effects
– High frequency ketamine administration is recommended
– A history of antidepressant treatment is NOTnecessary to start ketamine treatment
Repeated dosing extends the duration of ketamine effects
Studies suggest that repeated dosing may extend the duration of ketamine effects. Ketamine administration of 2–3 times per week over 2–3 weeks, followed by a taper period and/or continued treatments, may be most effective.
A patient with depression is prescribed mirtazapine as adjunctive treatment to venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Mirtazapine acts on alpha 2 receptors to produce what effect?
Disinhibition of norepinephrine and serotonin release via alpha 2 antagonism
Norepinephrine turns off its own release via alpha 2 presynaptic receptors; therefore, alpha 2 antagonism with mirtazapine facilitates disinhibition of norepinephrine. Furthermore, norepinephrine migrating from a norepinephrine terminal can also turn off serotonin release via alpha 2 presynaptic heteroreceptors on serotonin neurons. Therefore, alpha 2 antagonists like mirtazapine can have a dual effect on facilitating the release of both norepinephrine and serotonin.
A 34-year-old man with depression characterized by depressed mood, sleep difficulties, and concentration problems has not responded well to a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI). His clinician elects to switch him to vortioxetine, which has prominent 5HT7 antagonism. What may be a primary function of these receptors?
Regulation of serotonin-glutamate interactions 68%
5HT7 receptors are postsynaptic G protein-linked receptors. They are localized in the cortex, hippocampus, hypothalamus, thalamus, and brainstem raphe nuclei, where they regulate mood, circadian rhythms, sleep, learning, and memory. A major function of these receptors may be to regulate serotonin-glutamate interactions.
Serotonin can both activate and inhibit glutamate release from cortical pyramidal neurons. Serotonin released from neurons in the raphe nucleus can bind to 5HT2A receptors on pyramidal glutamate neurons in the prefrontal cortex, activating glutamate release. However, serotonin also binds to 5HT1A receptors on pyramidal glutamate neurons, an action that inhibits glutamate release. Additionally, serotonin binds to 5HT7 receptors on GABA interneurons in the prefrontal cortex. This stimulates GABA release, which in turn inhibits glutamate release.
Serotonin binding at 5HT7 receptors can also inhibit its own release. That is, when serotonergic neurons in the raphe nucleus are stimulated, they release serotonin throughout the brain, including not only in the prefrontal cortex but also in the raphe itself. Serotonin can then bind to 5HT7 receptors on GABA interneurons in the raphe nucleus. This stimulates GABA release, which then turns off serotonin release.
Serotonin binding at 5HT7 receptors in the raphe inhibits serotonin release; therefore, an antagonist at this receptor would be expected to enhance serotonin release. Specifically, by blocking serotonin from binding to the 5HT7 receptor on GABA interneurons, a 5HT7 antagonist would prevent the release of GABA onto serotonin neurons, thus allowing the continued release of serotonin in the prefrontal cortex.
A 32-year-old woman with major depressive disorder has been taking a selective serotonin reuptake inhibitor (SSRI) with good response for months. She presents now with complaints that she feels numb, and that even when she’s sad she can’t cry. Her clinician is considering reducing the dose of her SSRI in an effort to alleviate this problem. Is this a reasonable option?
Yes, data suggest that SSRI-induced indifference is dose-dependent and can be alleviated by reducing the dose
Apathy and emotional blunting can be symptoms of depression, but they are also side effects associated with selective serotonin reuptake inhibitors (SSRIs). These symptoms—termed “SSRI-induced indifference”—are under-recognized but can be very distressing for patients. They are theoretically due to an increase in serotonin levels and a consequent reduction of dopamine release. The first recommended strategy for addressing SSRI-induced indifference is to lower the SSRI dose, if feasible. Additional options include adding an augmenting agent or switching to an antidepressant in another class.
Theoretically, individuals with depression may display a lack of normal GABAergic tonic inhibition via:
Extrasynaptic benzodiazepine-insensitive GABA-A receptor
A 27-year-old patient who has been taking a selective serotonin reuptake inhibitor (SSRI) for depression for the last 2 years has just found out that she is 12 weeks pregnant. Cumulative data for SSRI use in pregnancy have established a small but clinically significant increase in absolute risk of:
– Cardiovascular malformations
– Persistent Pulmonary HTN
– Autism spectrum disorder
– None of the above
None of the above
Sasha is a 58-year-old patient with a history of depression who has been prescribed agomelatine. At present, she is relatively free of depressive symptoms, likely due in part to binding of agomelatine to what receptors in the suprachiasmatic nucleus?
– Melatonin receptors
– 5HT2C receptors
– Both
Both
Agomelatine is both a melatonin M1 and M2 receptor agonist and a serotonin 5HT2C receptor antagonist. This unique receptor profile gives agomelatine the ability to address impairments in neurotransmission as well as circadian rhythm dysfunction.
April is a 14-year-old patient recently diagnosed with moderate-to-severe major depressive disorder (MDD). She endorses passive suicidal ideation, but no specific plan or intention for suicide attempt. She denies any suicidal ideation or attempts prior to her current depressive episode. In addition to beginning cognitive behavioral therapy (CBT), which pharmacotherapy option would be best suited for treating her depressive episode?
– Imipramine
– Bupropion
– Fluoxetine
– No pharmacotherapy
Fluoxetine
Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has a good evidence base for efficacy treating pediatric MDD and is one of only two antidepressants with FDA approval for pediatric MDD. Escitalopram, also an SSRI, is the second antidepressant approved for treating pediatric MDD. There is no strong evidence to suggest that any particular SSRI is more effective than any other for pediatric MDD. However, both the National Institute of Clinical Excellence (NICE) and the American Academy of Child and Adolescent Psychiatry (AACAP) recommend evidence-based psychotherapy, such as CBT, and/or fluoxetine to treat moderate-to-severe depression in adolescence.
The hypothesis that the therapeutic effects of antidepressants are due to downstream changes in neuroplasticity is consistent with the fact that clinical improvement with antidepressants is typically delayed by several weeks. The downstream effects of monoamine antidepressants include:
r/t AMPA, NMDA, and glutamate
Increased AMPA receptor expression, decreased NMDA receptor expression, decreased glutamate
There is increasing evidence, the underlying mechanism of antidepressant treatment may not be alterations in the levels of monoamines themselves, but rather changes in the downstream molecular events and neuroplasticity triggered by those monoamines. Monoaminergic antidepressants likely exert their therapeutic effects by influencing downstream signaling, such as increased a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, or AMPA receptor expression, decreased N-Methyl-D-aspartate, or NMDA receptor expression, and decreased glutamate, suggesting agents with direct activity at these downstream targets may lead to faster treatment response. Antidepressant treatments may modify the AMPA:NMDA receptor ratio, resulting in downregulated NMDA receptors, and increased AMPA receptors.
Vortioxetine/Trintellix MOA
Blocks SERT
Multiple serotonin pathways in unique ways
May have a procognitive effect
Vortioxetine/Trintellix max dose with Wellbutrin
10mg
Vortioxetine/Trintellix SE
Wt neutral
Lower incidence of sexual SE
Nausea
