PHAR 253: Medications for Depression:

MAOIs and tazodone:

Risk of serotonin syndrome.

TCA discontinuation syndrome:

Rude dose by 50mg q2days until at 100mg/day, then by 25mg q2-3 days until stopped. Nortriptyline decrease dose in decrements by 50%

What is the mechanism of action of Second generation antipsychotics in the treatment of MDD?

SGA: almost all of them act on the prefrontal cortex to increase flow of norepinephrine and dopamine.

Quetiapine:

SGA: second generation antipsychotic agent. *first time we had an antipsychotic used for antidepressant therapy on its own. Quetiapine has a lot of side effects and does not have comparative evidence. 150-300mg daily.

*Desvenlafaxine* Venlafaxine:

SNRI 50-100mg daily. SNRI 75-225mg daily Recall from work: People taking Venlafaxine 75mg + 150mg

Milnacipran: not available in canada

SNRI 100mg daily.

Duloxetine:

SNRI 60mg

TCA: tricyclic antidepressants:

SNRI dose range is variable. Considerations in regard to tolerability. TCAs are much less tolerated than SSRIs and SNRIs.

Levomilnacipran:

SNRI fetzima. dose 40-120mg it's second line because there isn't much evidence for it to be added first line.

*Vortioxetine* multimodal drug:

SSRI + 5HT1A agonist; 5HT 1B partial agonist; 5HT 1D, 5HT3A and 5Ht7 antagonist. Dose 10-20mg.

Escitalopram:

SSRI 10-20mg daily.

Fluvoxamine:

SSRI 100-300mg daily. Note that fluvoxamine can be given in split dosing

Paroxetine:

SSRI 20-50mg daily or 25 to 62.5mg CR daily.

Fluoxetine:

SSRI 20-60mg daily:

Sertraline:

SSRI 50-200mg daily.

Trazodone:

SSRI and also 5HT2 antagonist. 150-300mg daily. Low dose 25mg used for HS sedation. It is an antidepressant at higher doses.

Citalopram:

SSRI: 20-40mg daily

*why is paroxetine not recommended to be initiated in pregnancy?

Small risk of pulmonary hypertension when the patient is born. *any increased risk is probably small and needs to be considered in the context of the potentially greater risk to the mother and child that may result from the mother's untreated depression.

*Adjust SNRIs with renal impairment:

So 75mg might actually be 150mg if renal dysfunction is present.

Drug holidays:

Some evidence of efficacy with sertraline, citalopram, and paroxetine Potential disadvantages = withdrawal side effects (especially venlafaxine) after missing more than 2 doses, relapse of depressive symptoms, and increasing patient non-adherence

Quetiapine dosing:

Start at 50mg po daily. Increase to 150mg po on day 3. Usual dose range = 150-300mg a day. Max dose for MDD = 300mg/day. *Max dose for quetiapine for schizophrenia is up to 800mg/day.

SNRI dosing:

Start low, go slow! especially with venlafaxine. *Want to at least get to 150mg/day of venlafaxine, hopefully 225mg/day and even up to 375mg/day.

Anaesthesia and moclobemide:

Stop MAOI at least 2 days prior to local or general anesthesia. This is because levels of moclebemide would increase.

*Stopping a serotonergic drug before starting moclobemide*

Stop serotonergic drug 2 weeks before starting MAOI to avoid precipitating a hypertensive reaction or serotonin syndrome. *Stop fluoxetine 5 weeks prior to starting MAOI*

4. Switching antidepressant: Bupropion: #1 Mirtazapine: #2

Switch to an agent with lower rates of sexual side effects Bupropion = greatest amount of evidence for successful treatment of sexual dysfunction when switching to bupropion Remember, this is not an ideal agent if concomitant anxiety Mirtazapine = some small RCTs show resolution of sexual dysfunction when switching to mirtazapine

MAOIs:

allow washout of 2 weeks between MAOI and other antidepressant.

Isocarboxazid Phenelzine Tranylcypromine

Irreversible MAOIs.

Dosing of trazodone in depression:

150mg to 200mg day in 2-3 divided doses. Taken after a meal: reduces A.E. *Max dose 600mg day Increased by 50mg/day every 3 to 7 days.

Bupropion as add on:

May be used with SSRI to reduce sexual dysfunciton because you can reduce the SSRI dose when bupropion is used as adjuvant therapy.

MAOI and moclobemide wash out period:

*allow 2 weeks of wash out before switching between MAOI and other antidepressants.

Untreated depression:

#1 cause of suicide

Sedative dosing of trazodone:

50mg po HS.

Doxepin:

Best tolerated of the 3rd amines. Works as an antihistamine for sleep. Silenor *doxepin is used for sedation*

Pregnancy: For a drug naive patient who is not suicidal tx:

CBT or interpersonal therapy, either short-term 10-12 weeks or with open-ended duration.

Bupropion consideration:

Switching to bupropion is not ideal if someone has concomitant anxiety.

Antagonism of 5HT2 is linked to:

lower anxiety

Mirtazapine dosing:

*15mg po HS. May increase q1-2 weeks up to a maximum of 45mg po HS.

GI Bleeding as an adverse effect:

*Additative risk factor. Peripheral 5HT stored and released during a thrombotic event, leading to platelet aggregation. via 5HT-2A Mature platelets are not capable of synthesizing 5HT, they are therefore dependent on the reuptake of 5HT from the plasma.

Caution drug interactions with moclobemide:

*Avoid concurrent sympathomimetics: Ex: pseudoephedrine, meperidine. Caution with opioids, antihypertensives, antipsychotics, SSRIs, selegiline, excessive tyramine: wine and cheese as well as alcohol*

Blood pressure increase due to venlafaxine:

*BP increases with venlafaxine doses that are greater than 150mg/day. This is due to NE action. Few people experience this but should monitor blood pressure*

Bupropion as an add on therapy rationale:

*Bupropion does not have an yeffect on 5HT or MAO so it has a potential role in as an add on therapy*

When do we caution with SSRIs?

*Caution in those with history of GI bleed and/or those on NSAIDs*

Antihistamine effect of mirtazapine:

*H1 histamine receptor antagonism associated with mirtazapine* causes sedation which can be desirable but also undesirable. Some anticholinergic effect but not a lot.

Adverse effects of SNRIs:

*HANDS, as with the SSRIs* Anticholinergic effects which is dose related: effects such as dry mouth, constipation: Can't see, can't pee, can't spit + confusion in elderly*

*Mirtazapine risk of serotonin syndrome*

*Increased risk of serotonin syndrome in combination with serotonergic agent.*

Sexual dysfunction from SNRIs:

*Less sexual dysfunction and weight gain with SNRIs than SSRIs. Duloxetine has less risk for withdrawal effects if missed doses versus venlafaxine, but may not be as tolerable or effective.

Sexual dysfunction as an adverse effect of SSRIs:

*More frequent with fluoxetine and paroxetine. Less frequent with citalopram and escitalopram*

Weight gain, GI effects and so on from SNRIs versus SSRIs:

*More nausea with SNRIs than SSRIs. Some of the SNRIs have anticholinergic effects. Cardiovascular concerns with venlafaxine can mimic tri-cyclics. We compare all information and data relative to TCAs.

SSRIs in pregnancy:

*Safe in pregnancy no reports of teratogenicity to date* most safety data is with SSRIs versus other antidepressants. *Fluoxetine has the most clinical experience of the SSRIs in pregnancy* Paroxetine should be avoided in pregnancy.

Mirtazapine consideration with sedation effect*

*Sedation effect of mirtazapine is less pronounced when the doses of mirtazapine exceed 30mg.

Sertraline bioavailability:

*Sertraline bioavailability increases with food.

Sexual dysfunction associated with SSRI use:

*Sexual dysfunction can be a reduction in libido and there can be functional inhibition. The libido component can improve with the treatment of depression. * This is not on a evaluated scale so we have to ask about this.

What are the major complaints people have with with SSRIs?

*The most common adverse effect with SSRIs is Sleep disturbance! *be aware that SSRIs affect REM sleep* Vague headache and nausea. sometimes vomiting.

*What occurs if you combine Bupropion and MAOI therapy?

*This is a contraindication and can lead to hypertensive crisis.

Relevant PK and DIs from SNRIs:

*Unlike SSRIs there are no effects from food* Will require dose-adjustment with renal impairment. *risk of serotonin syndrome with MAOIs, TCAs, SSRIs and other drugs: ex: tramadol.

*Triad presentation of Serotonin syndrome*

*abrupt onset, changes in CNS, patient is more agitated and a bit more confused. Blood pressure changes and same with muscle tone.* 1. CNS 2. abrupt onset 3. confusion/agitation. spasming of muscle that occurs in the lower limbs. Could be a precursor to a seizure.

Efficacy of Bupropion:

*can be added on to serotonergic antidepressant therapy without the concern of serotonin syndrome* Worrisome that it is on back order

Does Moclobemide require a low tyramine diet?

*does not require a low tyramine diet. the signs and symptoms of tyramine crisis: headache, vomiting, severe anxiety as well as increased blood pressure*

Dysregulation of serotonin 5Ht and norepinephrine in the brain are strongly associated with depression: Imbalances of 5HT and NE may explain the presence of both emotional and physical symptoms of depression.

*dysregulation of 5Ht and NE in the spinal cord may explain an increased pain perception among depressed patients.*

Take the following with a grain of salt: *MDD with anxious distress:

*go for an agent with efficacy in GAD*

How do you know when to switch antidepressants:

*if there is any improvement in 2 weeks, this is an good indicator of full response. do not usually switch at 2 weeks, unless patient has tolerability issues* Takes about 12 weeks for full response: if even will respond and remission of symptoms. Gotta optimize dose, add non-pharm.

Long term adverse effects of SSRIs:

*increased risk of fractures* Hyponatremia: can happen within the first 2 or 3 weeks but particularly in the elderly.

Moclobemide dose: 35-50% dose reduction suggested with severe hepatic impairment.

*no adjustment required with renal dysfunction* Moclobemide: 300mg/day in 2 divided doses. Usual dose: 450-600mg/day. High dose 900mg/day *With doses above 600mg per day, specificity for MAO-A is lost and thus caution regarding tyramine is required*

Functional connectivity between 5HT, DA and NE neurons:

*norepinephrine and dopamine are part of the same metabolic pathway and therefore a counterbalance one another. If DA increases then NE decreases. As well as if NE increases thenn DA decreases. *The sum being roughly the same between the 2 neurotransmitters*

When do we get concerned about QTc?

*once reaches 500msec or longer that's when we get concerned about QTc or if there is a change from baseline of greater than or equal to 60msec.

Constipation management:

*paroxetine associated with highest rates of constipation out all SSRIs.* This is because paroxetine has anticholinergic effects Management: should resolve on its own in up to 3 months. Adequate activity and fibre is needed. OTC/self-care as normal.

*adverse effects of mirtazapine* CNS

*sedation, can last until morning even if taken at supper* Endocrine: weight gain can limit use of mirtazapine. dyslipidemia can occur which results in an increase in TG.

Switching antidepressants:

*several studies have found comparable outcomes with switching with a class as between classes. clinicans usually try different class. STAR*D trial found that bupropion, sertraline and venlafaxine are all viable options.

Genitourinary effects of mirtazapine:

*significantly less sexual dysfunction with mirtazapine when compared to SSRIs*

Mirtazapine CANMAT for MDD:

*significantly more efficacious for the acute treatment of unipolar depression versus duloxetine, fluoxetine, fluvoxamine and paroxetine. *

Venlafaxine versus SSRIs:

*superior efficacy, response rate, over duloxetine (SNRI), fluoxetine, paroxetine and fluvoxamine (SSRIs) Level 1 evidence.

Adverse effects of bupropion: Activation:

*this can increase agitation and may aggravate anxiety symptoms. * This is why bupropion is not indicated for use in people with anxiety as well.

*Lack of response of early improvement at 2-4 weeks is also a predictor of later antidepressant non-response/non-remission*

*this is why we reassess every 2 weeks* in a 2 week period of time we want to check in. Titrate the dose, change the dose or optimize the dose. *Same as PHQ9 being tested over the past 2 weeks*

Withdrawal from SNRIs:

*we want to gradually taper down to avoid discontinuation syndrome* Withdrawal from SNRIs is more associated with venlafaxine. More people describe electrical shock-like feelings when abruptly stopping venlafaxine, or if multiple doses are missed.

Luke Cage is a 35-year-old male who has just been diagnosed with major depressive disorder. The physician on your primary health care team asks you what drug to use for Luke. What questions do you have / what information do you want to find out?

-any other medications -what else has been tried -any anxiety, suicidal thoughts -any other health conditions -whats his B12, TSH -concerned about sexual dysfunction?

Mirtazapine place in therapy:

1st line in MDD. *can be used as monotherapy or add-on therapy in patients with antidepressant-associated sexual dysfunction. *may be considered in patients with insomnia* Safe in overdose.

Place in therapy for SNRIs:

1st line in MDD: *duloxetine is used more in practice for pain.

Pregnancy: For a patient with a prior history of a good response to medication and with moderate to severe symptoms:

1st line treatment: initial episode or recurrence is a combination of psychotropic medications and psychotherapy with open-ended duration.

Adverse effects of quetiapine: *quetiapine is not first line because weight gain can be significant*

Anticholinergic effects: sedation Dizziness Weight gain Prolonged QT interval Tardive dyskinesia: Uncontrolled body movements Suicidal thoughts Priapism: prolonged boner

Treatment Goals for MDD:

1. Eliminate the symptoms of acute depression/ achieve remission. *remission means a HAM-D score of 7 or a PHQ score of 0 to 4.

Neurotransmitter action: In depressive patients any one of these steps in NT action may be disrupted and interfere with the transmission of signals from neuron to neuron.

1. Neurotransmitter synthesis 2. Neurotransmitter storage 3. Vesicles transport 4. Vesicle fusion and neurotransmitter release 5. Autoreceptor binding 6. Receptor binding 7. Neurotransmitter reuptake/ enzyme degradation.

Treatment of serotonin syndrome: most cases are mild and supportive care is sufficient.

1. discontinuation of all serotonergic agents 2. Supportive care: Airway, breathing, circulation, oxygen, blood pressure 3. Sedation with benzodiazepines 4. Administration of serotonin antagonists: Example ondansetron. 5. Assessment of the need to resume serotonergic agents after resolution of symptoms.

Moclobemide side effects

1. tachycardia 2. hypotension, think fall risk too 3. sleep disturbance 4. Agitation 5. Nervousness/anxiety 6. N/V/D 7. tremor Not much weight gain. ***moclobemide is an upper so don't take it late after supper. Not much weight gain or sexual dysfunction with moclobemide*

Foods that are high in tyramine:

1.) Avocados 2.) Figs and bananas 3.) Fermented meats 4.) Beer & wine 5.) Cheese 6.) Yeast extract Overripe or spoiled food, banana peel, smoked or aged fish/meat. *Sauerkraut, fava beans, soya sauce and packaged foods.

By adding a new medication to the existing one after trying two steps:

1/5 people will get better.

Out of those who did not get better after two medication treatment steps by switching to a different med:

1/7 people got better.

Atypical antipsychotics as add ons:

10 RCTs found that augmentation with olanzapine, quetiapine and risperidone was significantly better than placebo. *lower doses than used for schizophrenia or bipolar disorder*

Bupropion XL dosing:

150-300mg po daily. Max 450mg po daily. Split dosing not required with XL formulation! but dose early in the morning so that you can potentially lower risk of sleeping problems.

Other treatment goals in MDD:

2. prevent harm such as suicide. 3. Restore optimal functioning: improve quality of life to level similar to that prior to onset of illness. 4. Prevent recurrence.

Drug interactions with SSRIs:

3A4/1A2 inhibition due to SSRIs: Any drug metabolized by these will have increased levels. 2D6 inhibition: decreased efficacy of codeine, ttamoxifen 2C9/2C19 inhibition: warfarin, clopidogrel, antiplatelet agents - leads to increased bleeding risk. Check drug interactions on an individual basis.

Max recommended dose of citalopram in hepatic impairment or poor CYP 2C19 metabolizers:

20mg/day for citalopram or 10mg/day for escitalopram in hepatic impairment, poor CYP2C19 metabolizers, 65 years old or concomitant therapy with potent 2C19 inhibitor.

Trazodone role in therapy:

2nd line for MDD because true antidepressant effects require a large dose. Chance of abuse with trazodone is a lot less than zopiclone or a benzo. it is used a lot as a hypnotic. especially in chronic pain patients, help them sleep. It may help with pain due to its anti-depressive qualities.

Moclobemide place in therapy:

2nd line for MDD. It is well tolerated alt to SSRIs or SNRI agents especially in patients with a significant anxiety component to their depressive episode* 2nd line for social anxiety disorder

A drug is eliminated: including any active metabolites in:

5 x the half life of the drug.

Proposed mechanism of action of antidepressants:

Antidepressants modify one or more monoamine system. Depression is not simply the result of neurotransmitter abnormalities.

TCAs for migraine prophylaxis

8-12 weeks are required for an adequate migraine prophylaxis trial. 1-3 weeks for desired analgesic effect: ex. neuropathic pain.

Frequency of sexual dysfunction on different antidepressants:

<10% with bupropion, mirtazapine, moclobemide 10-30% in citalopram, duloxetine, escitalopram and venlafaxine. >30% in fluoxetine, fluvoxamine, paroxetine and sertraline.

Bottom line on suicidality:

<18 years old there is a possible association. 18-24 years old: Equivocal 25-64: Neural-protective >65 years: possible protective effect

Fentanyl combination with SSRIs:

Antidepressants and fentanyl is a big concern for serotonin syndrome.

*SSRIs and bupropion addition*

Add on therapy of bupropion can be effective but be aware of the increased risk of seizures. *bupropion can inhibit CYP 2D6 so be aware of that combi with SSRIs*

Using medications to augment sexual side effects:

Additional anti-depressant (bupropion, buspirone, or mirtazapine) Evidence is equivocal - some studies show benefit and others do not Sildenafil or tadalafil Greatest evidence for men with anti-depressant induced erectile dysfunction (ED) Efficacy in one trial was similar to those found in ED secondary to other causes

Absorption of SSRIs:

Adequate with or without food.

Place in therapy for quetiapine:

Adjunct to antidepressant therapy for treatment resistant depression. 2nd line for MDD based on CANMAT if used as monotherapy.

SSRI cost:

All SSRIs are on SK formulary and NIHB formulary except vortioxetine which isn't EDS.

*Serious adverse effects from SSRI use*

All SSRIs decrease seizure threshold. SSRIs like any antidepressant can increase the risk of manic episodes. - *QT prolongation* Citalopram over 40mg daily.

Cost and availability of SNRIs:

All listed on SK drug formulary and NIHB formulary. *Desvenlafaxine (pristiq) and levomilnacipran not on either formulary.

*weight gain associated with SSRIs*

All of the SSRIs can contribute to weight gain and it may not always be a problem. higher probability of weight gain with paroxetine than other SSRIs.

*SSRIs metabolism*

All or metabolized hepatically by CYP enzymes to varying degrees AND are inhibitors of CYP enzymes to varying degrees.

Mianserin: not available in canada.

Alpha 2 adrenergic agonist; 5HT 2 antagonist. 60 to 120mg daily.

Mirtazapine:

Alpha-2 adrenergic agonist; 5HT 2 antagonist. 15-45mg

Tricyclic Antidepressants (TCAs) Tertiary amine

Amitriptyline Doxepin Imipramine Trimipramine Clomipramine

TCA adverse effects:

Anticholinergic effects and sedation are byfar the most common. *Most concerning adverse effects with TCAs are the cardiovascular effects: - conduction abnormalities, arrhythmias. Particularly concerning in overdose situations. *caution using this agent in those with history of suicidal ideation/attempts* Linear dose response with these agents.

Clinical features of serotonin syndrome:

Anxiety, agitation, delirium, diaphoresis, tachycardia, hypertension, hyperthermia, GI distress, tremor, muscle rigidity, myoclonus, hyperreflexia.

General statement about sweating with medications used for depression:

Any drug that has effects on norepinephrine is associated with sweating. So SNRIs such as duloxetine and bupropion.

SSRI/SNRI + mirtazapine:

Appears to improve depressive symptoms, anxiety and sleep but this is based on limited evidence.

SSRI/SNRI + mirtazapine:

Appears to improve depressive symptoms, anxiety and sleep. *Based on limited evidence.

Quetiapine: MOA:

Atypical antipsychotic: Antagonist at 5HT-1 and 2, D1 and 2, Alpha 1 and 2. Works on serotonin more than dopamine Mechanism for depression is unknown. Anxiolytic effects. Long active metabolite.

Augmentation therapy:

Augmentation therapy means adding an agent that isn't actually an antidepressant.

Mirtazapine cost and availability:

Available as 15mg, 30mg and 45mg tablets as well as ODTs.

Gi bleeding Management:

Avoid ASA or other NSAIDs if on SSRI: Use acetaminophen instead. Note that many patients with MDD also have pain important to assess concurrent use of analgesics. Some possibility of changing the antidepressant: Ex: switch to buproprion which acts on ND. or mirtazapine which does not inhibit serotonin reuptake. can also look at adding a PPI

Discontinuation syndrome:

Be aware that discontinuation syndrome is more associated with venlafaxine. It is temporary and can goes away within 2 weeks at the most. This can still occur if we taper and less likely if we are switching agents.

*increased risk of GI bleeding with SSRIs Mechanism*

Be aware that serotonin is found on platelets! This is an additive risk for bleeding. *This is something we have to look at in terms of bleeding* *If they're taking the SSRI then you can do some prophylaxis with a PPI.

Meclobemide:

RIMA: Reversible Monoamine oxidase inhibitor. 300-600mg. Used to be a first line option and is an MAOi type drug. It has dietary restrictions and had some other concerns.

Moclobemide: 2nd line for the treatment of MDD:

Better tolerability and safety than TCAs and irreversible MAOIs. Inhibits metabolism, deaminaiton of 5HT, NE, DA *Irreversible MAOIs are 3rd line*

Bottom line with citalopram warning:

Bottom line: We should probably be most concerned in those with pre-existing risk factors for TdP Suggest an ECG in those you are worried about Low K+ and low Mg++ should be corrected before giving citalopram Monitor for signs of abnormal heart rate or rhythm: Dizziness, palpitations, syncope, seizures Patients should be cautioned to not just simply stop If starting citalopram in a patient who is otherwise healthy, you could push the dose past 40mg despite the Health Canada warning

Sexual dysfunction and weight loss with bupropion*

Bupropion has weight loss instead of weight gain due to reduced appetite! As well, there is less sexual dysfunction with bupropion.

Non pharm options in treatment resistant depression:

CBT, psychotherapy, counselling, group psycho education and exercise. Cognitive behavioural therapy: Get them out of bed in the morning and have small goals throughout the day

Trazodone:

CNS effects: Dizziness, sedation, insomnia which is a paradoxical effect, headache. Hypotension QT interval prolongation in overdose Dry mouth and other anticholinergic effects Rare: Seizure, suicidal ideation, serotonin syndrom and Priapism: 1 in 6000 which is a prolonged duration of erection.

TCA CV toxicity:

CV toxicity is well documented in depressed patients without pre-existing CV disease. common CV AEs: include tachycarda: some tolerance can develop and orthostatic hypotension. Cardiac conduction delays: - prolonged conduction time by delaying inward Na+ into cardiomyocytes, thereby slowing cardiac depolarization and prolonging QT. TCAs may induce heart block in patients with pre-existing conduction disorder: Ex: bundle branch block.

Mirtazapine metabolism:

CYP 1A2, 2C9, 2D6, 3A4. Many mechanisms for elimination of mirtazapine. 75% renally excreted.

use problem with bupropion:

Can be snorted as the metabolite to give a high somewhat similar to cocaine. Causes caustic burns.

TCA overdose:

Can produce arrhythmias usually due to QT prolongation: usually at doses 2g a day or more.

Serotonin reuptake:

Causes serotonin neurotransmitter to remain in the synapse.

Caution with mirtazapine:

Caution combining with other CNS depressants: e.x. diazepam: impairment of fine motor skills.

CNS depressants combined with Mirtazapine:

Caution when combined with diazepam: impairment of fine motor skills.

Monitoring suicidality:

Closely monitor suicidality in children and youth being newly prescribed antidepressants. Consider more frequent visits and increased involvement of family members.

How might you counsel a patient regarding sexual dysfunction?

Columbia Risk Score for assessment Assess its impact on patient's life Talk in third person E.g., do not say "YOU might have ... " Ensure counseling is done on initiation If this side effects presents, then the patient can come back and talk about it and make a plan before stopping the drug

Suicidality tx:

Consider CBT or other forms of psychotherapy in patients with severe MDD, suicidality, or psychotic features to their depression For those who develop suicidality during treatment, consider dose reduction, switching or discontinuing offending agent

Management of suicidality:

Consider hospitalizations for patients reporting suicidal ideation, planning or attempts. Treat with antidepressants that show best efficacy. *Sertraline in adults: greatest efficacy in reducing/preventing suicidality* Children <18 years old: fluoxetine and citalopram have the strongest evidence for efficacy in treatment of MDD.

CANMAT guidelines: Level 1 evidence:

Escitalopram > citalopram, paroxetine, pooled SSRIs Sertraline > fluoxetine, pooled SSRI.

Other drug:

Cross-tapering is recommended between drugs of different mechanisms of action.

MOA concerns:

Delivery restriction and drug-drug interaction. MAO is restrictive.

*Sertraline and fluoxetine stimulation*

Described as butterflies in the stomach and make you feel nauseous that is short term.

SSRIs switching:

Direct switch of equivalent doses between SSRI and SSRI and venlafaxine/duloxetine due to similar mechanisms of action.

Management of GI side effects

Divide doses/ reduce SSRI dose if patient is stable - Take medication with small amount of food such as crackers or toast. *some patients may benefit from ginger containing food or beverages. *may use H2RA or PPI especially if other indications. *

Management of SSRIs CV effects:

Do not use in patients with congenital long QT syndrome or known QT prolongation Do not dose citalopram > 40mg/day or escitalopram >20mg/day. *if electrolytes and ECG are fine, can use a higher dose*

Q-T prolongation:

Dose related and still relatively changes. More of a concern with citalopram at doses 60mg and higher.

SNRI CV effects:

Dose related increase in mostly diastolic blood pressure: Starts at 150mg/day but especially in doses > 225mg/day. Sustained BP elevation seen in 13% of people on doses > 300mg/day.

High doses of duloxetine offer:

Doses 60mg/day of duloxetine is not shown to be more effective.

MDD with somatic symptoms:

Duloxetine: pain level 1 Bupropion: fatigue: level 1

Serotonin syndrome:

Ranges from benign to lethal. Typical vital sign abnormalities: Tachycardia Hypertension: Hyperthermia and dramatic swings in pulse and blood pressure.

Non-pharm therapy in MDD:

ECT (electroconvulsive therapy) Counseling! Dietary and herbal supplements Mind-body interventions Music therapy Physical interventions Light therapy Acupuncture and massage Yoga Tai Chi Homeopathy Whole body magnetic field ... and many more ...

*how do you wait for a response from an antidepressant?*

Early improvement: Defined as greater than 20 to 30% reduction from baseline in a depression rating scale after 2-4 weeks --> this is correlated with response and remission at 6-12 weeks.

Discontinuation syndrome:

Exact mechanism is unknown but multiple theories exist. *more likely in those who have been treated for a duration longer than 6 to 8 weeks. *risk appears to also relate to affinity for serotonin transporter*

FINISH mnemonic to recognize discontinuation syndrome: This is temporary and self limiting: and likely won't last longer than 2 weeks.

F: flu-like symptoms I: insomnia N: Nausea I: imbalance S: sensory disturbances H: Hyperarousal: anxiety and agitation. *most common symptom of discontinuation syndrome is dizziness/vertigo.

No evidence that tapering or discontinuing antidepressant medication near term is necessary, safe or effective in terms of preventing transient neonatal complications:

Failing to adequately treat the anxious or depressed mother may lead to worsening symptoms and compromise maternal and fetal health, maternal-infant bonding, and infant care in the post-partum period.

SSRIs CV effects: *Citalopram and escitalopram*

Fewer and more benign side effect profile including CV when compared to TCAs due to lower affinity for histamine, muscarinic and alpha 1 adrenergic receptors *There is dose-dependent QT prolongation, potentially due to cardiotoxic metabolite: didesmethylcitalopram Risk factors include underlying heart conditions, those predisposed to low blood levels of potassium and magnesium.

*If someone is having a good response to antidepressant other than fluoxetine then we don't need to change it*

Fluoxetine and other SSRIs are first line in pregnancy *besides paroxetine* Fluoxetine: we have most experience with and largest exposure in pregnancy.

*What SSRI has a very long half life?*

Fluoxetine has a long half life. It can self-taper kind of because of how long it takes to be no longer clinically relevant.

*Fluoxetine and rates of GI side effects*

Fluoxetine has higher rates of GI side effects such as Nausea, vomiting and diarrhea.

Safer SSRI in pregnancy?

Fluoxetine.

Fluvoxamine and sertraline relationship with nausea:

Fluvoxamine and sertraline have higher rates of nausea.

*CANMAT overall tolerability with SSRIs*

Fluvoxamine has poorer tolerability than other SSRIs. *highest effects are nausea, sedation and constipation.* *Fluvoxamine has more side effects and drug interactions because it is a strong inhibitor of enzymes.

QT prolongation with SSRIs:

Greatest concern with citalopram and escitalopram

HANDS as the adverse effects of SSRIs:

H: Headache A: anxiety - usually transient N - Nausea D - Diarrhea S - Sexual dysfunction.

Learning objective 4: SSRI adverse effects: HANDS

HANDS: H: Headache A: Anxiety N: Nausea D: Diarrhea S: Sexual dysfunction

*anxiety adverse effect due to SSRIs*

Happens usually within the first 2 weeks, due to the changing in the balance of neurotransmitters - short term increased in anxiety that will go away.

What dietary restrictions do you have if you're on an irreversible MAOI?

Have to avoid foods that are easily fermented such as aged cheese, alcohol -- but mostly draft beer. 1-2 glasses of wine in an instance is relatively safe.

*dose disadvantage of TCAs*

Have to be titrated to a therapeutic dose. *their side effects include tiredness and orthostatic hypotension. *these drugs take more time to kick in* 4-8 weeks of treatment with TCas is needed before determining if a patient with depression is partially or non-responsive.

Physical examination findings:

Hyperthermia (temp. over 38 Celsius) Agitation Slow, continuous, horizontal eye movements Tremor Akathisia Deep tendon hyperreflexia (twitches or spasms) Muscle rigidity Dilated pupils Dry mucous membranes Increased bowel sounds Flushed skin Diaphoresis

Interpersonal therapy:

Identify issue, role transition, role dispute, grief and interpersonal deficits. focus on social context.

Lessons from STAR*D trial:

If a 1st treatment with one SSRI fails, 1/4 people who choose to switch to another medication will get better. *regardless if that's another SSRI or another agent* If patient chooses to add a new medication to existing SSRI: 1/3 wil lget better.

*If stopping MAOI how long do you wait before starting another antidepressant?*

If stopping MAOI, wait 2 weeks before starting another antidepressant.

Selegine:

Irreversible MAO-B inhibitor but not available in CAnada.

Behavioural activation:

Increase activity and access to rewarding experiences. Address inertia, avoidance, social withdrawal.

Endocrine effects of mirtazapine:

Increased TGs: weight gain. Limits use in many.

Amiodarone and dronedaron with trazodone:

Increased risk of QT prolongation when used concurrently.

Mechanism of Tricyclic antidepressants:

Increases the synaptic concentration of serotonin and or norepinephrine in the CNS by inhibition of their reuptake by their presynaptic neuronal membrane pump.

*A large body of evidence implicates a dysregulated endocrine and inflammatory response in the pathogenesis of depression*

Inflamamtion may be associated with certain subgroups and those who have experienced stressful life events such as childhood trauma or bereavement may be at higher risk of developing depression.

MOA of SSRIs: Efficacy:

Inhibit serotonin reuptake pump and increase the postsynpatic serotonin receptor occupancy. *Both time to onset 2-4 weeks and rate of response 60-70% are comparable to TCAs and MAOIs*

MOA of SNRIs:

Inhibits serotonin reuptake at low doses. *Dose-dependent reuptake inhibition of norepinehprine at higher doses. Also has weak dopamine reuptake inhibition.

Trazodone MOA:

Inhibits uptake of serotonin and acts as an antagonist of 5HT-2A/2C receptors. Trazodone is an antagonist at alpha-1 adrenergic receptors and histaminergic receptors.

TRD is not a subtype of depression:

It's a spectrum from partial response to complete treatment resistance.

Citalopram actual QT prolongation:

Less than 20msec. if the usual thresholds for concern were used in the study's interpretation, the warning would likely not exist.

Counselling on sexual dysfunction:

Libido on antidepressants can actually improve since we can improve the anhedonia and interest. Intermittent use such as Viagra may be effective but not affordable. May need to switch drug to something else because the functional does not improve.

Cost and availability of bupropion:

Listed on SK drug formulary and NIHB* 30-40$

Augmentation therapy in treatment resistant depression:

Lithium: mood stabilizer Atypical antipsychotic Thyroid: cytomel. T3 Others: buspirone, methylphenidate, modafinil, pindolol <-- not recommended.

In 6 months, Luke returns to your clinic and tells you he could not get to sleep last night, feels like he is getting ill, and feels nauseous. What further questions would you ask? Have you stopped taking citalopram? How might you proceed? Would probably feel better just getting right back on those meds

Luke returns in another 6 months and endorses sexual dysfunction (erectile difficulties). What further questions would you ask? How is the drug working for him? If not, just switch. If it is working, maybe lower the dose, or add on sildenafil. Other medical conditions can contribute to erectile dysfunction, or being elderly Other meds he's on that could interact with sildenafil How might you proceed? He's feeling great, PHQ9 score is getting better add on viagra/cialis, or add on buproprion/mertazapine

MDD with mixed features:

Lurasidone level 2 evidence Ziprasidone level 3.

*Moclobemide*

MAO-A selective. this is reversible. It still does have the MAO-B pathway that's open for metabolism.

Selegiline transdermal:

MAO-B inhibitor. 6-12mg daily. not available in canada.

Tranlcypromine:

MAOI 20-60mg

Third line antidepressants: Phenelzine:

MAOI 45-90mg. *if you're really not getting results on any of the first or second line agents* Specifically MAO because they require dietary restrictions and so on.

Approved indications for bupropion:

MDD SAD: Seasonal affective Disorder Smoking cessation. *Has a lower degree of sexual dysfunction: because it has no effect on 5HT. Less weight gain compared to SSRIs!*

Goals of therapy in pregnancy and depression:

Maintain euthymic mood in the mother throughout pregnancy and preventing postpartum decompensation are most important goals. *If using medication, achieving remission should still be a goal for the mother*

*what are the signs and symptoms of hyponatremia*

Manifests as personality change, more confusion or a change from normal.

T3 as an option:

May be better than lithium due to better tolerance. Also produced greater decreases indepression scores versus lithium, but not statistically significant.

Diarrhea adverse effect:

May be transient and resolve within weeks. Most experience this by 2 weeks and some will have it persist up to 3 months.

Summary recommendations for antidepressants: First-line Level 1 evidence: 1. Agomelatine: Valdoxan *meant to help circadian rhythm.

Melatonin 1 and Melatonin 2 agonist; 5HT antagonist. Dose 25-50mg daily. not coming to Canada because of liver abnormalities associated with it

Triad in serotonin syndrome:

Mental status changes, autonomic hyperactivity, neuromuscular abnormalities.

PK of Bupropion:

Metabolized by CYP 2B6 to active metabolite: Hydroxybupropion.

PK and DIs of moclobemide:

Metabolized by CYP2C19 major. CYP 2D6 is the minor route. 95% excreted in urine as metabolites. *Be aware that moclobemide loses its selectivity for MAO-A as the dose increases. This means that if you increase the dose above 600mg per day then you need to follow the tyramine diet*

Mirtazapine on H1:

Mirtazapine acts on the H1 receptors as an antagonist. Sedation from histamine. * moderate peripheral alpha-adrenergic and muscarinic receptor antagonist* The clinical effect of mirtazapine for depression is not clear.

Mirtazapine metabolism:

Mirtazapine is extensively metabolized by CYP 1A2, 2C9, 2D6 and 3A4, As well as demethylation and hydroxylation. Mirtazapine is 75% renally excreted. *mirtazapine has an increased risk of serotonin syndrome in combination with serotonergic agent* - recall from lab.

Mirtazapine CANMAT:

Mirtazapine is first line for MDD. Significantly more efficacious for the acute treatment of unipolar depression versus: duloxetine SNRI, Fluoxetine SSRI, fluvoxamine. SSRI and Paroxetine SSRI.

What medications have lowest rates of sexual dysfunction:

Mirtazapine, bupropion and vortioxetine as well as vilazidone. Moclobemide

Selegine role in therapy:

Moreso in parkinson's disease.

*General statement about sedation and SSRIs*

Most SSRIs are non-sedating. *Mild sedation can occur with sertraline and citalopram.*

Drug interactions with TCAs:

Most relevant drug interactions are those with similar pharmacodynamic effects 1. Anticholinergic: TCAs have very large anticholinergic side effects 2. Cardiotoxic: QT prolongation *TCAs check for drug interactions on individual bases* hepatically metabolized - multiple possible drug interactions exist.

First line- Bupropion:

NDRI: Norepinephrine dopamine reuptake inhibitor. 150-300mg daily.

Reboxetine *not available in Canada*

NRI 8-10mg.

Toxicity from SNRIs:

Similar to SSRIs: start with small dose and increased gradually.

General considerations about GI upset from antidepressants:

Nausea and upset stomach: Very common: majority of patients will experience this by the second week of treatment. up to 83% and up to 3 months into therapy.

*Does mirtazapine need to be dose adjusted?*

No adjustment required with renal or hepatic dysfunction! exclusive to mirtazapine and not bupropion. *taper down when discontinuing*

Do TCAs need dose adjustment?

No dose adjustments required in renal or hepatic impairment. TCas are renally eliminated and hepatically metabolzied so use with caution.

Management of sexual dysfunction in depression management:

No intervention: common side effect that we can't really do much about. Reducing the dose can help but we are unsure.

*Treatment resistant depression*

No standardized/consensus definition for treatment resistant depression:

What is first line for depression during pregnancy?

Non-pharmacological therapy but if medication is required: 1. Sertraline, escitalopram and citalopram

Secondary amine:

Nortriptyline, Aventyl: twice as potent and half the side effects of amitriptyline. Desipramine

TRD is not equivalent to:

Not equivalent to chronic depression or difficult to treat depression.

MOA of bupropion:

Not fully understood. Weak inhibitor of neuronal uptake of norepinephrine and dopamine. People think bupropion is a NDRI. *Efficacy of bupropion is very good as an add on treatment*

What are the atypical antipsychotics?

Olanzapine, clozapine, quetiapine, risperidone, aripiprazole, ziprasidone

*what SSRIs form active metabolites?* *only fluoxetine and sertraline

Only Fluoxetine and sertraline form active metabolites *if liver cannot metabolize these efficiently, drug will not work well, or potenitally cannot clear drug effectively. *this is a concern in liver dysfunction*

When would someone actually benefit from an antipsychotic?

Only if they're a risk to themselves or to other people. *elderly patients with dementia, being prescribed an antipsychotic has an associated increase in all cause mortality.

SSRI/SNRI + bupropion addition:

Optimal doses are unclear, though bupropion combined with usual doses of SSRI/SNRI are well tolerated *known advantage of adding bupropion is for SSRI/SNRI-induced sexual dysfunciton. Consider addition of bupropion at low dose 100mg.

What is the biggest adverse effect to watch out for with trazodone?

Orthostasis.

Pregnancy: risk versus benefit of treatment:

Overall risk of birth defects with SSRIs is generally low, but may cause transient neonatal effects. Risk of pregnancy complications such as miscarriage, still birth, preterm birth, shorter gestation, and low birth weight appears to be low but is controversial. 4% increase in abortion rate above baseline has been reported across all antidepressant classes.

Discontinuation syndrome in SSRIs: *greates to least*

Paroxetine, fluvoxamine, sertraline, citalopram and then last is paroxetine because fluoxetine pretty much tapers itself out.

Avoid which SSRI in pregnancy?

Paroxetine. *paroxetine may have higher risk of cardiac malformations in fetus* Paroxetine has higher risk of cardiac malformations in fetus

Vilazadone (Viibryd)

Partial agonist for 5HT1A instead of full agonist also has SSRI activity

*What is serotonin syndrome* Serotonin syndrome is incorrectly classified and it's really a toxicity. *usually due to two serotonergic drugs that work in different ways that are used together and typically can be due to aggressive dose or overdose situtation.

Potentially lethal condition caused by overstimulation of central and peripheral serotonin receptors. *results from an interaction between multiple medications that increase serotonergic transmission*

When do cases of serotonin syndrome present?

Present within 24 hours, and mostly within 6 to 8 hours of a change or initiation of a drug.

Place in therapy for trazodone:

Primarily as a hypnotic. Good choice as hypnotic for someone with MDD. Hypnotic - inducing sleep

Quetiapine PK and DI:

Primarily hepatically metabolized via CYP 3A4. Excreted mostly in urine. Quetiapine may potentiate effects of alcohol. May enhance effect of antihypertensives based on PD Caution with CYP 3A4 inhibitors and inducers

Elimination of bupropion:

Primarily through the kidneys. *renal dosing adjustments are recommended* - Best to just choose an antidepressant that isn't affected by the kidney function.

*Novel antidepressants: multi-modal drugs* Vortioxetine:

Pro-cognitive antidepressant. Vortioxetine has a big nausea side effect because of its opposite of ondansetron effect. *if nausea is seen with vortioxetine you have to take the drug at night* no sexual dysfunction and has no drug interactions and only indicated for MDD.

Sexual dysfunction in practice:

Rates of sexual side effects have bene as high as 60% in observational studies. Antidepressants associated with an increased frequency of sexual dysfunction are: SSRIs, SNRIs, TCAs,

Remission rates for MDD:

Rates seem to be higher with combination therapy when compared to switching therapy.

Confirming TRD:

Re-evaluate for comorbidities or medications that could be contributing to depression: - rate of psychiatric comorbidity in MDD is high and anxiety disorders, substance use disorders and personality disorders are associated with poorer response. Relevance of medications varies: Low relevance with low dose ASA versus steroids. *Ensure adherence: most people stop within 2-3 months Verify adequate doses and length of previous trial(s)

What add can be added to SSRIs if they affect sleep?

Recall that SSRIs affect REM sleep. So you may need adjunct treatment for sleep with a small dose of benzodiazepine or trazodone,

Goal of CBT:

Recognize negative cognitions Respond to negative thoughts and behaviours. Problem solve and test assumptions

Managing discontinuation syndrome with SSRI/SNRI:

Reduce the dose over 2 weeks at the end of treatment course. Faster if switching to another antidepressant. Except fluoxetine, which is self-tapering.

Reduction or elimination of doses to manage sexual dysfunction:

Reducing doses of antidepressants to improve antidepressant-related sexual dysfunction while still maintaining efficacy as antidepressant but can potentially have relapse.

Suicidality adverse effect:

Reference to suicidal thoughts or behaviour in treatment emergent situations: First 4 to 8 weeks of therapy. not for those on long term therapy.

SNRI CV management :

Regular BP monitoring: before, after starting and ongoing. Slow dose titration recommended. 75mg increase every 4 to 7 days. Caution in patients with history of hypertension or ischemic heart disease. Pre-existing HTN should be controlled before using venlafaxine! If sustained BP elevation, may require dose reduction or discontinuation of venlafaxine or switch to another agent.

Dosing for bupropion: *Caution in renal or hepatic impairment. Consider reducing dose and/or frequency*

Regular formulation: 1. Start at 100mg po daily 2. Usual dose: 100-150mg po Daily 3. Max dose: 450mg po Daily. Max 150mg per dose due to seizure risk.

Elimination of SSRIs:

Renal excretion; dose adjustment is needed in renal impairment. *all SSRIs have long half-lives, fluoxetine is the longest which is 4 to 6 days with all others having about 24 hours.

Adverse effects of mirtazapine: CNS:

Sedation: can last until morning even if taken at supper.

Partial agonist: aripirazole:

Sensing the environment to kick in. If there's too little dopamine and norepinephrine in the brain then this increases it.

Tyramine in the context of full MAO:

Sequelae: If you increase the production of serotonin through the tyramine which gives rise to serotonin then you have too much and there isn't MAO to break it down. - Sequelae: Acute hypertension Serotonin syndrome usually due to too much serotonin drug.

What SSRIs are the most stimulating for the stomach?

Sertraline and Fluoxetine. Can be described as butterflies in the stomach and make you feel nauseous and that is a short term.

*Elderly SSRI level 1 evidence?*

Sertraline, escitalopram and citalopram ahve the most evidence in the elderly. They also have the fewest drug interactions.

What medications are preferred in pregnancy:

Sertraline, escitalopram and citalopram.

Management of Diarrhea as an adverse effect of antidepressant therapy:

Should resolve on its own May use anti-diarrheal agent such as loperamide. May wish to try probiotics and/or psyllium etc.

STAR*D trial with bupropion:

Showed that bupropion as an add on had greater reduction in the number and severity of symptoms.

Escitalopram and sertraline from CANMAT:

Shows that they are better in acceptability. Based on overall withdrawal rates, compared to other antidepressants.

What limits use of TCAs?

Side effects and risk of overdose limits their use as an antidepressant.

Mirtazapine: Genituourinary effects:

Significantly less sexual dysfunction versus other antidepressants: SSRIs.

PDE5 inhibitors best in sexual dysfunction due to antidepressant therapy:

Sildenafil and tadalafil.

Augmentation in treatment resistant depression: T3

T3 - Triiodothyronine: *Improves and accelerates antidepressant effect in RCTs. 25-50mcg/day is recommended and rarely affects peripheral thyroid measures at this dose. trial is 2 weeks at 50mcg.

TCA CV management:

TCA contraindicated in heart block or post-MI during acute recovery phase. Use with caution in patients with history of CVD: previous MI, stroke, tachycardia, conduction abnormalities, or in patients with family history of sudden death, dysrhythmias, or conduction disorders. Closely monitor with doses > 300mg/day. No known difference between secondary and tertiary amine TCAs for the major CV events.

Beers' List of Inappropriate drugs for Older Adults antidepressants:

TCAs. one of the reasons is due to risk of osteoporotic fractures.

MOA of mirtazapine: Remeron

Tetracyclic four ringed chemical structure. Antagonist of presynaptic central alpha adrenergic receptor. *Leads to increased release of NE and 5HT.* Also antagonism of 5HT2 and 5HT3 receptors: post synaptic side which can have anxiolytic properties. *by blocking these it can increase the flow of serotonin through the neuron*

Mirtazapine: MOA:

Tetracyclic: four ringed chemical structure) *antagonist at pressynaptic central alpha- adrenergic receptors: leading to increased release of NE and 5HT. *antagonism at 5HT-2 and 5HT-3 Receptors - linked to lower anxiety and GI side effects respectively.

*Flat dosing with SSRIs*

The drug doesn't have much more benefit by exceedingly increasing the dose for SSRIs. When you're assessing a patient every 2 weeks you don't have a big dose to move. This is important because this is a difference between using these medications for depression than using them for anxiety.

Switching from amitriptyline to nortriptyline:

The newer agents are better tolerated. *know that nortriptyline is the active version of amitriptyline. *

Bottom line from STAR*D trials:

The odds of getting better diminishes with every additional treatment strategy needed.

Sedation effect with mirtazapine:

The sedation effect is lost or at least is much less pronounced with doses starting at 30mg. *could overcome sedation effect if start right at 30mg* this is because the NE effects are increased as the dose increases.

*presynpatic receptors*

These auto receptors are key in the negative feedback. Reuptake inhibitors prevent the negative feedback loop so that more is brought to the synapse.

Initial TCA considerations:

These medications are not safe in overdose situations, but otherwise work pretty good. Would only really be dispensing TCAs for other indications that aren't depression.

*how do atypical antispychotics work?

They are effective in treating depression by blocking the 5-HT2C or 5HT2A receptors located on the interneurons. By doing so, they increase activity in the norepinephrine and dopamine circuits.

Second line agents Level 1 evidence: When are they used?

They are used if you do not achieve 50% decrease and or remission we change therapy. We may look at these options if they don't have effectiveness.

SSRIs do not cause bleeding:

They only influence the duration of bleeding and or volume of blood loss in conditions that involve underlying disease or concomitant use of drugs: Ex: NSAIDs. *try to take off NSAID*

Trazodone PK and DIs:

Trazodone has increased absorption with food but delays abosrption. *Active metabolite is important for trazodone's antidepressant effect, thus a drug interaction that alters metabolism could have significant effects. 75% excreted via kidney 25% liver

Mirtazapine Dosing:

Typically 15mg po HS. May increase q1-2 weeks up to max. of 45mg po HS. *no adjustment required with renal or hepatic dysfunction but use with caution* Taper down when discontinuing.

What occurs if we don't treat depression effectively in the mother:

Untreated, or undertreated, maternal depression poses significant risks to both the mother and child. *the risks of stopping often outweigh the risks associated with pharmacotherapy*

Cognitive behavioural analysis system of psychotherapy (CBASP)

Use cognitive, behavioural and interpersonal strategies Focus on negative relationship patterns

CV effect in SNRI:

Usually occurs within 2 months of dose-stabilization. Baseline BP is not a useful predictor of occurrence of BP elevation with venlafaxine. Small changes with duloxetine but clinically insignificant.

Dosing for SSRIs?

Usually once a day. *fluvoxamine is the only one that is dosed BID* Know that SSRIs are first line in depression.

*SNRIs currently available*

Venlafaxine (effexor) Desvenlafaxine (Pristiq): Flat dosing Duloxetine (cymbalta) Levomilnacipran (Fetzima)

Which SNRIs are first line for depression according to CANMAT?

Venlafaxine and duloxetine. There is no reason why an SNRI cannot be used first line.

Vilazodone: Multimodal drug that works as an SSRI but has other modes.

Viibryd: SSRI; 5HT1 partial agonist. 20-40mg daily.

*What meds have the most nausea associated with them?*

Vortioxetine (multimodal) > Venlafaxine > SSRIs > bupropion > moclobemide > mirtazapine.

MDD with cognitive dysfunction:

Vortioxetine: level 1. Not the only drug to work but a study showed it has a high lee lof evidence.

Combining antidepressants in treatment resistant depression:

advantage: not losing any benefit from the first antidepressant. Various combinations can be used in theory but there is not good-quality evidence to support specific ones.

*Duloxetine dose for dual 5HT and NE reuptake inhibition*

You get 50% reuptake for 5HT and NE from the get go! duloxetine can be a bit faster in its onset of effect in this case.

Caution if a patient is on zyban:

Zyban is the same drug as bupropion so be aware of that.

What is desvenlafaxine:

active metabolite of venlafaxine

Lithium augmentation therapy:

antidepressant effect: particularly noted in bipolar disorder. Most investigated augmentation strategy. *suggested dosing: 600mg po daily x 1 week, then 900mg po daily for 1 week, then titrate to achieve optimal lithium plasma levels. *Target: 0.4 to 0.6mEq/L. Added on once a day at bedtime. *

Psychoeducation about the anxiety risk with SSRIs:

anxiety is normal and will get better. If it's really bothersome start from a low dose and titrate even slower.

TCA concerns:

are lethal in overdose and have anticholinergic effects.

Aripiprazole

atypical antipsychotic 2nd gen that was found to be effective when added to SSRI/SNRI.

*SSRI + TCA*

based on older studies not recommended anymore.

If a pregnant woman is already on a medication:

doesn't matter what the drug is. If the patient is doing very well and they're in remission. General consensus is you don't stop the drug or change it if the mom is doing particularly well. Unless a defined period of time is there and an appropriate time to come off, first episode and it's been a year.

Pregnancy is a stressful period of time. So, if a woman becomes depressed: if you can go without the drug you can go along with non-drug measures. It's risky for mom and or baby for mom to be depressed throughout the pregnancy. Best thing: is to try and get the mom as good as possible.

don't be too scared to treat them.

Dose adjustment of antihypertensives due to trazodone:

dose adjustments may be required since trazodone may cause hypotension via alpha 1 antagonism.

Seizures associated with bupropion:

dose related effect: people with known history of seizures can be a consideration and especially people with active eating disorder is at higher risk due to electrolyte imbalance.

Anticholinergic effects

dry mouth, blurred vision, constipation, urinary retention

*Increasing norepinephrine levels through the Alpha 1 receptor*

enhances activity in the serotonin system. If activity in the dopamine system through the D2 receptor is enhanced, activity in the serotonin system is also enhanced.

What SSRIs are most commonly prescribed in pregnancy?

escitalopram and sertraline. This is due to safety in pregnancy and breast feeding.

*when to switch antidepressants:

faiilure to respond or if the side effects are intolerable

What quantifies a response based on HAM-D?

greater than or equal to 50% reduction from baseline HAM-D score.

*** COUNSELLING POINT***

if a patient is using an antidepressant for a prolonged period of time: Longer than 6 to 8 weeks then we have to mention potential discontinuation syndrome.

*what do we consider if abrupt TCA discontinuation required?*

if abrupt discontinuation required consider benztropine to minimize autonomic symptoms.

General statement about increased risk of suicidal thinking with antidepressant therapies:

increased risk of suicidal thinking and behaviour in children, adolescents, and young adults in short term studies. *no increase in suicidality in patients > 24 years old and actually have reduced risk of suicidality in elderly >65 of age.

Working definition of treatment resistant depression:

lack of improvement or <20% reduction in depression scores following adequate trials of two or more antidepressants. do we have diagnosis correct? Are they taking the drug? any substance use?

When do we look at lithium levels?

levels would be drawn 10-12 hours after dose.

Antagonism of 5HT3 is linked to:

lower GI Side effects.

Cross taper:

lowering the dose of the first drug wile starting 2nd drug at low dose.

*Paroxetine considerations*

more weight gain than any other SSRI and this is due to anticholinergic effects.

*Clomipramine*

most potent antidepressant to increase serotonin but it is not the most tolerated but it is the most effective drug for OCD.

Desipramine:

relatively better tolerated in terms of orthostatic hypotension.

Assume you, the physician, and patient, chose to start citalopram 20mg PO daily. What information would you include in your counseling session?

sexual dysfunction -HANDS -discontinuation syndrome -other substances -explain to give it a fair trial -non-pharmacological measures -have him fill out a PHQ-9 to monitor therapy

SSRI and SNRI complaints:

some may complain of feeling numb and emotionless. this is due to down regulation of norepinephrine and dopamine in the prefrontal cortex.

Discontinuation syndrome onset:

start 24-72 hours after stopping antidepressant. Generally mild and transient. *symptoms resolve spontaneously in 1-2 weeks.*

adverse effects of T3: Triodothyronine:

stopped due to tachycardia, insomnia or sweating.

*citalopram, nortriptyline, sertraline and paroxetine are first line in breast feeding:

this is because they have low to undetectable serum concentrations in breast-fed infants/children/

Anxiety and SSRIs:

we do not have flat dosing and they can be more beneficial at higher doses.

When do you get NE reuptake inhibition with venlafaxine?

you get NE reuptake inhibition when you dose venlafaxine above 150mg per day. *Important to ask their dose of Venlafaxine because at low dose it is just an SSRI*