Mod 8 Serotonergic Drugs

Depression

• Mood disorder

• Refers to MDD

• Can be medicine-induced or side effect of other disease

• Characterized by:

  • Melancholia / Persistent feeling of sadness

  • Loss of interest in activities

  • Inability to perform daily activities

  • Can lead to suicide

Major Depressive Order (MDD)

• Unipolar depressive disorder

• >= 5 symptoms for at least 2 weeks

Disruptive Mood Dysregulation Disorder

• Chronic severe persistent temper outbursts

• >= 3x / week of persistent angry / irritable mood outside of outbursts most of the day, almost daily, that’s observable by others

Persistent Depressive Disorder

• Formerly Dysthymia

• Depressed mood most of the day, in more days than not, for at least 2 years

Premenstrual Dysphoric Disorder

• Expression of mood lability, irritability, dysphoria, and anxiety

• Occurs repeatedly during pre-menstrual phase

• Remit shortly around the onset of menses or shortly thereafter.

Substance/Medication-Induced Depressive Disorder

• Acyclovir, anticonvulsants, isotretinoin

• INF-α, β-blockers, CCBs, antibiotics, sex hormone drugs

Other Depressive Disorder

Due to another medical condition (Hyperthyroidism, Cushing’s, TBI, etc.)

Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM5)

 -For depression diagnosis

• Symptoms cause clinically significant distress OR impairment in social, occupational, or other important areas of functioning

• Rule out:

  • Comorbidities and other drugs or substances

  • Schizophrenia spectrum disorder

  • Bipolar disorders

Mania

Differentiating factor between depression and bipolar disorder

Suicide

• Act of deliberately killing oneself

• Lifetime risk of people with untreated depression: 20%

Suicidal Ideation

Contemplation of ending one’s own life, -Ranging from fleeting thoughts to detailed plans

Non-suicidal self injury (NSSI)

Intentional self-infliction of poisoning or injury, which may or may not have a fatal intent or outcome

Negative Cognitive Styles

Things around you don’t illicit positive reactions

Learned Helplessness

Culture may lead to low self-esteem and sense of control (i.e. laging sinasabihan ng walang kwenta since bata)

“Selective” Serotonin Reuptake Inhibitor (SSRI)

• Escitalopram

• Fluoxetine

• Sertraline

• Paroxetine

• Fluvoxamine

• Dapoxetine

Serotonin-

Norepinephrine Reuptake Inhibitor (SNRI)

• Duloxetine

• Venlafaxine

• Desvenlafaxine

Multimodal Serotonin Receptor Modulator

Vortioexetine

Noradrenergic and Specific Serotonergic Antidepressant

Mirtazapine

Melatonergics

Agomelatine

Glutamatergic

Eskatamine

Less Used Depression Treatment

Tricyclic antidepressant (TCA)

Treatment Adjuncts

• D2-5HT Blockers

• Mood stabilizers

• Hormones

• Stimulants

• Anxiolytics

Neuroplasticity Pathway

• SSRIs increase serotonin levels

• More serotonin boosts BDNF

• BDNF → activates receptor TrkB → activates Akt → activates mTOR

• Activation of mTOR → Synaptogenesis, increasing neuroplasticity

Brain-derived Neurotrophic Factor (BNDF)

Protein that supports the survival, growth, and maintenance of neurons, playing a crucial role in synaptic plasticity, learning, and memory

Mammalian Target for Rapamycin (mTOR)

• Protein kinase that acts as the central regulator of cell growth, proliferation, and survival.

• Controls protein synthesis, autophagy, and metabolism

Negative Affective Biases

• Dark cloud/black dog/negative filter inside the brain

• Paying more attention to negative information & experiences over positive or neutral ones

Antidepressants

• SERT Blocker

• Increased affective processing

  • Increased recognition of happy faces

  • Improved recognition and response to social cues

  • Improved self-referrent memory

• Blocked SERT lead to increased 5-HT adaptive neuronal or receptor events in brain circuits:

  • Fear (Amygdala)

  • Worry (PFC, Striatum, Thalamus)

• Can treat neuropathic pain

SSRI Antidepressants Indications

• Depressive disorders

• Eating disorders (binge-eating disorder, bulimia nervosa)

• Anxiety & anxiety-related disorders (PTSD, OCD)

• Body dysmorphic disorder

• Alternative for vasomotor Sx

SNRI Antidepressants Indications

• Anti-depressant – not for eating disorders

• Neuropathic pain – Duloxetine preferred

• Multimodal: MDD only

• Non-SERT blockers: generally MDD only

Relapse

Return of symptoms

Recurrence

New episode

Antidepressant Interaction with Anticoagulants, Antiplatelets, Omega-3, and Vit. E

Increased bleeding risk

Antidepressant Interaction with Antipsychotics

Increased serotonin syndrome risk and neuroleptic malignant syndrome

Antidepressant Interaction with Desmopressin

• Increased hyponatremia risk

• Water intoxication

Antidepressant Interaction with NSAIDs

• Impair SSRI efficacy

• Increased bleeding risk

Antidepressant Interaction with Fluoxetine

LSD false positive

Antidepressant Interaction with Sertraline

Benzodiazepine and LSD false positives

Desvenlafaxine

Phencyclidine and Amphetamine false positive

Escitalopram

Prolongs QT Interval

Fluoxetine

• Stimulating (5-HT2C antagonist) → take in AM

• Weak NET blocker

• Preferred antidepressant in children

• Specific indication for bulimia nervosa

Sertraline

• Ser is stimulated when discussing benzodiazepine SARs, and he finds it rewarding

• Slightly increases dopamine (DAT blockade), causing stimulation (take in AM)

• Decreased risk of heart attack in those with MDD+CAD

• *σ1 antagonist

Paroxetine

• Chicken pox at par with being mad as a hatter, dry as a bone, etc.

• Has anticholinergic side effects (M1 antagonism) and more sexual dysfunction (NO synthase inhibition)

• *NET blocker

Fluovoxamine

• σ1 binder for OCD

  • COVID??? - σ1 agonism reduces inflammatory response

• CYP1A2 inhibitor

  • Inhibits the metabolism of Clozapine and Melatonin

Dapoxetine

• Premature ejaculation

• Short half-life

Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)

• Venlafaxine

• Duloxetine

• Desvenlafaxine

• Block SERT and NET 

• Neuropathic pain 

  • Avoid in angle closure glaucoma

Vortioxetine (Multimodal)

• MOA:

  • Blocks SERT

  • 5-HT1A agonist

  • 5-HT1B partial agonist

  • 5-HT1D antagonist

  • 5-HT7 antagonist (metabotropic)

  • 5-HT3 antagonist (ionotropic)

• Less sexual dysfunction BUT more expensive

Sedating Non-SERT Blockers

• Mirtazapine

• Chlorpromazine

• Fluphenazine

• Carbamazepine

• Clozapine

• Olanzapine

• Kechapin

• Zolpidem

Agomelatine (Melatonergic Non-SERT Blocker)

• MOA:

  • MT1, MT2 receptor agonist

  • 5-HT2B,  5-HT2C antagonist

  • Resynchronizes circadian rhythm

• Side effects:

  • No SERT blockade = less N/V, less sexual dysfunction

  • Hepatotoxicity

Tricyclic Antidepressant Interaction with Anticholinergics

Paralytic ileus, hyperthermia

Tricyclic Antidepressant Interaction with Antihypertensives

TCAs may alter activity, may inhibit clonidine effects

Tricyclic Antidepressant Interaction with Methylphenidate

May inhibit TCA metabolism

Tricyclic Antidepressant Interaction with Phenothiazines and Haloperidol

May decrease TCA serum concentrations

Tricyclic Antidepressant Interaction with Sympathomimetics

TCAs may increase sympathomimetic activity

Tricyclic Antidepressant Interaction with Amitriptyline

False positive for LSD

Tricyclic Antidepressant Interaction with Clomipramine

• Frequent false-negatives

• False positive for Methadone

MAO Inhibitors Indications

• CNS depressants

• Serotonin syndrome

• Hypertensive crisis – with sympathomimetics

• Seizures – increased risk with tramadol

Cognitive Behavioural Therapy

• Unhelpful behaviors

• Inaccurate thoughts

• Beliefs about oneself, others, and the future

Interpersonal Psychotherapy

• Person’s relational

• Stressors:

  • Losses

  • Changes

  • Disagreements

  • Interpersonal Sensitivity

Behavioral Activation

• Escape and avoidance of aversive emotions

• Stimuli that become self-reinforced

• Prevents positive reinforcement of nondepressive behavior

Mindfulness-based Cognitive Therapy

• Teach people to disengage from maladaptive cognitive processes

  • Mindfulness meditation training

  • Cognitive behavioural techniques

Cognitive Behavioural Analysis System of Psychotherapy

• Utilizes cognitive, behavioural, and interpersonal strategies

• Helps patients recognize maladaptive cognitions and behaviors influence

Non-Pharmacologic Psychotherapy

• Cognitive Behavioural Therapy

• Interpersonal Psychotherapy

• Behavioral Activation

• Mindfulness-based CognitiveTherapy

• Cognitive Behavioural Analysis System of Psychotherapy

Electroconvulsive Therapy

• Induction of a seizure by applying an electrical stimulus to the brain

• Delivered in a controlled clinical setting, after induction of general anesthesia and application of a muscle relaxant

• 80-90% success as acute treatment, 50-60% success for treatment resistant-depression

Complementary and Alternative Treatments

• Aerobic exercise

• Light therapy

• Yoga

• St. John’s wort

Non-Pharmacologic Neurostimulation

• Electroconvulsive Therapy

• Complementary and Alternative Treatments