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Depression (Treatment (Second Generation Antidepressants (

Depression

Treatment

Second Generation Antidepressants

Selective Serotonin Reuptake Inhibitors
(SSRIs)
MOA: block 5-HT re-uptake, increasing synaptic levels.
5-HT re-uptake and release are regulated via stimulation of post-synaptic 5-HT receptor subtypes, somatodendritic, and presynaptic terminal receptors
Effective in treating:

Major Depression

GAD

Panic Disorder

Social Anxiety Disorder

Obsessive Compulsive Disorder

Sertraline and Paroxetine approved for:

PTSD

Pre-menstrual dysphoric syndrome

Preventing vasovagal sx in post-menstrual women

Long-Term Treatment Outcomes

Down-regulation and desensitization of presynaptic auto-receptor mechanisms while postsynaptic 5-HT receptors remain responsive

Increased BDNF expression

Increased cAMP signaling and phosphorylation of CREB

Increased neurogenesis in hippocampus and subventricular zone

Reduced expression of SERT

Persistent behavioral changes depend on increased 5-HT neurotransmission

Serotonin-Norepinephrine Reuptake Inhibitors
(SNRIs)
MOA: Inhibit SERT and NET; enhance serotonergice and/or noradrenergic neurotransmission

Initial action activates 5-HT1A and 5-HT1D auto-receptors, followed by auto-receptor densensitization

Enhanced 5-HT concentration in the synapse interacts with post-synaptic 5-HT receptors

Selective NE Reuptake Inhibitors

First Generation Antidepressants

Monoamine Oxidase Inhibitors
(MAOIs)

MOA:
Inhibit monoamine metabolism and enhance neurotransmitter storage

Effects on metabolizing endogenous monoamines and exogenous monoamines (tyramine)

Significant food and drug interactions due to protection of the monoamines

Tricyclic Antidepressants
(TCAs)

MOA
Inhibit both 5-HT and NE re-uptake

Amitriptyline
Doxepin

Effects

Primary Effects on 5-HT and NE

Efficacy of antidepressants depend on enhanced 5-HT or NE transmission

The pathways for 5-HT and NE are independent.

Long-Term Effects

Increased adrenergic or serotonergic receptor density or sensitivity

Increased G-Protein coupling and cyclic nucleotide signaling

Induction and presence of neurtrophic factors

Increased neurogenesis in the hippocampus

Sustained signaling via 5-HT or NE increases brain-derived neurotrophic factor

Persistent Antidepressant Effects

Require continued 5-HT or NE transporter inhibition or

Enhanced 5-HT or NE neurotransmission

Clinical Considerations

Therapeutic lag between initiation (~3-4 weeks)

2/3 patients show a 50% decrease in sx over 8 weeks

1/3 experience complete remission

If no response after 8 weeks, switch to another MOA

If partial response, add more drugs

CON → S/E emerge before therapeutic effects

Patients can switch from depressed to manic episode (SSRIs and Bupropion less likely to induce "switch")

Non-pharmacological

CBT

ECT

Transmagnetic Brain Stimulation

Deep Brain Stimulation

Bupropion
MOA: Enhances NE and DA via re-uptake inhibition of NET, DAT, and VMAT2
Widely used in combination with SSRIs for greater antidepressant response (but limited clinical data to support this)
Used for:

Depression

Seasonal Depressive Disorder

Smoking Cessation

ADHD

Neuropathic pain

Weight loss

Atypical Antipsychotics

MOA: Weak D2-receptor block with 5-HT2A ANTAgonism/Inverse Agonism
Used to Treat:

Schizophrenia

Bipolar Depression

Major Depression

in combination with SSRIs and SNRIs for treatment-resistant major depression

Aripiprazole
Olanzapine

Major Risks:

Weight Gain

Metabolic Syndrome

General Background

Classifications

Major Depression (unipolar)

Bipolar Depression (manic depressive)

Prevalence

Lifetime risk of unipolar depression (15%)

Females affected 2x more than males.

Incidence

Difficult to determine because depression is underdiagnosed and undertreated.

There's an inherent risk of suicide associated with depression (10-15% of depresssed individuals attempt suicide at some point)

Symptoms
Depressive episode lasting ~2 week period:

Depressed mood

Sleeping (more or less)

Interest has decreased

Guilty feelings increased

Energy has decreased

Concentration has decreased

Appetite is altered

Pleasure in activities has decreased

Suicidal thoughts or ideation

Link to Anxiety

Both often linked together

Most common mental illnesses (affecting 10-15% of the population EACH)

Very amenable to pharmacological tx

Treatment moved from psych to primary care

Depression and OTHER Illnesses

Depression is Secondary to:

HYPOthyroidism

Parkinson's Disease

Inflammatory Conditions

Depression Complicates Treatment of:

Severe Trauma

Cancer

Diabetes

CVD