Antidepressants

Antidepressants

# Overview

– Mood disorders are a prevalent neurological condition.

– Women experience depression at a higher rate than men.

– Symptoms include hallucinations and delusions.

# Nature of Depression

– Depression is a mood disorder that affects thoughts and perceptions.

– It manifests through hallucinations and delusions.

– The consequences of depression can lead to disability and premature death.

– Depression encompasses both emotional and biological symptoms.

# Emotional Symptoms

– Feelings of sadness, negative thoughts, anxiety.

– Guilt, shame, low self-esteem, hopelessness.

– Loss of motivation, dissatisfaction.

– Suicidal behavior.

# Biological Symptoms

– Slowed thinking and actions.

– Loss of libido.

– Sleep disturbances and appetite changes.

# Classification

– Major Depressive Disorder

– Bipolar Disorder

# Characteristics of Major Depressive Disorder

– Mood shifts in one direction.

– Approximately 75% of cases lack a genetic component.

– Stress and anxiety are primary contributing factors.

# Characteristics of Bipolar Disorder

– Mood swings between depression and mania over several weeks.

– Less common than major depressive disorder.

– Onset typically occurs in adulthood.

– Tends to be hereditary.

– Specific susceptibility genes remain unidentified.

# Symptoms of the Manic Phase in Bipolar Disorder

– Enthusiasm.

– Delusions of grandeur.

– Excessive joy.

– Grandiosity, impulsivity.

# The Manic Phase in Bipolar Disorder Can Be Mistaken for Psychosis.

# Three Core Symptoms of Depression

– Depressed mood.

– Decreased activity.

– Diminished interest.

# Brain Imaging Studies

– Three brain regions affected: Prefrontal cortex, amygdala, hippocampus.

# The Prefrontal Cortex is Responsible for

– Intelligence, memory, temperament, personality, concentration.

# The Amygdala is Responsible for

– Emotional decision-making.

– Memory processing.

# The Hippocampus is Responsible for

– Consolidating short-term memories into long-term memories.

– Spatial memory for navigation.

# Theories of Depression

– Monoamine

– Neuroendocrine

– Neurotrophic Factor

– Glutamate

– Neurodegeneration

# Monoamine Theory

– Depression is caused by a functional deficiency in the monoamine neurotransmitters: norepinephrine (NA) and serotonin (5-HT).

– Mania is caused by an excess in their function.

# Neuroendocrine Theory

– Resulting from hyperactivity of the hypothalamic-pituitary-adrenal axis in response to stress.

– Cortisol levels in the blood of depressed patients are elevated.

– The hypothalamus releases corticotropin-releasing factor (CRF).

– The pituitary releases adrenocorticotropic hormone (ACTH).

– The adrenal glands release cortisol.

# Neurotrophic Factor Theory

– Caused by a decline in the function of the protein BDNF (Brain-derived neurotrophic factor).

– BDNF protects and nourishes neurons; its decline leads to neuronal degeneration, resulting in depression.

– Antidepressants have BDNF-enhancing properties.

# What is BDNF?

– Neurotrophic protein present in: Hippocampus, Prefrontal cortex.

– DNF (Differentiation and neurotrophic factor): Nutritional factor.

# Glutamate Theory

– Increased activity of glutamate at the NMDA receptor.

– Elevated glutamate levels in the cortex.

– Requires reducing glutamate release and inhibiting NMDA receptor function.

# Neurodegeneration Theory

– Reduced serotonin function.

– Degeneration and decline of neurons in the hippocampus and prefrontal cortex.

– Requires preventing and restoring lost neurons.

# Mechanisms of Action of Antidepressants (Acute)

– Inhibition of monoamine reuptake.

– Antagonism at monoamine receptors.

– Inhibition of the monoamine oxidase enzyme: NA & 5-HT.

# Inhibition of Monoamine Reuptake

– SNRIs (Selective Norepinephrine Reuptake Inhibitors) and TCAs (Tricyclic Antidepressants) inhibit the reuptake of serotonin and norepinephrine.

# Antagonism at Monoamine Receptors

– Blocking the action of NA at ?2 receptors, 5-HT at 5-HT receptors.

# Inhibition of Monoamine Oxidase Enzyme

– Inhibits the metabolism of NA and 5-HT.

# Characteristics of Antidepressant Mechanisms of Action (Chronic)

– Rapid pharmacological effect.

– Delayed clinical effect.

– Long-lasting changes in neuronal signaling.

# Chronic Mechanisms of Action of Antidepressants

– Inactivation of NA ?1, ?2 receptors.

– Inactivation of 5-HT receptors, inhibition of 5-HT release.

– Alterations in gene expression through transcription factors, promoting neuron production.

# Monoamine Oxidase Inhibitors (MAOIs)

– Non-selective MAOIs: Increase levels of neurotransmitters (NA, 5-HT, dopamine) centrally and peripherally, causing numerous unwanted side effects.

– Selective MAOa inhibitors (5-HT, NA, dopamine): Less toxic. MAOb –> NA, dopamine, phenylethylamine.

# Characteristics of Non-Selective MAOIs

– Avoid combining MAOIs with each other.

– Avoid combining with tricyclic antidepressants, addictive analgesics, sympathomimetics, and tyramine-rich foods (cheese, bananas, red wine).

– Rarely used.

# Non-Selective MAOI Medications

– Phenelzine, isocarboxazid, tranylcypromine.

# Characteristics of Selective MAOIs

– Avoid combining with non-selective MAOIs.

# Selective MAOI Medications

– Toloxatone and moclobemide.

# Most Significant Side Effect of MAOIs

– Interactions with food and other medications.

# Characteristics of Tricyclic Antidepressants (TCAs)

– Undergo stronger hepatic metabolism than the parent compound.

– Inhibit the reuptake of NA and 5-HT back into presynaptic nerve terminals, increasing their levels in the synaptic cleft.

# Tricyclic Antidepressant (TCAs) Medications

– Imipramine, desipramine, clomipramine, amitriptyline, nortriptyline.

# MAOIs + Tyramine

– Acute hypertension –> death, intracranial hemorrhage due to increased arterial pressure.

# TCAs + MAOIs

– Cause hyperactivity, seizures, coma.

# MAOIs + SSRIs

– Cause serotonin syndrome: tremors, hyperthermia, cardiovascular collapse.

# SSRIs + TCAs

– Fluoxetine, Paroxetine.

– Inhibit hepatic metabolism of TCAs.

# MAOIs + ?-adrenergic and indirect sympathomimetics

– Cause paroxysmal hypertension, high fever, potentially fatal.

# Mechanism of Selective Serotonin Reuptake Inhibitors (SSRIs)

– Selectively inhibit serotonin reuptake.

# Fluoxetine (Prozac)

– Belongs to the SSRI group.

– Most commonly prescribed antidepressant.

– T1/2=24-96h.

– Fewer side effects than tricyclics, less effective in treatment.

– Overdose less dangerous.

– Treats anxiety disorders.

– Treats premature ejaculation.

– Not to be used in individuals under 18 years old –> increased risk of suicide.

# Lithium

– Mood stabilizer.

– Increases BDNF levels, reduces glutamate activity.

– Effective after 3-4 weeks.

– Treats depression in bipolar disorder and recurrent depression.

# SNRIs & TCAs

– Inhibit the reuptake of both serotonin and adrenaline.

# Mechanism of TCAs

– Reuptake of monoamines.

# Secondary Mechanism of TCAs

– Inhibit 5-HT & NA.

– Affect: Muscarinic, histamine, ?-receptors –> numerous side effects.

# TCAs Action on Histamine Receptors

– Block H1 –> sedative effect, reduced concentration.

# TCAs Action on 5-HT Receptors

– Anticholinergic effects –> constipation, urinary retention.

– Dry mouth.

# Indications for TCAs

– Depression, treatment of nerve pain.

– Cheese reaction occurs.

– Overdose is highly dangerous.

# Side Effects of TCAs

– Dry mouth, constipation, blurred vision, urinary retention.

– Postural hypotension (due to ?-adrenergic receptor blockade).

– Drowsiness, difficulty concentrating.

# Drug Interaction TCAs + Alcohol

– Respiratory depression –> death.

# Pharmacokinetics of SSRIs

– Highly protein-bound: 70-90%.

– T1/2=18-24h.

– Well absorbed orally.

# Pharmacokinetics of TCAs

– Highly protein-bound: 90-95%.

– T1/2=10-18h.

– Rapid absorption orally.

– Rapid distribution, slow elimination.

# Structure of TCAs

– Tertiary amine: Amitriptyline.

– Secondary amine: Nortriptyline, desipramine.

# SNRIs

– Inhibit the mixed reuptake of NA + serotonin.

– Partially inhibit 5-HT but to a lesser extent than SSRIs.

# Indications for SNRIs

– Depression, anxiety disorders, chronic depression, nerve pain, fibromyalgia, urinary incontinence.

# Side Effects of SNRIs

– Dry mouth, constipation, nausea, loss of appetite, insomnia, negative thinking, suicidal thoughts, decreased libido.

# NRIs

– Selectively inhibit norepinephrine.

# Mechanism of Monoamine Receptor Antagonists

– Increase serotonin levels through ?2l antagonism.