Nervous System - Drugs for Mood Disorders

What are 7 small molecular neurotransmitters?

1. Acetylcholine -> major involvement in ANS, implications in Alzheimers + Delirium

2. Dopamine -> Implications in schizophrenia (increased activity) and Parkinson's (decreased activity)

3. Norepinephrine -> Implications in depression + bipolar disorder

4. Epinephrine -> Implications in depression + bipolar disorder

5. Serotonin -> Implications in depression + bipolar disorder

6. Glutamate -> involved in memory + mostly excitatory, implications in Alzheimers

7. GABA -> mostly inhibitory, implications in anxiety and sedation

What is the noradrenergic neurotransmitter system?

Neuronal network responsible for releasing norepinephrine

Neurons originate in locus ceruleus and project to limbic system and cerebral cortex. Involves alpha and beta adrenergic receptors.

Responsible for maintaining emotional tone, including mood, arousal, and maintaining alertness + wakefulness

What is the serotonergic neurotransmitter system?

Neuronal network responsible for releasing serotonin

Neurons originate in raphe nuclei and project to limbic system and cerebral cortex. Involves 5-HT to 5-HT7 receptors (many)

Responsible for maintaining sleep wake cycle, emotional tone, and sensory perceptions (pain). The majority of receptors are located outside of the CNS, especially in the gut

What is the role of the noradrenergic system?

Responsible for maintaining emotional tone, including mood, arousal, alertness and wakefulness

What is the role of the serotonergic system?

Responsible for maintaining sleep-wake cycle, emotional tone, and sensory perceptions (pain suppression)

Many receptors are also located in the gut (relationship between gut and psych health)

What are mood disorders?

Disorders characterized by persistent disturbances in mood that impairs a person's ability to engage in normal activities and are not associated with the effects of a drug, another medical condition, or a significant life event

What is major depressive disorder?

Psych disorder characterized by a depressed mood for the majority of the day and marked diminished interest or pleasure in all activities

How do pharmacological interventions for major depressive disorder work?

Pharmacological interventions cause changes in serotonergic tone, which creates the "context" for neuronal plasticity in the brain, allowing rebuilding of normal and healthy neural networks

Which neurotransmitters are targeted in pharmacological interventions for major depressive disorder?

Serotonin (SSRIs, SNRIs, TCAs, MAOIs)

Norepinephrine (SNRIs, NDRIs, TCAs, MAOIs)

Dopamine (TCAs, NDRIs, MAOIs)

What are the 4 antidepressant drug classes?

1. SSRIs

2. Atypical antidepressants (SNRIs and NDRIs)

3. Tricyclic antidepressants

4. Monoamine oxidase inhibitors (MAOIs)

What is the use of antidepressant drugs?

1. Used to restore all symptoms of major depressive disorders

2. Used to treat depressive phases in bipolar disorder

3. Used to manage anxiety disorders

4. Used to manage OCD

5. Used to treat psychological and physical components of pain

6. Used to manage childhood enuresis (bed wetting) -> anticholinergic effect -> lower parasymp activation -> lower urination

What should be monitored in patients who are under 25 years of age and prescribed with antidepressants?

Should be monitoring closely for signs of self harm, especially at start of treatment

What are SSRIs? (Use, Mechanism of Action, Adverse Effects, Withdrawal management)

Use

Preferred antidepressant used for treatment of MDD and other psychological disorders

Mechanism of Action

Inhibits serotonin reuptake in presynaptic neuron, with the presynaptic serotonin neurons being less sensitive and less in density, and post synaptic neurons becoming more sensitive

Improved side effect profile compared to other antidepressants due to no affinity for histamine, a adrenergic or muscarinic receptors - preferred drug class as an antidepressant

Adverse Effects

-WEIGHT GAIN

-Sexual dysfunction

-Nausea

-Headache

-Anxiety/nervousness

-Akathisias (inability to remain still)

-Sleep disturbances

-Serotonin syndrome (if co-administered with other drugs)

Withdrawal management

Gradual discontinuation of drug to minimize withdrawal effects, need for open dialogue with patient

Withdrawal effects include

-Nausea

-Dizziness

-Lethargy

-Anxiety

-Tremors

-Palpitations

-Irritability

-Reemergence of depression

What is the use of SSRIs?

Preferred antidepressant used for treatment of MDD and other psychological disorders

What is the mechanism of action of SSRIs?

Increased serotonin synapse concentration

Inhibits serotonin reuptake in presynaptic neuron, with the presynaptic serotonin neurons being less sensitive and less in density, and post synaptic neurons becoming more sensitive

Improved side effect profile compared to other antidepressants due to no affinity for histamine, a adrenergic or muscarinic receptors - preferred drug class as an antidepressant

What are adverse effects of SSRIs?

Preferred antidepressant due to low adverse effect profile - no affinity for histamine, alpha adrenergic or muscarinic receptors

-WEIGHT GAIN

-Sexual dysfunction

-Nausea

-Headache

-Anxiety/nervousness

-Akathisias (inability to remain still)

-Sleep disturbances

-Serotonin syndrome (if co-administered with other drugs)

What is the withdrawal management for SSRIs?

Gradual discontinuation of drug to minimize withdrawal effects, need for open dialogue with patient

Withdrawal effects include

-Nausea

-Dizziness

-Lethargy

-Anxiety

-Tremors

-Palpitations

-Irritability

-Reemergence of depression

What is serotonin syndrome?

Adverse effect of SSRIs associated with extreme increases in serotonin levels caused by co-administration of drugs that increase serotonin

(SSRIs with MAOIs, TCAs, Lithium, St John's Wart, Fentanyl, Meperidine, MDMA/ecstasy)

Management strategies include discontinuation of SSRIs and inclusion of supportive care. May require mechanical ventilation and muscle relaxants in severe cases

What medications cause serotonin syndrome when they are co-administered with SSRIs?

MAOIs, TCAs, Lithium, St John's Wart, MDMA/Ecstasy, Fentanyl, Meperidine (pain medication)

What is the management strategy for serotonin syndrome?

Discontinuation of SSRIs

Initiation of supportive care

Mechanical ventilation and muscle relaxants prescription in severe cases

What are SNRIs? (Use, Mechanism of action, Adverse Effects)

Use

Atypical antidepressant used for treatment of MDD and other psychological disorders

Duloxetine -> effective in neuropathic pain management in fibromyalgia and diabetic neuropathy

Mechanism of action

Serotonin + norepinephrine reuptake inhibition

Adverse Effects

Esp duloxetine -> may increase risk of post-partum hemorrhage due to inhibition of platelet aggregation

What are Duloxetine as a SNRI?

Use

Atypical antidepressant used to treat MDD and psychological disorders as well as neuropathic pain management related to fibromyalgia and diabetic neuropathy

Mechanism of action

Serotonin + norepinephrine reuptake inhibition

Adverse Effects

May increase risk of post-partum hemorrhage due to inhibition of platelet aggregation

What is the mechanism of action of SNRIs?

Increases serotonin and norepinephrine synapse concentration

Causes inhibition in serotonin and norepinephrine reuptake

What are NDRIs? (Use, Mechanism of Action, Adverse Effects, Contraindications)

Use

Atypical antidepressant used to treat MDD and psychological disorders.

Bupropion as Zyban -> used as smoking cessation treatment

Mechanism of action

Norepinephrine and dopamine reuptake inhibition

Adverse Effects

Good side effect profile, less likely to induce sexual dysfunction, weight gain, or insomnia compared to SSRis

Contraindications

Seizure disorders, Hx of epilepsy

What is the use of NDRIs?

Atypical antidepressant used to treat MDD and psychological disorders.

Bupropion as Zyban -> used as smoking cessation treatment

What is the mechanism of action of NDRIs?

Increases norepinephrine and dopamine synapse concentration

Inhibits reuptake of norepinephrine and dopamine

What are adverse effects of NDRIs?

Good side effect profile, less likely to induce sexual dysfunction, weight gain, or insomnia compared to SSRis

What are contraindications of NDRIs?

Seizure disorders, Hx of epilepsy

What are two atypical antidepressants?

SNRIs -> serotonin + norepinephrine reuptake inhibitor

NDRIs -> norepinephrine + dopamine reuptake inhibitor

What are tricylic antidepressants? (Use, Mechanism of Action, Adverse Effects, Pharmacokinetics - distribution)

Use

Used as a refractory (last case) drug for treatment of MDD and other psych disorders, as well as treatment of neuropathic pain and childhood enuresis

Mechanism of action

Inhibits norepinephrine, serotonin, and dopamine reuptake

Expresses affinity for histaminergic, muscarinic, and a1 adrenergic receptors - resulting in increased adverse effect profile

Adverse Effects

-Sedation

-Blurred vision

-Dry mouth

-Urinary retention

-Constipation

-Tachycardia

-Orthostatic hypotension

-WEIGHT GAIN

-Sexual dysfunction

Distribution

90% bound to serum albumin, thus exerts systemic effects long after drug dose is discontinued

What is the use of tricylic antidepressants?

Used as a refractory (last case) drug for treatment of MDD and other psych disorders, as well as treatment of neuropathic pain and childhood enuresis

What is the mechanism of action of tricylic antidepressants?

Inhibits norepinephrine, serotonin, and dopamine reuptake

Expresses affinity for histaminergic, muscarinic, and a1 adrenergic receptors - resulting in increased adverse effect profile

What are the adverse effects of tricylic antidepressants?

Expresses affinity for histaminergic, muscarinic, and a1 adrenergic receptors - resulting in increased adverse effect profile (thus used in refractory cases for depression)

-Sedation

-Blurred vision

-Dry mouth

-Urinary retention

-Constipation

-Tachycardia

-Orthostatic hypotension

-WEIGHT GAIN

-Sexual dysfunction

What is bipolar I disorder?

Psychological disorder characterized by altering periods of manic and major depressive episodes - resulting in impairments in social or occupational functioning

What is lithium treatment? (Use, Mechanism of Action, Drug Interactions, Monitoring, Adverse Effects)

Use

Used to treat manic episodes in bipolar I disorder

Mechanism of action

- Inhibits excitatory neurotransmitters (dopamine, glutamate)

-Promotes inhibitory neurotransmitters (GABA)

Drug Interactions

-Narrow therapeutic index

-Drugs like indomethacin - NSAID - decreases renal clearance and increase lithium levels -> causing toxicity

Monitoring

-Lithium serum levels (5 days after change in regimen, every 3 months)

-Kidney function -> urinalysis + creatinine (every 3-6 months)

-Kidney protection -> 2-3L of fluids per day, take drug at bedtime

Adverse Effects

aka lithium toxicity

-Muscle weakness

-Lack of coordination

-Vomiting

-Diarrhea

-Tremors

-Twitching

-Lethargy

-Mental confusion

-Polyuria

What is the use of lithium treatment?

Used to treat manic episodes in bipolar I disorder

What is the mechanism of action of lithium treatment?

- Inhibits excitatory neurotransmitters (dopamine, glutamate)

-Promotes inhibitory neurotransmitters (GABA)

What are drug interactions of lithium treatment? (NSAID, therapeutic index)

-Drugs like indomethacin - NSAID - decreases renal clearance and increase lithium levels -> causing toxicity

What monitoring should be done for patients on lithium treatment?

-Lithium serum levels (5 days after change in regimen, every 3 months)

-Kidney function -> urinalysis + creatinine (every 3-6 months)

-Kidney protection -> 2-3L of fluids per day, take drug at bedtime

What are adverse effects of lithium treatment?

aka lithium toxicity

-Muscle weakness

-Lack of coordination

-Vomiting

-Diarrhea

-Tremors

-Twitching

-Lethargy

-Mental confusion

-Polyuria

What are anticonvulsants? (Use, Adverse effects)

Includes Carbamazepine and divalproex

Use

Used to treat seizures and manic episodes associated with bipolar I disorder

Adverse Effects

Carbamazepine -> dizziness, drowsiness, blurred vision, confusion, muscle tremor, nausea, vomiting, sensitivity to sun, skin sensitivity, rashes, poor coordination (more than divalproex)

Valproic acid -> dizziness, drowsiness, headaches, nausea, blurred vision, sedation

What is the use of anticonvulsants?

Used to treat seizures and manic episodes associated with bipolar I disorder

What are the adverse effects of anticonvulsants?

Carbamazepine -> dizziness, drowsiness, blurred vision, confusion, muscle tremor, nausea, vomiting, sensitivity to sun, skin sensitivity, rashes, poor coordination (more than divalproex)

Valproic acid -> dizziness, drowsiness, headaches, nausea, blurred vision, sedation

What drug classes can be prescribed to manage maniac episodes in bipolar I disorder?

-Lithium

-Anticonvulsant Drugs

-Atypical antipsychotics

What drug classes can be prescribed to manage depressive episodes in bipolar I disorder?

-SSRIS

-Atypical antidepressants (SNRIs, NDRIs)

-TCAs

-MAOIs

-Atypical antipsychotics