Tertiary amines:

Secondary amines:

Re-uptake inhibitors that show preference for 5-HT re-uptake above NA re-uptake.

ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (Includes involved receptor related side effects also)

I.e. NE such as: Impotence, blurred vision, midriasis, palpitations, tachycard, constipation, dry mouth, weight gain.

Re-uptake inhibitors that show preference for NA re-uptake above 5-HT re-uptake.

ANTI-CHOLINERGIC and ALIFATIC (α1) EFFECTS (Includes involved receptor related side effects too) (Much more potent than the tertiary amines).NE = worse such as: Impotence, blurred vision, mydriasis, palpitations, tachycardia, constipation, dry mouth, weight gain.

Substance:

Indication:

MOA:

Notes:

Amitriptyline

Imipramine

Trimipramine

Chlorimipramine (Clomipramine)

Dothiepine

Butriptyline

Treatment of depression (major)

Amitriptyline: Chronic pain

Clomipramine especially also in OCD (Obsessive compulsive disorder).

FIRST CHOICES AT:

- Phobias

- Anxiety

- Panic = SSRI'S

THEN: Tertiary amines (NOT second amines).

Especially imipramine: Enuresis, acute panic, phobias.

Reuptake inhibitors some preferred for 5-HT reuptake inhibition above NA reuptake inhibition.

ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (NE too) - (Much more potent than the secondary amines).

Substance:

Indication:

MOA:

Note’s:

Nortriptyline

Desimipramine (Metabolite of Imipramine).

Amoxapine

Maprotiline

Lofepramine

Treatment of depression (major)

Nortriptyline and BMI: Can be used in healthy elderly people).

Reuptake inhibitors some preferred NA reuptake inhibition above 5-HT reuptake inhibition.

ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (NE too).

Maprotiline Toxicities: Like TAD's, dosage-related convulsions. (Caution in patients with epilepsy )

Substance:

Clinical indication:

MOA:

Notes:

Tranylcypromine

Treatment of depression (ELECTIVE IN ATYPICAL DEPRESSION)

- When the person's state of mind is low but there is not necessarily a lack of motivation.

Severe anxiety

Phobias

Hypochondriasis

Panic

Irreversible non-selective inhibitor of MAO-A+B with the result that fewer mono-amines (5-HT, DA and NA) are broken down and the concentrations increase.

CAUSE CHEESE REACTION

- Give the person recommendations on diet.

Effects still last for several weeks after withdrawal.

Moclobemide:

Reversible inhibitor of MAO-A with the result that fewer mono-amines (NA, DA and 5-HT) are broken down and that lg. concentrations increase.

Diet recommendations are therefore not necessary here unless the person is already experiencing blood pressure problems.

Substance:

Clinical indication:

MOA:

Notes:

• Fluoxetine (Prozac®)
• Paroxetine (Aropax®)
• Fluvoxamine (Luvox®)
• Sertraline (Zoloft®)
• Citalopram (Cipramil®)
• Escitalopram (Cipralex®)

Depression treatment (1st choice in the elderly)

FIRST CHOICES AT:

- Phobias

- Anxiety

- Panic

THEN: Tertiary amines (NOT second amines).

OCD (40mg/day plus)

Bulimia (80mg/day plus)

PMS

Resistant schizophrenia

Alcoholism (Not going to help an alcoholic, but will for a depressed person who drinks)

Bipolar disorder

Fluoxetine is the only AD approved in children.

These drugs selectively block the serotonin re-uptake at the pre-synaptic neuron.

Paroxetine has the most anti-cholinergic effects – exceptional because the other drugs have practically no anti-cholinergic effects, the drug also has a very short t1/2 and must be administered more than once p.d. – exceptional because the other drugs are only administered once a day. Especially severe withdrawal symptoms

The drugs are less cardiotoxic than the TAD's.

Possible association between fluoxetine and premature birth and delayed fetal growth rate.

The drugs have a better NE profile than many other drugs and are safer in acute overdosage. Can reduce appetite and result in weight loss.

Fluoxetine has a 5-week wash-out period

Substance:

Clinical indication:

MOA:

Notes:

• Venlafaxine (Efexor®)
• Duloxetine (Cymbalta®)

Depression treatment

Severe anxiety and phobias

Block both 5-HT and NA re-uptake, more potent for 5-HT than for NA.

Venlafaxine toxicity:

Nausea, sedation, dizziness, sweat, sexual disturbances, hypertension, anxiety.

Venlafaxine has less anti-cholinergic and cardiotoxic SE.

Substance:

Clinical indication:

MOA:

Notes:

Mianserin

Mirtazepine

Bupropione

Treatment of depression.

Bupropion in lower doses: Nicotine withdrawal

Bupropion: Obesity

Bipolar disorder

Mirtazepine: Induce sedation

Block α2, 5-HT2A and 5-HT3. Also block H1 and α1.

A naSSA – Noradrenaline and specific serotonin anti-depressant. Block α2 (Blockade of this inhibitory receptor promotes both NA (auto receptor) and 5-HT release (heteroreceptors)), 5-HT2A and 5-HT3. Also block H1 and α1. Also, indirect stimulation of 5-HT1A.

Blockade of the inhibitory α2 receptors advance both NA (autoreceptors) & 5-HT release (heteroreceptors) •Indirect stimulation of 5-HT1A: anxiolytic •Blockade 5-HT3: anxiolytic, ↓ nausea •Blockade 5-HT2: anti-depressive effects

Block DA, as well as NA re-uptake.

H1 blockade can cause sedation and mass gain. α1 blockade can cause postural hypotension. Causes blood disorders (agranulocytosis) – limited use.

Stimulation of 5-HT1A = anxiety myolities Blockade of 5-HT3 = anxiety insulating and lowers nausea. Blockade of 5-HT2A = Antidepressive

Toxicities: Sedation, increased appetite and mass gain.

Alerting. May induce convulsions in certain patients. (Caution in epilepsy sufferers).

•Lower dosages nicotine withdrawal (Zyban®

Fewer anti-cholinergic and cardiac effects.

Toxicities: Dizziness, dry mouth, sweating, tremor, psychoses, convulsions (high doses).

Substance:

Clinical indication:

MOA:

Notes:

Trazodone (Molipaxin)

• Effective initial and maintenance treatment for MDD (20 mg/d) • Well tolerated in older people • May have cognitive benefits, especially in older people • Considered as an alternative to other AD’s on market.

5-HT2 antagonist • Weak 5-HT re-uptake inhibitor, weak α2 blocker • Trazodone also blocks H1 (severe sedation) & α1: (priapism)

Currently: unlabeled hypnotic, highly sedating, not associated with tolerance or dependence

Vortioxetine (Brintellix )

Treatment of depression

Trazodone: Currently often used as hypnotic, due to severe sedative effects. (Not associated with tolerance/dependency).

Vortioxetine: Major depressive syndrome: effective + maintenance treatment. For beneficial cognitive effects (especially the elderly). Also helps for insomnia (a multimodal AD). Alternative to other ADs.

• Block several 5-HT receptors (3, 7, 1D), agonist on 5-HT1A, partial agonist on 5-HT1B • Weak SERT inhibitor • MDD, Procognitive effects??

• Animal studies: Increase in extracellular levels:

• NA, DA, Glutamate, ACh, Histamine in brain areas associated with depression, including the prefrontal cortex and hippocampus.

• Additional in vivo testing is necessary to determine whether this multimodal action produces an additional clinical benefit

SE:

Substance:

Clinical indication:

MOA:

Notes:

Agomelatine

Major depression

Restores the body's biorhythms. Primary agonist on melatonin 1+2 receptors and a m antagonist on 5-HT2C receptors.

MT1 and MT2 agonist and 5-HT2c antagonist • 5-HT2c-antagonism: disinhibition of DA and NA release in FC (Increase  DA and NA release)

(Melatonin is a by-product of 5-HT. Responsible for directing biological beating (fatigue/body temperature etc.), melatonin therefore restores these rhythms because during depression these circadian rhythms are disturbed. Thus, depression affects melatonin secretion.

S/E: Headache, dizziness, GIT discomfort, fatigue, liver enzyme increases

• CI: Hepatic impairment

• Valdoxane

THERE IS SINNERGISM BETWEEN MELATONIN RECEPTORS AND 5—HT RECEPTORS:

• 5-HT2/M1+2 receptors:

                        Higher density in SCN

                        Regulation of circadian rhythms

• M1+2 agonism beneficial for sleep but is not antidepressant.

For example, in the meantime, you cannot give someone only melatonin to totally alleviate depression, the insomnia that occurs in depression can be alleviated by a melatonin agonist.

• 5-HT2C agonism worsens sleep disturbances
• 5-HT2C antagonism promotes sleep
• 5-HT2C antagonism promotes Antidepressive action. As a result, DA and NA increase in the pre-frontal cortex which then results in an anti-depressant effect, the one receptor is therefore blocked with the greater purpose of boosting NA and DA transmission.

Hypertensive crisis

5. Sympathomimetic amines (cold and flu preparations)
5. Tyramine containing food > 10 mg tyramine + MAOA inhibitor (Cheese, wine, beans, Marmite, biltong, yoghurt, etc.)

Symptoms of hypertensive crisis: Enlarged pupils, light sensitivity, severe headache, chest pains, arrhythmias, stiff neck, sweat, nausea, vomiting.

5. Potentiates CNS suppressors, hyperpyrexia with pethidine.
5. Potentiates toxic effects of TAD’s, SSRI’s: hyperpyrexia, convulsions, coma

Clinical use: general principles

Treatment Resistant Depression

5. All available AD’s: 6 – 8 weeks needed with sufficient dosages before AD’s effects are optimal ⇒ Don’t stop too early
5. After response: Therapy for at least 6 – 12 months after a single episode to prevent a relapse.
5. Multiple episodes: longer maintenance therapy needed.
5. Gradual withdrawal (severe withdrawal reaction with paroxetine)
5. Combination of AD’s not recommended, except for resistant depression.
5. Combination with anxiolytic not advised, except during 1st week or two prn
5. Major Depression:

• Clinical effectiveness the same for all drugs
• Individual response to different drugs varies.
• 65 – 70% of pt’s with major Depression improve with drugs
• TCA require titration to minimum effective dose, while SSRI’s can be started immediately at full doses, although must be aware of anxiety and jitteriness.
• Psychotic characteristics: ECT / AD + anti-psychotic drug
• Drugs with the least association with sexual side effects: Bupropion, mirtazapine and agomelatine.

5. SSRI’s and other newer drugs preferred due to:

• Better side-effect profile
• Safer in acute overdose
• SSRI’s can suppress appetite; overweight patients may lose weight.

5. TAD’s alternative for:

• Patients unresponsive to commonly used AD’s

5. MAOI’s:

• Rarely used because of toxicity and potential lethal food and drug interactions.
• Patients unresponsive to other AD’s
•  Anxiety disorders, social anxiety and panic disorder

5. Mostly because of insufficient therapy
5. Other AD can be tried.
5. Potentiating therapy:

• Lithium
• Liothyronine
• Carbamazepine, valproate
• SSRI plus atypical antipsychotic (e.g., olanzapine, quetiapine)

5. Combination of two different classes (never SSRI + MAOI), but caution!

Elderly:

Children, teenagers

Pregnancy:

• Vascular, neurochemical, neurodegenerative and age-related changes in the frontal-striatal circuits leads to reduced treatment response to antidepressants in the elderly.

• SSRI’s 1’st choice

• Healthy geriatrics: Secondary TAD (Nortriptyline, DMI)

• Bupropion, venlafaxine (less anticholinergic and cardiac side-effects)

• Data scarce

• Warning!! AD’s may induce suicidal thoughts in young people (18 - 24 yrs)

• SSRI’s better tolerated, safer in overdose.

• Fluoxetine is the only AD approved in children

• Drugs only used if other therapy is insufficient.

• Teratogenic effects not reported with TAD’s or SSRI’s.

• Possible association between fluoxetine and premature births and delayed foetal growth tempo

Tertiary amines:

Secondary amines:

Re-uptake inhibitors that show preference for 5-HT re-uptake above NA re-uptake.

ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (Includes involved receptor related side effects also)

I.e. NE such as: Impotence, blurred vision, midriasis, palpitations, tachycard, constipation, dry mouth, weight gain.

Re-uptake inhibitors that show preference for NA re-uptake above 5-HT re-uptake.

ANTI-CHOLINERGIC and ALIFATIC (α1) EFFECTS (Includes involved receptor related side effects too) (Much more potent than the tertiary amines).NE = worse such as: Impotence, blurred vision, mydriasis, palpitations, tachycardia, constipation, dry mouth, weight gain.

Substance:

Indication:

MOA:

Notes:

Amitriptyline

Imipramine

Trimipramine

Chlorimipramine (Clomipramine)

Dothiepine

Butriptyline

Treatment of depression (major)

Amitriptyline: Chronic pain

Clomipramine especially also in OCD (Obsessive compulsive disorder).

FIRST CHOICES AT:

- Phobias

- Anxiety

- Panic = SSRI'S

THEN: Tertiary amines (NOT second amines).

Especially imipramine: Enuresis, acute panic, phobias.

Reuptake inhibitors some preferred for 5-HT reuptake inhibition above NA reuptake inhibition.

ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (NE too) - (Much more potent than the secondary amines).

Substance:

Indication:

MOA:

Note’s:

Nortriptyline

Desimipramine (Metabolite of Imipramine).

Amoxapine

Maprotiline

Lofepramine

Treatment of depression (major)

Nortriptyline and BMI: Can be used in healthy elderly people).

Reuptake inhibitors some preferred NA reuptake inhibition above 5-HT reuptake inhibition.

ANTI-CHOLINERGIC and ALIPHATIC (α1) EFFECTS (NE too).

Maprotiline Toxicities: Like TAD's, dosage-related convulsions. (Caution in patients with epilepsy )

Substance:

Clinical indication:

MOA:

Notes:

Tranylcypromine

Treatment of depression (ELECTIVE IN ATYPICAL DEPRESSION)

- When the person's state of mind is low but there is not necessarily a lack of motivation.

Severe anxiety

Phobias

Hypochondriasis

Panic

Irreversible non-selective inhibitor of MAO-A+B with the result that fewer mono-amines (5-HT, DA and NA) are broken down and the concentrations increase.

CAUSE CHEESE REACTION

- Give the person recommendations on diet.

Effects still last for several weeks after withdrawal.

Moclobemide:

Reversible inhibitor of MAO-A with the result that fewer mono-amines (NA, DA and 5-HT) are broken down and that lg. concentrations increase.

Diet recommendations are therefore not necessary here unless the person is already experiencing blood pressure problems.

Substance:

Clinical indication:

MOA:

Notes:

• Fluoxetine (Prozac®)
• Paroxetine (Aropax®)
• Fluvoxamine (Luvox®)
• Sertraline (Zoloft®)
• Citalopram (Cipramil®)
• Escitalopram (Cipralex®)

Depression treatment (1st choice in the elderly)

FIRST CHOICES AT:

- Phobias

- Anxiety

- Panic

THEN: Tertiary amines (NOT second amines).

OCD (40mg/day plus)

Bulimia (80mg/day plus)

PMS

Resistant schizophrenia

Alcoholism (Not going to help an alcoholic, but will for a depressed person who drinks)

Bipolar disorder

Fluoxetine is the only AD approved in children.

These drugs selectively block the serotonin re-uptake at the pre-synaptic neuron.

Paroxetine has the most anti-cholinergic effects – exceptional because the other drugs have practically no anti-cholinergic effects, the drug also has a very short t1/2 and must be administered more than once p.d. – exceptional because the other drugs are only administered once a day. Especially severe withdrawal symptoms

The drugs are less cardiotoxic than the TAD's.

Possible association between fluoxetine and premature birth and delayed fetal growth rate.

The drugs have a better NE profile than many other drugs and are safer in acute overdosage. Can reduce appetite and result in weight loss.

Fluoxetine has a 5-week wash-out period

Substance:

Clinical indication:

MOA:

Notes:

• Venlafaxine (Efexor®)
• Duloxetine (Cymbalta®)

Depression treatment

Severe anxiety and phobias

Block both 5-HT and NA re-uptake, more potent for 5-HT than for NA.

Venlafaxine toxicity:

Nausea, sedation, dizziness, sweat, sexual disturbances, hypertension, anxiety.

Venlafaxine has less anti-cholinergic and cardiotoxic SE.

Substance:

Clinical indication:

MOA:

Notes:

Mianserin

Mirtazepine

Bupropione

Treatment of depression.

Bupropion in lower doses: Nicotine withdrawal

Bupropion: Obesity

Bipolar disorder

Mirtazepine: Induce sedation

Block α2, 5-HT2A and 5-HT3. Also block H1 and α1.

A naSSA – Noradrenaline and specific serotonin anti-depressant. Block α2 (Blockade of this inhibitory receptor promotes both NA (auto receptor) and 5-HT release (heteroreceptors)), 5-HT2A and 5-HT3. Also block H1 and α1. Also, indirect stimulation of 5-HT1A.

Blockade of the inhibitory α2 receptors advance both NA (autoreceptors) & 5-HT release (heteroreceptors) •Indirect stimulation of 5-HT1A: anxiolytic •Blockade 5-HT3: anxiolytic, ↓ nausea •Blockade 5-HT2: anti-depressive effects

Block DA, as well as NA re-uptake.

H1 blockade can cause sedation and mass gain. α1 blockade can cause postural hypotension. Causes blood disorders (agranulocytosis) – limited use.

Stimulation of 5-HT1A = anxiety myolities Blockade of 5-HT3 = anxiety insulating and lowers nausea. Blockade of 5-HT2A = Antidepressive

Toxicities: Sedation, increased appetite and mass gain.

Alerting. May induce convulsions in certain patients. (Caution in epilepsy sufferers).

•Lower dosages nicotine withdrawal (Zyban®

Fewer anti-cholinergic and cardiac effects.

Toxicities: Dizziness, dry mouth, sweating, tremor, psychoses, convulsions (high doses).

Substance:

Clinical indication:

MOA:

Notes:

Trazodone (Molipaxin)

• Effective initial and maintenance treatment for MDD (20 mg/d) • Well tolerated in older people • May have cognitive benefits, especially in older people • Considered as an alternative to other AD’s on market.

5-HT2 antagonist • Weak 5-HT re-uptake inhibitor, weak α2 blocker • Trazodone also blocks H1 (severe sedation) & α1: (priapism)

Currently: unlabeled hypnotic, highly sedating, not associated with tolerance or dependence

Vortioxetine (Brintellix )

Treatment of depression

Trazodone: Currently often used as hypnotic, due to severe sedative effects. (Not associated with tolerance/dependency).

Vortioxetine: Major depressive syndrome: effective + maintenance treatment. For beneficial cognitive effects (especially the elderly). Also helps for insomnia (a multimodal AD). Alternative to other ADs.

• Block several 5-HT receptors (3, 7, 1D), agonist on 5-HT1A, partial agonist on 5-HT1B • Weak SERT inhibitor • MDD, Procognitive effects??

• Animal studies: Increase in extracellular levels:

• NA, DA, Glutamate, ACh, Histamine in brain areas associated with depression, including the prefrontal cortex and hippocampus.

• Additional in vivo testing is necessary to determine whether this multimodal action produces an additional clinical benefit

SE:

Substance:

Clinical indication:

MOA:

Notes:

Agomelatine

Major depression

Restores the body's biorhythms. Primary agonist on melatonin 1+2 receptors and a m antagonist on 5-HT2C receptors.

MT1 and MT2 agonist and 5-HT2c antagonist • 5-HT2c-antagonism: disinhibition of DA and NA release in FC (Increase  DA and NA release)

(Melatonin is a by-product of 5-HT. Responsible for directing biological beating (fatigue/body temperature etc.), melatonin therefore restores these rhythms because during depression these circadian rhythms are disturbed. Thus, depression affects melatonin secretion.

S/E: Headache, dizziness, GIT discomfort, fatigue, liver enzyme increases

• CI: Hepatic impairment

• Valdoxane

THERE IS SINNERGISM BETWEEN MELATONIN RECEPTORS AND 5—HT RECEPTORS:

• 5-HT2/M1+2 receptors:

                        Higher density in SCN

                        Regulation of circadian rhythms

• M1+2 agonism beneficial for sleep but is not antidepressant.

For example, in the meantime, you cannot give someone only melatonin to totally alleviate depression, the insomnia that occurs in depression can be alleviated by a melatonin agonist.

• 5-HT2C agonism worsens sleep disturbances
• 5-HT2C antagonism promotes sleep
• 5-HT2C antagonism promotes Antidepressive action. As a result, DA and NA increase in the pre-frontal cortex which then results in an anti-depressant effect, the one receptor is therefore blocked with the greater purpose of boosting NA and DA transmission.

Hypertensive crisis

5. Sympathomimetic amines (cold and flu preparations)
5. Tyramine containing food > 10 mg tyramine + MAOA inhibitor (Cheese, wine, beans, Marmite, biltong, yoghurt, etc.)

Symptoms of hypertensive crisis: Enlarged pupils, light sensitivity, severe headache, chest pains, arrhythmias, stiff neck, sweat, nausea, vomiting.

5. Potentiates CNS suppressors, hyperpyrexia with pethidine.
5. Potentiates toxic effects of TAD’s, SSRI’s: hyperpyrexia, convulsions, coma

Clinical use: general principles

Treatment Resistant Depression

5. All available AD’s: 6 – 8 weeks needed with sufficient dosages before AD’s effects are optimal ⇒ Don’t stop too early
5. After response: Therapy for at least 6 – 12 months after a single episode to prevent a relapse.
5. Multiple episodes: longer maintenance therapy needed.
5. Gradual withdrawal (severe withdrawal reaction with paroxetine)
5. Combination of AD’s not recommended, except for resistant depression.
5. Combination with anxiolytic not advised, except during 1st week or two prn
5. Major Depression:

• Clinical effectiveness the same for all drugs
• Individual response to different drugs varies.
• 65 – 70% of pt’s with major Depression improve with drugs
• TCA require titration to minimum effective dose, while SSRI’s can be started immediately at full doses, although must be aware of anxiety and jitteriness.
• Psychotic characteristics: ECT / AD + anti-psychotic drug
• Drugs with the least association with sexual side effects: Bupropion, mirtazapine and agomelatine.

5. SSRI’s and other newer drugs preferred due to:

• Better side-effect profile
• Safer in acute overdose
• SSRI’s can suppress appetite; overweight patients may lose weight.

5. TAD’s alternative for:

• Patients unresponsive to commonly used AD’s

5. MAOI’s:

• Rarely used because of toxicity and potential lethal food and drug interactions.
• Patients unresponsive to other AD’s
•  Anxiety disorders, social anxiety and panic disorder

5. Mostly because of insufficient therapy
5. Other AD can be tried.
5. Potentiating therapy:

• Lithium
• Liothyronine
• Carbamazepine, valproate
• SSRI plus atypical antipsychotic (e.g., olanzapine, quetiapine)

5. Combination of two different classes (never SSRI + MAOI), but caution!

Elderly:

Children, teenagers

Pregnancy:

• Vascular, neurochemical, neurodegenerative and age-related changes in the frontal-striatal circuits leads to reduced treatment response to antidepressants in the elderly.

• SSRI’s 1’st choice

• Healthy geriatrics: Secondary TAD (Nortriptyline, DMI)

• Bupropion, venlafaxine (less anticholinergic and cardiac side-effects)

• Data scarce

• Warning!! AD’s may induce suicidal thoughts in young people (18 - 24 yrs)

• SSRI’s better tolerated, safer in overdose.

• Fluoxetine is the only AD approved in children

• Drugs only used if other therapy is insufficient.

• Teratogenic effects not reported with TAD’s or SSRI’s.

• Possible association between fluoxetine and premature births and delayed foetal growth tempo