Clinical Psychopharmacology: An Update

© Springer Nature Singapore Pte Ltd. 2019

Prakash B. Behere, Anweshak Das and Aniruddh P. BehereClinical Psychopharmacologyhttps://doi.org/10.1007/978-981-13-2092-7_1

1. Antidepressants

Prakash B. Behere¹ , Anweshak Das² and Aniruddh P. Behere³

(1)

Department of Psychiatry, D Y Patil Medical College & D. Y. Patil Education Society (Deemed University), Kolhapur, Maharashtra, India

(2)

Consultant Psychiatrist, Psychiatric Clinic, Guwahati, Assam, India

(3)

Pediatric Behavior Health , Helen Devos Childrens’s Hospital, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA

1.1 Tricyclic and Tetracyclic Antidepressants

Class of Drug

Tricyclic and Tetracyclic antidepressants.

History and Introduction

Tricyclics were the first drugs introduced for the treatment of depression. Like lithium and chlorpromazine the invention was serendipitous. In 1957, Ronald Kuhn, a Swiss psychiatrist, observed the effects of imipramine as antidepressant.

Chemistry

These compounds are characterized mainly on the basis of their structures. The tricyclics have a three-ring central structure, and tetracyclics have a four-ring central structure. The tertiary amine tricyclics such as Imipramine and Amytriptiline have two methyl groups at the end of side chain. These compounds can be demethylated to secondary amines such as desipramine and nortriptyline.

Pharmacokinetics

Absorption of Tricyclics and Tetracyclics occur in the small intestine and is reasonably complete and rapid. Peak levels are reached after 2–8 h of ingestion, except for the drugs Protryptiline and Maprotiline, which reach their peak level after 8 h. These compounds are basic lipophilic amines. As a result, they are concentrated in a variety of body tissues such as cardiac tissue and cause cardiac side effects. These compounds are highly lipid soluble and are 90% bound to serum proteins. After absorption, they first pass metabolism in the liver. Clearance is principally through metabolism in the liver. Renal clearance accounts for a very small amount of drug. Elimination half-lives are approximately more than 24 h with an exception, which has half-life of 5–10 h. Most of TCAs follow the linear kinetics.

Pharmacodynamics

Reuptake blockade—These drugs block the reuptake of serotonin and norepinephrine at presynaptic sites and increase the amount of these amines. The tertiary amines have a higher affinity for norepinephrine, and secondary amines have a higher affinity for serotonin. TCAs also increase dopamine transmission in frontal cortex.

Receptor sensitivity changes—The Tricyclic agents sensitize or upregulate postsynaptic 5-HT1A receptors. These changes in sensitivity of the presynaptic and postsynaptic receptors occur over a period of 2 weeks, and the onset of these changes is more consistent with the timing of antidepressant response than the initial uptake blockade.

Secondary effects—The Tricyclic and Tetracyclic compounds have effects on a variety of receptors. In particular, these drugs act on muscarinic receptors producing anticholinergic effects. They block Histamine 1 receptors producing sedation. They also block alpha 1 and alpha 2 receptors. They have effects on fast sodium channels which explain their cardiac side effects.

Doses [1, 2]

Augmenting Agents

Gabapentin for neuropathic pain along with amitriptyline. Fluvoxamine can be added along with clomipramine for treatment of resistant OCD. Atypical antipsychotics can also be added for OCD Thyroid hormones, and lithium can be added for resistant depression as a form of psychotherapy.

Drug Interactions

Sudden increases in catecholamine levels if used with MAOIs.

Concomitant use of quinidine can cause a heart block.

Drugs that inhibit CYP 2D6 like Fluoxetine and Paroxetine can increase the levels of amines.

Drugs which induce CYP enzymes like Carbamazepine and barbiturates can decrease the levels of these drugs.

Use of TCAs with sympathomimetics may increase sympathetic activity.

Haloperidol may increase levels of TCAs.

TCAs with anticholinergics can cause paralytic ileus and hypothermia.

Indications

Depressive disorders—It has been suggested that TCAs are more effective than SSRIs in severe depressive episodes with melancholic features. For depressive disorders with predominant anxiety symptoms drugs like Doxepin, Amoxapine, and Maprotiline are more effective. Patients of depression with atypical features are more effective. These compounds are not so useful in psychotic depression. They are also useful in insomnia.

Panic disorders, migraine, Enuresis, Cataplexy—Imipramine.

Obsessive compulsive disorders, Cataplexy syndrome—Clomipramine.

Neuropathic pain, Headache, Fibromyalgia—Amytriptiline.

ADHD—Desipramine.

Side Effects

Central nervous system side effects—The central anticholinergic effects can produce seizures and delirium. Both of these side effects are dose dependent and become more likely to occur at elevated blood levels. Incidence of delirium increases if blood levels raise more than 300 ng/mL and seizures after levels greater than 450 ng/mL, especially with Amytriptiline.

The tricyclics can cause fine rapid tremors which is also a dose-related side effect. Because the 7-Hydroxymetabolite of Amoxapine has Neuroleptic effects, it can cause Neuroleptic Malignant Syndrome.

Autonomic side effects—Anticholinergic side effects like dry mouth, constipation, blurring of vision, urinary hesitancy, delirium, and ocular crisis in patients with narrow angle glaucoma. Desipramine has the least anticholinergic side effects.

Cardiovascular effects—Orthostatic hypotension is the most common side effect. Elderly people are more prone to falls. Tachycardia occurs with all the tricyclics.

Cardiac conduction defects—The Tricyclic antidepressants have type 1 antiarrhythmic effects. In patients with conduction delay, it can cause heart block. It causes QT prolongation.

Hepatic effects—liver enzyme AST levels can be raised.

Other adverse effects—sexual dysfunction, allergic skin rashes.

Teratogenicity—Isolated reports of morphogenesis reported, neonatal drug withdrawal can occur which is characterized by tachypnea, cyanosis, irritability, and poor suckling reflex.

Weight gain: Commonly causes weight gain. If a patient has gained 5% of initial weight, consider evaluating for diabetes or dyslipidemia.

Rarely can cause paralytic ileus which can be life threatening.

Overdose

Death most commonly occurs as a result of cardiac toxicity. It causes seizures, cardiac dysrhythmias, hypotension, and coma.

Special Populations

Precautions

Should not be used with MAO inhibitors.

Should be used in patients who are on calcium channel blockers or beta blockers.

Should be used with caution in patients who have hypokalemia and hypomagnesemia.

Should be avoided in patients having history of seizures, glaucoma.

To decrease withdrawal symptoms should be tapered down slowly.

1.2 Specific Serotonin Reuptake Inhibitors [6]

1.2.1 Fluoxetine

Class of Drug

Selective Serotonin Reuptake Inhibitor.

History and Introduction

Fluoxetine was the first SSRI to be introduced in 1987.

Pharmacokinetics

It is well absorbed orally with 70–90% bioavailability. Food may delay absorption for 1–2 h. It is 95% bound to serum proteins. Its active metabolite norfluoxetine has a half-life of 2 weeks. Parent drug has a half-life of 2–3 days. It inhibits CYP 450 2D6 and CYP 450 3A4.

Pharmacodynamics

Therapeutic activity is due to specific 5-HT reuptake inhibition at the presynaptic serotonergic nerve terminal. It desensitizes serotonin receptors, especially serotonin 1A receptors. Fluoxetine has partial antagonist action at 5HT2C receptors which could increase norepinephrine and dopamine neurotransmitter.

Doses

Onset of Action

Onset of therapeutic action is not immediate. It may take 2–4 weeks to show its action.

Augmenting Combination

Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression, or treatment-resistant depression.

Modafinil for fatigue, sleepiness, and lack of concentration.

Fluoxetine has been specially studied in combination with olanzapine, with excellent results for bipolar depression, treatment-resistant unipolar depression, and psychotic depression.

Drug Interactions

Increases the levels of TCAs.

Can cause Serotonin syndrome if combined with Mono amine Oxidase Inhibitors (MAOIs).

Can cause Serotonin syndrome if combined with dopamine antagonists.

By inhibition of CYP, it can increase serum concentration of many drugs, e.g., beta blockers, thioridazine, alprazolam, buspirone, and pimozide.

Possible increased risk of bleeding especially when combined with anticoagulants like warfarin and NSAIDS.

Indications

Major depressive disorder

Bipolar depression

Dysthymia

Seasonal affective disorder

Obsessive compulsive disorder

Bulimia Nervosa

Panic disorder

Premenstrual dysphoric disorder

Trichotilomania

Post-traumatic stress disorder

Social anxiety disorder

Body dysmorphic disorder

Substance dependence

Smoking cessation

Premature ejaculation

Chronic fatigue syndrome

Fibromyalgia

Raynaud’s phenomenon

Post stroke depression

Postmenopausal hot flashes

Side Effects

Fluoxetine unique 5HT2C antagonist properties could contribute to agitation and anxiety.

Sexual dysfunction: delayed ejaculation in men and decreased sexual desire in women.

Gastrointestinal dysfunction: loss of appetite, nausea, diarrhea, constipation, dry mouth.

CNS: Insomnia, agitation, tremors, headache, dizziness, rarely seizures.

Autonomic: sweating.

Rare induction of mania.

Overdose

May be lethal in overdoses.

Precautions and Contraindications

Use in seizure disorder may decrease seizure threshold.

In bipolar depression, it should be used along with mood stabilizer.

Should not be given if patient is taking MAOIs, thioridazine, or pimozide or has any proven allergy to Fluoxetine.

Monitor patients for suicidal ideation, especially in children and adolescents.

Special Populations

1.2.2 Sertraline

Class of Drug

Selective Serotonin Reuptake inhibitor.

History and Introduction

Sertraline was the second member of SSRI to be introduced in 1992.

Pharmacokinetics

It is well absorbed orally. When given with food, plasma concentration reaches maximum value in 5–6 h, as compared to when it is given without food (which is 8 h). It is 98% bound to serum proteins. Half-life of Sertraline is 26 h and its metabolite’s (N-desmethylsertraline) half-life is 62–104 h. It inhibits CYP 450 2D6 and CYP 450 3A4.

Pharmacodynamics

Therapeutic activity is due to specific 5-HT reuptake inhibition at the presynaptic serotonergic nerve terminal. It also has some ability to block dopamine reuptake pumps. It desensitizes serotonin receptors, especially serotonin 1A receptors.

Onset of Action

Onset of therapeutic action is not immediate. It may take 2–4 weeks to show its action.

Augmenting Combination

Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression, or treatment-resistant depression.

Modafinil for fatigue, sleepiness, and lack of concentration.

Doses

Drug Interactions

Increases the levels of TCAs.

Can cause Serotonin Syndrome if combined with Monoamine Oxidase Inhibitors (MAOIs).

By inhibition of CYP, it can increase serum concentration of many drugs, e.g., beta blockers, thioridazine, alprazolam, and buspirone.

Indications

Atypical depression (may be a first line of choice)

Major depressive disorder

Dysthymia

Chronic depression

Obsessive compulsive disorder

Panic disorder

Premenstrual dysphoric disorder

Post-traumatic stress disorder

Social anxiety disorder

Premature ejaculation

Side Effects

Increasing serotonin can cause diminished dopamine release, and might cause emotional flattening, cognitive slowing, and apathy in some patients.

Sexual dysfunction: delayed ejaculation in men and decreased sexual desire in women.

Gastrointestinal dysfunction: loss of appetite, nausea, diarrhea, constipation, dry mouth.

CNS: insomnia, agitation, tremors, tics, headache, dizziness, rarely seizures.

Autonomic: sweating, orthostatic hypotension.

Rarely induction of mania.

Hyponatremia and hypotension mostly in elderly (rarely).

Overdose

Causes vomiting, sedation, heart rhythm disturbances, dilated pupils, and agitation.

Precautions and Contraindications

Use in seizure disorder may decrease seizure threshold, add/initiate other antidepressant with caution for up to 2 weeks of discontinuation of Sertraline. In bipolar depression, it should be used along with a mood stabilizer. The drug should not be administered if patient is taking MAOIs, thioridazine, or pimozide, or if patient has any proven allergy to Sertraline.

Special Populations

1.2.3 Fluvoxamine

Class of Drug

Selective Serotonin Reuptake inhibitor.

History and Introduction

Fluvoxamine was initially introduced in Switzerland in 1983.

Pharmacokinetics

Oral bioavailability is about 50%. Its absorption is not affected by food. Plasma concentration reaches maximum in 3–8 h. The primary site of metabolism is liver. It follows nonlinear pharmacokinetics. The half-life of the drug is 9–28 h.

Pharmacodynamics

Therapeutic activity is due to specific 5-HT reuptake inhibition at the presynaptic serotonergic nerve terminal. It also has antagonist properties at sigma 1 receptors.

Onset of Action

Some patients may experience relief from insomnia and anxiety, early after initiation of treatment. Onset of therapeutic action is not immediate. It may take 2–4 weeks to show its action.

Augmenting Combination

For OCD clomipramine can be added on.

Mood stabilizers or atypical antipsychotics for bipolar depression, psychotic depression, treatment-resistant depression, or treatment-resistant anxiety disorders.

For anxiety disorders gabapentin may also be added.

Modafinil for fatigue, sleepiness, and lack of concentration.

Doses