Psychopharmacology

Dr. Layali Abbasi Psychiatrist

Yarmouk University

5th year/Faculty of Medicine October, 2017

Depression: Treatment goals

1. Increase remission rates.

2. Prevent relapse.

3. Restore physical functioning.

4. Restore social functioning.

General principles of anti-depressant action

• When treatment of depression results in at least 50% improvement in symptoms, it is called a response.

• When treatment of depression results in removal of essentially all symptoms, it is called remission for the first several months and then recovery if it is sustained for longer than 6 months.

• When depression returns before there is a full remission of symptoms or within the first several months following remission of symptoms, it is called a relapse.

• When depression returns after a patient has recovered, it is called a recurrence.

Treatment options for depression

Pharmacological: • Selective Serotonin Reuptake Inhibitors • Noradrenergic and Specific Serotonergic

Antidepressant (NaSSA). • Selective Serotonin and Norepinephrine Reuptake

Inhibitors • Tricyclic antidepressants • Monoamine-oxidase inhibitors • Combination/ augmentation therapies • Atypical antipsychotics

Treatment options for depression

Non-pharmacological:

• Psychotherapy: e.g. CBT,interpersonal therapies.

• Electroconvulsive therapy

• Vagus nerve stimulation, transcranial magnetic stimulation

Selective Serotonin Reuptake Inhibitors( SSRI’s)

• Fluoxetine

• Sertraline

• Paroxetine

• Citalopram

• Escitalopram

• Fluvoxamine

Mechanism of action of SSRIs

In depression, the 5HT neuron is conceptualized as having a relative deficiency of the neurotransmitter 5HT. Also, the number of 5HT receptors is upregulated, including presynaptic 5HT1A autoreceptors as well as postsynaptic 5HT receptors.

When an SSRI is administered, it immediately blocks the serotonin reuptake pump. However, this causes serotonin to increase initially only in the

somatodendritic area of the serotonin neuron (left) and not very much in the axon terminals (right).

The consequence of serotonin increasing in the somatodendritic area of the serotonin (5HT) neuron, is that the somatodendritic 5HT1A autoreceptors desensitize or downregulate (red circle)

Once the somatodendritic receptors downregulate, there is no longer inhibition of impulse flow in the serotonin (5HT) neuron. Thus, neuronal impulse flow is turned on. The consequence of this is release of 5HT in the axon terminal (red circle). However, this increase is delayed as compared with the increase of 5HT in the somatodendritic areas of the 5HT neuron. This delay is the result of the time it takes for somatodendritic 5HT to downregulate the 5HT1A autoreceptors and turn on neuronal impulse flow in the 5HT neuron. This delay may explain why antidepressants do not relieve depression immediately. It is also the reason why the mechanism of action of antidepressants may be linked to increasing neuronal impulse flow in 5HT neurons, with 5HT levels increasing at axon terminals before an SSRI can exert its antidepressant effects.

Once the SSRIs have blocked the reuptake pump (or serotonin transporter [SERT], increased somatodendritic serotonin(5HT), desensitized somatodendritic 5HT1A autoreceptors, turned on neuronal impulse flow, and increased release of 5HT from axon terminals, the final step may be

the desensitization of postsynaptic 5HT receptors. This desensitization may mediate the reduction of side effects of SSRIs as tolerance develops.

Side effects

• Gastrointestinal :

Very common.

Mediated through effects on serotonin 5-HT3 receptors.

The most frequent GI complaints: nausea, diarrhea, anorexia, vomiting, flatulence, dyspepsia.

Side effects

• Headache

Fluoxetine is the most likely to cause headache.

• Anxiety

• Vivid dreams or nightmares, bruxism, nocturnal myoclonus and sweating.

• Emotional blunting.

• Yawning

Side effects

• Sexual dysfunction

Is the most common adverse effects of SSRIs associated with long term treatment.

It has an estimated incidence of between 50 and 80 %.

The most common complaints are anorgasmia, inhibited orgasm, and decreased libido.

Withdrawal syndrome

• The abrupt discontinuation of SSRI use, especially one with a shorter half-life such as paroxetine or fluvoxamine, has been associated with a withdrawal syndrome.

• Most often emerge within 1-3 days.

• It usually does not appear until after at least 6 weeks of treatment and usually resolves spontaneously in 3 weeks.

• SSRI discontinuation symptoms have been reported most frequently with paroxetine (short elimination half life) and least frequently with fluoxetine (long elimination half-lives of parent compound and active metabolite).

• The most common physical symptoms are dizziness, nausea and vomiting, fatigue, lethargy, flulike symptoms.

• The psychological symptoms are anxiety, irritability and crying spells.

Selective Serotonin and Norepinephrine Reuptake Inhibitors(SNRI’s)

• SNRIs combine the robust SERT inhibition of the SSRIs

with various degrees of inhibition of the norepinephrine transporter (or NET).

• NET inhibition increases both NE and DA in prefrontal cortex.

• Thus, SNRIs have “two-and-a-half” mechanisms: Boosting serotonin throughout the brain. Boosting norepinephrine throughout the brain.

Boosting dopamine in prefrontal cortex (but not in other DA projection areas).

Selective Serotonin and Norepinephrine

Reuptake Inhibitors(SNRI’s)

• Venlafaxine

• Duloxetine

• Venlafaxine is approved for treatment of four disorders:

-Major depressive disorder

-Generalized anxiety disorder

-Social anxiety disorder

-Panic disorder

Venlafaxine

• Side effects : Nausea is the most frequently reported

adverse effect. Sexual side effects, predominantly decreased libido

and a delay to orgasm or ejaculation. Headache, insomnia, somnolence, dry mouth,

dizziness, constipation, sweating and nervousness. Higher-dose is associated with an increased risk of

sustained elevations of blood pressure. Cardiotoxic Discontnuation syndrome can be severe.

Duloxetine

• Side effects :

Nausea, dry mouth, dizziness, constipation, fatigue, decreased appetite, anorexia, somnolence and increased sweating.

Mirtazapine

• Noradrenergic and Specific Serotonergic Antidepressant (NaSSA).

• Presynaptic alpha-2 blockade.

• Postsynaptic selective 5HT2A receptors, 5HT2C receptors, and 5HT3 blocker.

• Also a potent histamine blocker.

• 5HT2C antagonist action as a potential antidepressant and should theoretically contribute to the antidepressant effects of mirtazapine.

• The H1 antihistaminic actions of mirtazapine should theoretically relieve insomnia at night, and improve anxiety during the day, but could also cause drowsiness during the day.

• Combined with the 5HT2C antagonist properties the H1 antihistaminic actions of mirtazapine could also cause weight gain.

• 5HT3 receptors are localized in the chemoreceptor trigger zone of the brainstem, where they mediate nausea and vomiting, and in the gastrointestinal tract, where they mediate nausea, vomiting, and diarrhea/ bowel motility when stimulated.

• Blocking these receptors can therefore protect against serotonin-induced gastrointestinal side effects that often accompany agents that increase 5HT release.

Mirtazapine

• Sedating

• Increased appetite

• Relatively cardiac safe

• Limited sexual side effects.

Heterocyclic antidepressants (tricyclic and tetracyclic antidepressants)

• Block the reuptake pumps for norepinephrine (i.e., NET), or for both norepinephrine and serotonin (i.e., SERT).

• Some tricyclics have equal or greater potency for SERT inhibition (e.g., clomipramine); others are more selective for NET inhibition (e.g., desipramine, maprotiline, nortriptyline, protriptyline).

• Most, however, block both serotonin and norepinephrine reuptake to some extent.

• In addition, some tricyclic antidepressants have antagonist actions at 5HT2A and 5HT2C receptors which could contribute to their therapeutic profile.

Therapeutic actions of tricyclic antidepressants(TCAs)

Tricyclic antidepressants ( TCAs)

• The problem with drugs in this class is the fact that all of them share at least four other unwanted pharmacologic actions, namely, blockade of muscarinic cholinergic receptors, H1-histaminic receptors, α1-adrenergic receptors, and voltage-sensitive sodium channels.

Side effects of tricyclic antidepressants (TCAs)

• Contraindications: Absolute contraindications: MI (until 6 months after the MI) Narrow-angle glaucoma Relative contraindications: Cardiac disease ( a baseline ECG is recommended). Prostatic hypertrophy or other obstructive uropathy ( secondary to anti-cholinergic side effects).

Tricyclic antidepressants

• Tricyclic antidepressants are not merely antidepressants, since one of them (clomipramine) has anti-obsessive–compulsive disorder effects and many of them have anti-panic effects at antidepressant doses and efficacy for neuropathic and low back pain at low doses.

Tricyclic antidepressants

• Because of their side effects and potential for death in overdose, tricyclic antidepressants have fallen into second-line use for depression.

Tricyclic antidepressants (TCAs)

• Clomipramine

• Imipramine

• Amitriptyline

• Nortriptyline

MAO inhibitors

• MAO exists in two subtypes, A and B. • The A form preferentially metabolizes the monoamines

most closely linked to depression (i.e., serotonin and norepinephrine) whereas the B form preferentially metabolizes trace amines such as phenylethylamine.

• Both MAO-A and MAO-B metabolize dopamine and tyramine.

• Both MAO-A and MAO-B are found in the brain. Noradrenergic neurons and dopaminergic neurons are thought to contain both MAO-A and MAO-B, with perhaps MAO-A activity predominant, whereas serotonergic neurons are thought to contain only MAO-B.

MAO inhibitors

• Exert their antidepressant effects by raising monoamine levels in the synaptic cleft by blocking monoamine metabolism through deactivation of the enzyme monoamine oxidase (MAO).

• Are only FDA approved for MDD and are especially effective for MDD with atypical features and for treatment-resistant depression.

MAO inhibitors

• One of the biggest barriers to using MAOIs has traditionally been the concern that a patient taking one of these drugs may develop a hypertensive crisis after ingesting tyramine in the diet.

• Normally, the release of norepinephrine by tyramine is inconsequential because MAO-A safely destroys this released norepinephrine.

MAO inhibitors

• However, tyramine in the presence of MAO-A inhibition can elevate blood pressure because norepinephrine is not safely destroyed.

• Tyramine-rich foods( e.g., aged cheese, beef or chicken liver, smoked pickled meats or fish, banana peel, broad bean pods).

MAO inhibitors Hypertensive crisis

• Defined by diastolic blood pressure > 120 mmHg Potentially fatal reaction characterized by:

Occipital headache that may radiate frontally. Palpitation . Neck stiffness or soreness. Nausea. Vomiting. Sweating (sometimes with fever) . Dilated pupils, photophobia . Tachycardia or bradycardia, which can be

associated with constricting chest pain.

Drug–drug interactions for MAOIs

• There are two general types of potentially dangerous drug interactions with MAOIs to avoid:

Those that can raise blood pressure by sympathomimetic actions

Those that can cause a potentially fatal serotonin syndrome by serotonin reuptake inhibition.

MAO inhibitors serotonin syndrome

• At least three of the following: -Agitation -Myoclonus -Hyperreflexia -Diaphoresis -Shivering -Tremor -Diarrhea -Ataxia/incoordination -Fever

Mood Stabilizers

Mood Stabilizers

• Lithium

• Valproic acid

• Carbamazepine

• Lamotrigine

Lithium

• Acute bipolar mania (FDA) o Classic euphoric mania. o Fewer than three previous bipolar episodes. o Prior positive response to lithium. o Good interepisode functioning and euthymia

between episodes. o Absence of neurological impairment, psychotic

symptoms, and active substance abuse.

• Maintenance treatment of bipolar disorder (FDA) • Bipolar depression (not FDA)

Lithium

• Pretreatment workup: o Routine chemistries.

o CBC with differential.

o Thyroid panel with TSH.

o Blood urea nitrogen.

o Serum creatinine.

o ECG if the patient is older than 40 years or has a history of heart disease.

o Pregnancy test (if applicable).

• Well-known side effects: Gastrointestinal symptoms such as dyspepsia, nausea,

vomiting, and diarrhea. Weight gain Hair loss Acne Tremor Sedation Decreased cognition • There are also long-term adverse effects upon the thyroid

and kidney.

Lithium

• Thyroid o Hypothyroidism occurs in 5%--35% of lithium

users, is more frequent in women, typically develops 6--18 months after starting lithium, can be diagnosed by an elevated TSH level, and is reversible by stopping lithium. Treatments include changing medications or adding a thyroid medication.

o Diffuse nontoxic goiter with or without hypothyroidism (reversible by stopping lithium).

Lithium

• Renal Renal insufficiency: o Most often develops in patients on long-term lithium

therapy. Changes include interstitial fibrosis, tubular atrophy, and glomerular sclerosis, possibly reflected by increased serum creatinine.

Decreased urine-concentrating ability, resulting in: o Polyuria (excessive urination) with accompanying

polydipsia (excessive thirst), secondary to the antagonism of antidiuretic hormone. Can be especially problematic at night.

o Nephrogenic diabetes insipidus (i.e., “severe polyuria”).

Lithium

• Cardiac:

o Benign electrocardiographic conduction changes resemble hypokalemia, with T-wave flattening or inversion.

o Arrhythmias and, rarely, sudden death have been reported in patients with preexisting cardiac disease.

o Impaired sinus node function with potential heart block.

o Lithium should not be used in patients with sick sinus syndrome.

Lithium

• Lithium is potentially teratogenic (pregnancy risk category D): Ebstein’s anomaly (a severe and sometimes fatal malformation of the tricuspid valve that enters the right ventricle) is the most common finding. Recent studies give an incidence of l per 1,000.

Lithium

• Lithium has a narrow therapeutic window, requiring monitoring of plasma drug levels.

• Therapeutic blood level range is 0.6-1.2 mEq/L.

Lithium

• Signs of mild to moderate lithium intoxication (lithium level=1.5–2.0 mEq/ L) include gastrointestinal symptoms (nausea, vomiting, diarrhea, dry mouth) and neurological symptoms (ataxia, slurred speech, dizziness, nystagmus, lethargy, and muscle weakness).

Lithium

• Signs of moderate to severe lithium toxicity (serum level=2.1–2.5 mEq/L) include gastrointestinal symptoms (anorexia, persistent nausea, and vomiting), neurological symptoms (blurred vision, muscle fasciculations, choreoathetoid movements, seizure, and/or delirium), and cardiovascular symptoms (ECG changes such as QTc prolongation, T-wave flattening, and arrhythmias in addition to circulatory failure and/or syncope).

Lithium

• Signs of severe lithium intoxication (lithium level more than 2.5 mEq/L) include generalized seizures, oliguria and renal failure, and possibly death.

Lithium

• Management of lithium toxicity includes discontinuation of lithium, supportive hospital care, and, in severe cases, hemodialysis.

Lithium

• Is FDA approved for the treatment of acute mania (effective for classic euphoric mania, mixed episodes and rapid cycling).

Valproic acid

Valproic acid (also valproate) may work by interfering with voltage-sensitive sodium channels (VSSCs), enhancing the inhibitory actions of γ-aminobutyric acid (GABA), and regulating downstream signal transduction cascades, although which of these actions may be related to mood stabilization is not clear. Valproate may also interact with other ion channels, such as voltage-sensitive calcium channels (VSCCs), and also indirectly block glutamate actions.

• Pretreatment workup:

o Routine chemistries.

o CBC with differential.

o Platelet count.

o Liver function tests.

o Renal function tests.

o Serum amylase.

o Pregnancy test (if applicable).

Valproic acid

• Common side effects:

o Gastointestinal upset.

o Sedation.

o Hair loss.

o Increased appetite with weight gain.

o Tremor.

o Skin rash.

o Benign leukopenia/ thrombocytopenia.

Valproic acid

Valproic acid

• Serious and life threatening side effects:

o Black box warnings for hepatic toxicity (possibly fatal), Hemorrhagic pancreatitis.

o Teratogenicity, with 1-2 % incidence of neural tube defects (spina bifida).

o Stevens-Johnson syndrome. o Polycystic ovarian syndrome ( PCOS). o Agranulocytosis. o Platelet dysfunction, dose related thrombocytopenia and

coagulopathies.

• FDA approved only as the extended-release formulation for the treatment of manic and mixed episodes of bipolar I disorder.

Carbamazepine

Carbamazepine may work by binding to the α subunit of voltage-sensitive sodium channels (VSSCs) and could perhaps have actions at other ion channels for calcium and potassium. By interfering with voltage-sensitive channels, carbamazepine may enhance the inhibitory actions of γ-aminobutyric acid (GABA).

Carbamazepine

• Pretreatment workup:

o Routine chemistries.

o CBC with differential.

o Platelet count.

o Liver function tests.

o Renal function tests.

o Pregnancy test (if applicable).

• Carbamazepine induces its own metabolism (i.e., autoinduction), gradually resulting in a decrease in the carbamazepine serum level without a change in the dose. Dosage increases may eventually be needed.

Carbamazepine

• Common side effects include:

o Dermatitis (common finding). o Nausea, vomiting, and diarrhea (an especially common

complaint that is markedly improved with the extended release formulation).

o Dizziness, acute confusional states, ataxia, and diplopia (all dosedependent).

o Mild anticholinergic side effects due to the tricyclic structure. o CNS depression, sedation (common), and cognitive impairment. o Mild nonprogressive decreases in blood indices.

Carbamazepine

• Potentially serious or life-threatening side effects: o Stevens-Johnson syndrome and toxic epidermal

necrolysis especially during the first 2-8 weeks of treatment.

o Hepatitis or hepatic failure.

o Agranulocytosis or aplastic anemia (1 in 20,000; black box warning).

o Syndrome of inappropriate antidiuretic hormone (SIADH) due to vasopressin release.

Carbamazepine

• Carbamazepine is potentially teratogenic (pregnancy risk category D), with a 0.5%--1 % incidence of spina bifida. Craniofacial defects and developmental delay in the neonate have also been reported. The danger is greatest during the first trimester of pregnancy.

Carbamazepine

Lamotrigine

• Is approved as a mood stabilizer to prevent recurrence of both mania and depression.

• FDA has not approved its use for bipolar depression.

Lamotrigine may work by blocking the α subunit of voltage-sensitive sodium channels (VSSCs) and could perhaps also have actions at other ion channels for calcium and potassium. Lamotrigine is also thought to reduce the release of the excitatory neurotransmitter glutamate.

Lamotrigine

• Side effects include headache (the most commonly reported side effect) and an early-onset prominent skin rash (approximately 10% of patients), which can be minimized by a slow titration schedule.

Lamotrigine

• Lamotrigine is generally well tolerated for an anticonvulsant, except for its propensity to cause rashes, including (rarely) the life-threatening Stevens– Johnson syndrome (toxic epidermal necrolysis).

• Rashes caused by lamotrigine can be minimized by very slow up-titration of drug during initiation of therapy, avoiding or managing drug interactions such as those with valproate that raise lamotrigine levels.

Lamotrigine

• Dangerous complications are “serious rashes” (e. g., Stevens-Johnson syndrome, toxic epidermal necrolysis), occurring at a rate of 1:1,000, which can be life-threatening.

• These serious rashes occur most often within the first8 weeks of treatment and can be minimized (but not entirely avoided) by initiating treatment at a low dosage and titrating upward slowly.

• Discontinue lamotrigine and, unless absolutely necessary, do not rechallenge.

Lamotrigine

• Lamotrigine is pregnancy risk category C and is associated with an approximately two-fold increase in major congenital malformations, including cleft palate.

THE END