Drug Treatment: Antipsychotics, Antidepressants, Lithium And Other Mood Stabilizers

• Acute Dystonia
• Akathesia
• Parkinsonian-like Side Effect
• Tardive Dyskinesia
• Tardive Dystonia

These are side effects of antipsychotics, especially typical medications. They result from the blockade of dopaminergic receptors at the basal ganglia and manifest with abnormal body movements. Major extrapyramidal side effects include:

Acute Dystonia

A common side effect characterized by sustained painful muscle spasms, acute dystonia occurs within days of commencing an antipsychotic, with 50% of cases happening within 48 hours.

It is more common with butyrophenones and phenothiazines, affecting 3-10% of those exposed to antipsychotics.

Symptoms include:

• Grimacing
• Torticollis
• Opisthotonus
• Oculogyric crisis
• Trismus
• Tongue protrusion

It is usually more generalized in the young and more localized in the elderly, occasionally being confused with posturing or histrionic behavior.

Management

1. Review the medications
2. Discontinue suspected agent if possible
3. Emergency treatment with parenteral anticholinergics (e.g., benztropine, biperidine, procyclidine) in severe cases
4. Oral anticholinergics (e.g., benzhexol) for mild cases
5. The anticholinergic should be continued but tapered off gradually over 2 to 3 weeks
6. Consider Amantadine

Akathesia

Akathesia is an unpleasant, distressing feeling of inner restlessness manifested as pacing, inability to sit still, rocking, or constant crossing and uncrossing of legs. The term is derived from the Greek word meaning inability to sit still and was first described by Haskovec in 1901.

It typically occurs in the first two weeks of treatment, and risk factors include:

• Use of high doses of antipsychotics
• High-potency antipsychotics
• Rapid or sudden withdrawal of antipsychotics
• Intramuscular antipsychotics
• Organic brain disease
• Previous history of akathisia
• Concomitant use of other medications such as lithium

Akathesia may be mistaken for restlessness, anxiety, or agitation in a psychotic patient.

Management of Akathesia

1. Review the medications
2. Reduce the dose of antipsychotics if the clinical state of the patient permits
3. Consider a switch to a lower potency antipsychotic
4. Consider Beta blockers (e.g., propranolol, pindolol, betaxolol)
5. Consider Anticholinergics
6. Consider Benzodiazepines

Parkinsonian-like Side Effect

This is a frequent side effect of antipsychotic medications, occurring in about 20% of patients being treated with antipsychotics. It is a major cause of non-compliance with medications and typically appears after a few months of commencing medications.

It is said to be due to D2 blockade at the nigrostriatal pathway and presents with symptoms such as:

• Tremors
• Rigidity with reduced arm swing
• Bradykinesia
• Stooped posture
• Festinant gait in severe cases

Management of Parkinsonian-like Side Effects

1. Reduce the dose of antipsychotics if the clinical state permits
2. Consider Oral Anticholinergics
3. Switch to another antipsychotic (e.g., atypicals)
4. Consider Amantadine

Tardive Dyskinesia

Tardive Dyskinesia is a late-onset side effect of antipsychotics, often associated with long-term use but may occur in patients with schizophrenia who are not on antipsychotics.

Symptoms of Tardive Dyskinesia:

• Involuntary repetitive purposeless movements, manifesting as:
• Perioral chewing and sucking movements
• Torticollis or retrocolis
• Shoulder shrugging
• Pelvic thrusting
• Trunk twisting
• Repeated movements of the fingers and legs
• Hand clenching
• Most patients initially don’t notice these movements, and they are pointed out by others.
• When patients become aware, they may consciously suppress these movements for short periods of time.

It is a very worrisome side effect.

Pathophysiology of Tardive Dyskinesia

• Super sensitivity of post-synaptic D2 receptors due to prolonged blockade.
• GABA hypo-function.

Risk Factors for Tardive Dyskinesia

• Chronic use of antipsychotics
• Previous history of head injury
• Organic brain disease
• Women
• Mood disorder
• Elderly
• Previous history of drug-induced akathisia
• Concomitant use of drugs that can induce akathisia

Management of Tardive Dyskinesia

1. Review the medications
2. Reduce the dose of antipsychotics
3. Reduce the dose of anticholinergics
4. Increasing the dose of antipsychotics may give temporary relief
5. Benzodiazepines
6. Adrenergic agents such as propranolol, clonidine
7. Anticonvulsants (e.g., valproate, gabapentin)
8. Antioxidants (e.g., vitamin E)
9. Consider switching to an atypical antipsychotic

Tardive Dystonia

Tardive Dystonia is the long-term persistence of a dystonic movement disorder. It presents similarly to acute dystonic reactions but persists for an extended period, sometimes even after the antipsychotic has been withdrawn.

Treatment with anticholinergics is often not satisfactory.

Treatment of Tardive Dystonia

1. Discontinue medications if the patient’s clinical state permits.
2. Switch to an atypical medication, especially clozapine.
3. Consider injection of botulinum into the affected muscle group.

• Sedation
• Postural hypotension
• Inhibition of ejaculation
• Nasal congestion

• Dry mouth
• Urinary hesitancy and retention
• Blurred vision
• Reduced sweating
• Precipitation of glaucoma

Neuroleptic Malignant Syndrome is a rare and fatal side effect of antipsychotics, occurring idiosyncratically, often within the first 10 days of initiating the use of antipsychotics. It occurs in 0.07% to 0.2% of patients on antipsychotics and is more common in females than males.

Risk factors for Neuroleptic Malignant Syndrome:

• Rapid antipsychotic initiation
• Depot preparations
• High potency antipsychotics
• Previous history of NMS
• Affective disorder
• Organic brain disease
• Concomitant use of predisposing drugs

Symptoms of Neuroleptic Malignant Syndrome

Motor:

• Generalized muscular hypertonicity
• Stiffness of muscles of the throat and chest causing dysphagia and dyspnea
• Tremors
• Seizures

Mental:

• Akinetic mutism, stupor, impaired consciousness, confusion, agitation

Autonomic:

• Hyperpyrexia
• Increased sweating
• Increased salivation
• Hypo or hypertension
• Incontinence or retention of urine

Pathophysiology of Neuroleptic Malignant Syndrome

• Blockade of D2 receptors at the striatum and the hypothalamus
• Sympathetic nervous system dysfunction

Complications of Neuroleptic Malignant Syndrome

• Aspiration pneumonitis
• Renal failure
• Arrhythmias
• DIC (Disseminated Intravascular Coagulation)
• Respiratory failure

Management of Neuroleptic Malignant Syndrome

It is a psychiatric emergency. Steps to take:

1. Resuscitate the patient.
2. Stop the offending antipsychotic.
3. Administer intravenous fluids.
4. Alkalinization of urine.
5. Treat muscle stiffness with benzodiazepines.
6. Manage malignant hyperthermia with dantrolene, antipyretics, bromocriptine.
7. Treat intercurrent infections.

If the clinical state of the patient necessitates reintroduction of an antipsychotic, restart treatment cautiously with an atypical antipsychotic in low doses after about 2 weeks.

Cardiac Conduction Defects: Prolongation of QT interval (e.g., in pimozide, thioridazine)

Endocrine Side Effects: Amenorrhea, galactorrhea, breast tenderness, weight gain, impaired glucose tolerance, diabetes mellitus

Photosensitive Rashes: Chlorpromazine

Seizures

Depression

Eye Problems: Retinitis pigmentosa

Blood Dyscrasias: Commonly with clozapine

1. Give antipsychotics only to those who really need them.
2. Enquire about previous side effects of antipsychotics.
3. Start with a low dose and titrate upwards.
4. Avoid the use of very high doses of antipsychotics, especially the typicals.
5. Consider atypical antipsychotics first in patients who are antipsychotic naïve.
6. Exercise cautious prescribing in the elderly and the very young.
7. Avoid poly-pharmacy as much as possible.

Depression is a heterogeneous disorder characterized and classified in various ways. According to the American Psychiatric Association's fourth edition (1994) of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), several diagnoses of affective disorders are possible.

Major depression and dysthymia (minor) are pure depressive syndromes, whereas bipolar disorder and cyclothymic disorder signify depression in association with mania.

Amine Hypothesis

The amine hypothesis of mood postulates that brain amines, particularly norepinephrine (NE) and serotonin (5-HT), are neurotransmitters in pathways that function in the expression of mood.

According to the hypothesis, a functional decrease in the activity of such amines is thought to result in depression, while a functional increase in activity results in mood elevation.

Selective Serotonin Reuptake Inhibitors (SSRI)

• Fluoxetine (Prozac)
• Sertraline (Zoloft)
• Paroxetine (Paxil)
• Fluvoxamine (Luvox)
• Citalopram (Celexa)
• Escitalopram (Lexapro)

Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)

• Venlafaxine (Effexor)
• Duloxetine (Cymbalta)

Serotonin Receptor Agonists and Antagonists/Reuptake Inhibitor (SARI)

• Trazodone (Desyrel)
• Nefazodone

Norepinephrine-Dopamine Reuptake Inhibitors (NDRI)

• Bupropion (Wellbutrin)

Tricyclic Antidepressants

• Nortriptyline (Pamelor)
• Imipramine (Tofranil)
• Desipramine (Norpramin)
• Clomipramine (Anafranil)

Monoamine Uptake Inhibitors

• Selegiline (EMSAM patch)
• Tranylcypromine (Parnate)
• Phenelzine (Nardil)
• Isocarboxazid (Marplan)

Most antidepressants are fairly well absorbed after oral administration.

Serum concentrations of most tricyclic antidepressants peak within several hours.

Tricyclic antidepressants are oxidized by hepatic microsomal enzymes, followed by conjugation with glucuronic acid.

They are lipophilic.

Antidepressants are metabolized more rapidly by children and more slowly by patients over 60 years of age as compared with young adults.

All known antidepressants affect monoamine neurotransmission, and this is believed to be their mechanism of action.

• Tricyclic Antidepressants (TCA)
• SSRI (Selective Serotonin Reuptake Inhibitors)
• MAOI (Monoamine Oxidase Inhibitors)

Pharmacologic Effects

• Amine uptake blockade
• Sedation: mainserin, trimipramine, and dothiepin
• Muscarinic receptor blockade: more in amitriptyline and doxepin
• Cardiovascular effect: hypotension from α-adrenoceptor blockade, depresses conduction
• Seizures: TCA and MAOI lower seizure threshold; maprotiline also

• Major Depressive Disorder
• Bipolar Depression (acute treatment)
• Panic Disorder
• Social Phobia
• Generalized Anxiety Disorder
• Post-Traumatic Stress Disorder
• Obsessive-Compulsive Disorder (e.g., clomipramine and selective serotonin-reuptake inhibitors)
• Depression with Psychotic Features in Combination with Antipsychotic Drugs
• Bulimia Nervosa
• Neuropathic Pain (Tricyclic Drugs and Noradrenergic Reuptake Inhibitors)
• Insomnia (e.g., Trazodone, Amitriptyline)
• Enuresis (Imipramine Best Studied)
• Atypical Depression (Selective Serotonin-Reuptake Inhibitors or Monoamine Oxidase Inhibitors)
• Attention-Deficit Disorder with Hyperactivity (e.g., Desipramine, Bupropion)
• Others include Narcolepsy, Organic Mood Disorders

Occasionally, patients show physical dependence on the tricyclic antidepressants, with malaise, chills, muscle aches, and sleep disturbance following abrupt discontinuation, particularly of high doses.

Similar reactions, along with gastrointestinal and sensory symptoms (paresthesias) and irritability, also occur with abrupt discontinuation of serotonin reuptake inhibitors, particularly with paroxetine and venlafaxine.

Withdrawal reactions from MAO inhibitors may be severe, commencing 24 to 72 hours after drug discontinuation.

Cardiovascular Disease: SSRIs are the safest. Nortriptyline may also be used. Trazodone may cause a complete heart block.

Elderly: The half-lives and steady-state concentrations of the SSRIs are only minimally affected by age. Paroxetine may be an exception to this, and it may have an increased half-life in the elderly.

Medically Ill Patient: Nortriptyline and desipramine can be considered as alternatives for them.

Children and Adolescent: Nortriptyline and desipramine can be used as first-line agents since they have the least sedative, anticholinergic, and orthostatic hypotensive effects.

Nursing Mothers: Antidepressants are secreted in breast milk. Nursing should be deferred if antidepressant treatment is required.

To monitor side effects and drug reactions, consider the following:

• ECG and thorough cardiovascular examination
• Liver function test

It is also important to note that while antidepressants may reduce the overall suicide rate, they may also transiently increase suicidal tendencies during periods of cessation or initiation of treatment.

SSRIs

As a group, their main side effects are nausea, headache, neuromuscular restlessness (resembling akathisia), insomnia or sedation, and delayed ejaculation/anorgasmia.

SSRIs combined with MAOIs are dangerous: a fatal serotonin syndrome may result.

Nefazodone has caused life-threatening hepatotoxicity requiring liver transplantation. Duloxetine is also reported to cause liver dysfunction.

Serotonin Syndrome

First described for an interaction between fluoxetine and an MAOI.

This life-threatening syndrome includes severe muscle rigidity, myoclonus, hyperthermia, cardiovascular instability, and marked CNS stimulatory effects, including seizures.

Drugs implicated include MAOIs, TCAs, dextromethorphan, meperidine, and St. John's Wort.

Treated with antiseizure drugs, muscle relaxants, and blockers of 5-HT receptors (e.g., cyproheptadine) have been used in the management of the syndrome.

Tricyclic Antidepressants (TCA)

• Excessive sedation, lassitude, fatigue, and, occasionally, confusion;
• Sympathomimetic effects, including tachycardia, agitation, sweating, and insomnia;
• Atropine-like effects;
• Orthostatic hypotension, electrocardiogram (ECG) abnormalities, and cardiomyopathies;
• Tremor, paresthesias, and weight gain.

Overdosage with tricyclics is extremely hazardous, and the ingestion of as little as a 2-week supply has been lethal. The "3 Cs"—coma, convulsions, and cardiotoxicity—are characteristic.

MAO Inhibitors

Hypertensive crisis (consumption with tyramine).

Foods that must be avoided include cured meats or fish, beer, red wine, all cheese except cottage and cream cheeses, and overripe fruits.

Many over-the-counter cold and pain remedies must also be avoided.

Tricyclic Drug Interactions

Include additive depression of the CNS with other central depressants, including ethanol, barbiturates, benzodiazepines, and opioids.

TCA inhibit the effect of guanethidine, methylnorepinephrine, and clonidine by blocking its transport into sympathetic nerve endings.

SSRIs and virtually any agent with serotonin-potentiating activity can interact dangerously or even fatally with MAO inhibitors.