Extrapyramidal Symptoms (EPS): with antipsychotics, medications cannot just directly target positive symptoms without affecting other pathways. Decreased dopamine levels specifically in the nigrostriatal pathway, contribute to EPS. Types of EPS:
- Akathisia: motor restlessness or an inner subjective feeling “my bones are on fire” or how I remember it, Kathy is moving!
- Dystonic: muscle spasms such as eyes (oculogyric crisis), the back, neck (wryneck or torticollis), twisting motions, twitching, weakness of extremities, very painful
- Parkinsonism: difficulty speaking or swallowing, drooling, stooped posture, loss of balance, shuffling gait, pill-rolling, mask-like face
- Perioral Tremor (Rabbit syndrome): a rare side effect that appears after months or years of drug treatment. Characterized by fine, rapid, rhythmic movements along the vertical axis of the mouth. Abnormal movements are limited exclusively to the territory of the oral and masticatory muscles-does not involve the tongue.
Use screening tools to track worsening side-effects
EPS sometimes occurs early or later with antipsychotics, treatment includes prn scheduling, reducing or changing the antipsychotic, and treatment with different classes of medications:
- Alpha-adrenergic antagonists: propranolol
- Anticholinergics: benztropine and trihexyphenidyl
- Antihistamine: diphenhydramine
- Benzodiazepine: clonazepam and lorazepam
- Dopamine agonists: amantadine
Tardive Dyskinesia (TD): sometimes TD is separated from EPS because it’s NOT reversible and thus not treated the same, but it is related to the side-effects of long-term use of antipsychotics so it’s a part of the EPS spectrum. This IRREVERSIBLE side effect usually occurs with high-dose, high-potency medications:
Risk of TD by Medication (from low to high): Quetiapine/Clozapine -> Aripiprazole/Asenapine/Iloperidone/Lurasidone/ Olanzapine/Ziprasidone -> Paliperidone/Risperidone -> Low-potency FGA i.e. chlorpromazine (Thorazine) -> High-potency FGA i.e. haloperidol (Haldol) or fluphenazine (Prolixin)
Side-Effects: uncontrol muscle movements around the mouth, lip-smacking, grimacing, tongue movements, writhing movements of fingers and toes
Strategies in the pharmacological treatment of TD include: tapering the offending drug, switching to a second-generation antipsychotic, or adding a drug to neutralize the side effects. Suggested drugs are: clozapine, vitamin E, buspirone, benzodiazepines, among others. The only drug that has shown substantial evidence of efficacy is clozapine:
Risk of TD by Medication Classes (from low to high): Clozapine (none reported) -> SGA -> Low Potency FGA -> High Potency FGA
Various Complications from Treatment
Sometimes medications like the conventional antipsychotics have long half-lives or are eliminated slowly and contribute to some side effects. However, sometimes the side-effects will go away on their own or self-limiting but could also lead to a medical emergency if left untreated.
A syndrome is a collection of signs and symptoms that consistently occur together or a condition characterized by a set of associated symptoms. Complications from the use of antipsychotics and SSRIs are compiled into syndromes, which is helpful for understanding what’s NOT expected and when to seek immediate assistance:
Neuroleptic Malignant Syndrome (NMS): Rare life-threatening complications that can occur anytime with neuroleptics. Reported with clozapine risperidone, and olanzapine, and rare in SGA but can occur with any antipsychotic drug. NMS begins with marked muscle rigidity, which leads to serious symptoms related to instability of the motor and autonomic system. Other symptoms include:
- Motor/Behavioral: dystonia, akinesia, mutism, agitation
- Autonomic: hyperpyrexia, sweating, and increased HR and BP
Stop the dopamine receptor antagonistic drug and cool the patient and medically support the vital signs, electrolytes, fluid balance, and renal system.
Metabolic Syndrome: The most notable adverse effect of atypical antipsychotics is the metabolic changes. Obtain baseline weight, BP, waist circumference, fasting glucose, and cholesterol. Obtain a personal and family history of obesity, dyslipidemia, hypertension, and cardiovascular disease. Managing and preventing metabolic side-effects:
- Weight Gain: monitor weight, and BMI, consider physical activities, dietary management
- Hyperglycemia: monitor fasting glucose
- Hyperlipidemia: monitor cholesterol and lipid levels
Risk of Metabolic Complications (from low to high): Aripiprazole/Lurasidone/Ziprasidone -> Asenapine -> Iloperidone/Paliperidone/Quetiapine/ Risperidone/High Potency FGAs -> Clozapine/Olanzapine/Low Potency FGAs
Serotonin Syndrome: a condition resulting from too much serotonin in the brain with antidepressants. Signs include diarrhea, restlessness, extreme agitation, hyperreflexia, autonomic instability, seizures, coma, and possible death. Mnemonic; HARM (hyperthermia, autonomic instability, rigidity, myoclonus)
Serotonin Discontinuation Syndrome: a condition caused by rapid or sudden discontinuation of an SSRI or serotonin medication. Educate the patient to not abruptly stop taking medications and should be tapered off to avoid adverse effects: agitation, nausea, disequilibrium, and dysphoria.
Steven Johnson Syndrome (SJS): a rare toxic necrolysis that’s a life-threatening skin condition of cell death that causes the epidermis to be separated from the dermis. Children and adolescents have a higher incidence, some medications i.e. lamotrigine needs to be started low and titrated slowly to r/o or decrease the complication. Read about; Teen’s Skin Began Bubbling, Burns from the Inside Out, & Khaliah’s heartbreaking story. Once again SJS is rare compared to the millions of people who take medications but is extremely serious.
“SJS and toxic epidermal necrolysis (TEN) are considered to be the same condition on two ends of a spectrum, differing only by the extent of the epidermal detachment. Both SJS and TEN are debatably included in the same spectrum as erythema multiforme (EM). This mucocutaneous condition has similarities in clinical presentation to SJS/TEN but has some distinct differences” – U.S. Pharmacists:
Additional Complications
Ocular: Thioridazine (Mellaril or Melleril) is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis.
- Deposits in the anterior portions of the eye (cornea and lens) are a common complication of Chlorpromazine therapy. They may accentuate the normal processes of aging of the lens.
- Thioridazine is the only antipsychotic drug that causes retinal deposits, which in advanced cases may resemble retinitis pigmentosa. The deposits are usually associated with “browning” of vision. The maximum daily dose of thioridazine has been limited to 800 mg to reduce the possibility of this complication.
- The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the US.
-Wiki
Prolonged QTC: in the past, antipsychotics have been linked to an increased risk of sudden death. It has been recently suggested that this risk may be associated with QT prolongation. The structural difference of the antipsychotics makes it difficult to assess the effects these agents may have on QT intervals.
Although the exact mechanism by which antipsychotics lead to QT prolongation is unclear, they appear to exert their effects by blocking the IKr potassium channels, leading to delayed repolarization. Interference with sodium and calcium channels is another potential mechanism.
Regardless of the mechanism, QT prolongation associated with antipsychotics appears to be related to the dose and plasma concentration of the drug.
Check out an additional list of drugs that prolong QT and/or cause Torsades de Pointes (TDP)
TCA’s and Cardiac Effects: an overdose of tricyclic antidepressants (TCAs) or high concentrations have serious and fatal cardiac effects.
The most common serious cardiovascular complication of most TCAs is orthostatic hypotension but is essentially free of any other serious adverse effects in depressed patients without cardiovascular disease.
In patients with preexisting bundle-branch disease, there is a risk of heart block. On the other hand, patients with ventricular arrhythmias are likely to have their arrhythmias improve with TCA therapy.
Finally, therapeutic doses of TCA have a little adverse effect on left ventricular performance. As a result, TCA drugs can often be used to benefit depressed patients with overt heart disease.
Tyramine-Induced Hypertensive Crises: tyramine is an amino acid that helps regulate blood pressure. It occurs naturally in the body and it’s found in certain foods. Medications called monoamine oxidase inhibitors (MAOIs) block an enzyme known as monoamine oxidase, which breaks down excess tyramine in the body. Blocking this enzyme helps relieve depression.
If you take an MAOI and you eat high-tyramine foods, tyramine can quickly reach dangerous levels. This can cause a serious spike in blood pressure and require emergency treatment.
- Avoid consuming foods that are high in tyramine if you take an MAOI. You may need to continue following a low-tyramine diet for a few weeks after you stop the medication.
- Tyramine is naturally found in small amounts in protein-containing foods. As these foods age, the tyramine levels increase. Tyramine amounts can vary among foods due to different processing, storage, and preparation methods. You can’t reduce the amount of tyramine in food by cooking it. Examples of foods high in tyramine include: cheese, pork, soy products, beer, dried fruit…anything that ages or ferments. Combination foods that contain any of the above ingredients.
- Improperly stored foods or spoiled foods. While you’re taking an MAOI, your doctor may recommend eating only fresh foods — not leftovers or foods past their freshness dates.
Selegiline in patch form (Emsam) delivers the medication through your skin. If you use the lowest dose of the patch, you may not need to be as strict with the foods you eat, but check with your doctor or pharmacist.
It’s wise to learn the emergency signs of a rapid and severe rise in blood pressure (hypertensive crisis), which may include: severe headache, nausea, and vomiting, sweating and severe anxiety, nosebleeds, fast heartbeat, chest pain, changes in vision, shortness of breath, confusion.
Gynecomastia: this is a condition that is primarily associated with risperidone (Risperdal) & FGA’s related to the tuberoinfundibular pathway—hyperprolactinemia. Normally dopamine is released into the anterior pituitary gland and inhibits or regulates prolactin release. However, blocking these D2 receptors (via inhibiting reuptake), thus creating more dopamine, increases prolactin levels causing hyperprolactinemia. Other than antipsychotics, other medications/substances can cause gynecomastia: steroids, HIV medications, diazepam (Valium). tricyclic antidepressants, ulcer medications, chemotherapy, heart medications, street drugs, and alcohol (and many more).
Gynecomastia caused by medications usually does not go away even if the drug is discontinued. In mild cases where not much mammary tissue has developed, liposuction may be used to remove the tissue but in more extensive cases, a breast reduction or mastectomy surgery will be required. This may also require the removal of skin in a chest reconstructive procedure. In addition to the emotional trauma that is likely to result from the development of gynecomastia, the patient may be subjected to significant surgical pain and may require a lengthy period of healing.
Best Ways to Limit Side-Effects
Know the Patient’s Drug History: allergies and effect, adverse drug Rx. Ht/Wt, BP, pulse, current drugs: dose, route, frequency, reason, perceived efficacy and ADRs, adherence to the regimen, nonprescription med use: alternative, OTC, and complimentary, pregnant or lactating, support systems if needed, financial resources, co-morbidities, caffeine, nicotine, ETOH, illegal drug use…etc. The more you know, the fewer amount of issues.
Testing Recommendations with Atypical Antipsychotics
| AIMS | baseline -> q6 months |
| Blood Pressure | baseline -> q3months -> annually |
| Glucose | baseline -> q3 months -> annually |
| Lipids | baseline -> q3 months -> annually |
| Waist Circumference | baseline -> annually |
| Weight | baseline -> qmonth x3 -> q3 months |
Patient Education: adequate education will increase adherence and promote therapeutic regimen, assess patient’s need/willingness to learn (caution w/illiteracy). Include in education:
- Drug name (generic/trade)
- Purpose, the expected response, and possible black box warnings
- Proper use (route, dose, schedule)
- Common SE, how to manage or when to seek assistance
- Interactions (inhibitors/metabolites)
- What to do if a dose is missed
- Special precautions (driving, food, avoiding alcohol, etc.)
Consider genetic testing if treatment is becoming resistant/complicated. Genetic testing may help to understand the body’s response to the following medications: antidepressants, anxiety, ADHD, pain, and antipsychotics.
Related Information:
- Alcohol Abuse and Drug Interactions
- Cytochrome P450 and Metabolism
- Black box warnings and pending lawsuits
- Resources for suicidal prevention
- What is an emergency?
