Neuroleptic Physical Side Effects

All neuroleptics impact upon the brain. This results in many organs of the body becoming dysfunctional.  

CARDIAC DEATH

• Risk of sudden cardiac death (Straus et al 2004)
  
• Atypicals and Typicals caused sudden cardiac death rate compared with non neuroleptic patients (Kuehn 2009)  (Dome et al 2007) (Hibbard et al 2009)

DEATH

• Sudden deaths of patients who were medicated with high dosages of neuroleptics -. Reports are available from Simpson et al (1987), Mehtonen et al (1991) and Thompson. (1994).
• UK, there were thirteen sudden deaths of patients who were medicated with Pimozide. 
• Thomas (1997) refers to the death of Orville Blackwood in 1991 from heart failure, which resulted from being injected with a cocktail of Promazine and Fluphenazine.
• Whitaker (2002): reports 20 people died whilst taking Olanzapine out of 2,500.

EXTRA PYRAMIDAL SYSTEM IN THE BRAIN

This system is implicated by neuroleptics and pertain particularly to abnormal body movements. They include: Extra Pyramidal Side Effects, Tardive Dyskinesia, Tardive Dystonia and  Akathesia - the latter is included in the psychological side effects section as the emotions are highly negatively implicated. All three iatrogenic conditions are thought to stem from the brains dopamine nigrostriatal pathway due to the blocking of dopamine by neuroleptics.

 1. Extra pyramidal side effects (E.P.S.)

Discovered in 1954, these side effects result from the neuroleptic prescribing - the patient displays Parkinsonion symptoms.

• Fine body tremor, which ranges from being almost imperceptible to incessant shaking.
• Bradykinesia  - the slowing down of large muscle movement so that the patient appears stupid and/or clumsy.
• Unresponsive to everyday situations going on around them.
• Flat, vacant expression.
• Zombie appearance
• Excessive salivation

EPS are more prominent with typical neuroleptics

To combat the EPS side effects, anti-cholinergic drug,which are alsoprescribed for Parkinson's disease, have their own side effects.

1a Anticholinergic Side Effects

A. Within the Peripheral Nervous System (Leiberman 2004)

• Blurred vision
• Headaches
• Dry eyes
• Dry mouth
• Increased heart rate
• Difficulty in urinating
• Constipation

B. Within the Central Nervous System (Lieberman 2004) 

• Impaired Concentration
• Confusion
• Attention deficit
• Memory impairment

Several studies have indicated that long-term neuroleptic use is associated with cognitive deterioration and atrophy of the brain. Chronic use of neuroleptics precedes Parkinson's disease.

2. TARDIVE DYSKINESIA (TD)

Grossly disfiguring and include:

• The lower jaw moves in sideways movement.
• The lips become pursed with the patient sucking and smacking of the lips.
• Blowing in and out of the cheeks.
• Facial grimacing.
• Abnormal tongue movements i.e. the tongue quivers - protrudes
• Finger movements as though an invisible guitar is played.
• Body actions are involuntary, potentially irreversible and there is no proven treatment

Also :

• 1959 TD first reported with link to neuroleptics – TD
• TD = damage to brain neurons – long term causes nerve degeneration
• TD risk increases from chronic long-term exposure Klawans (1973), Smith et al. (1978) and Mukherjee et al (1982).
• TD can appear within 6 months
• TD caused by both typical and atypical drugs
• Neuroleptic means the neurone is literally 'seized’
• 90% of patients diagnosed with TD resulting from typical neuroleptics. Crane, (1968).

• Supplements which help elimination of free radicals, which causes brain damage:Vitamin E, Eye Q

Tardive Dyskinesia causes damage to the brain tissue:

• Neuroleptics and Brain Damage: An Annotated Bibliography http://www.mindfreedom.org/mindfreedom/ioc/scan3.shtml

• Madson (Madsen Al, Keiding N, Karle A, Esbjerg S, Hemmingsen R: (1998) “Neuroleptics in progressive structural brain abnormalities in psychiatric illness.”

• An associated factor with TD is dementia. Research by Thomas and McGuire, (1986) showed that subjects with high TD scores had memory impairment.

 3. TARDIVE DYSTONIA

"Zyprexa, Risperdal and Seroquel, among the 10 most commonly prescribed medications, are just as likely as older antipsychotic drugs to cause a fatal heart attack, a study finds".

HYPOTHERMIA /HYPERTHERMIA

 Likely cause:

• Unawareness of body temperature
• Hypothermia or hyperthermia can occur.
• Death from heat stroke
• Due to an Anticholinergic side effect -  reduced sweating

HYPOTHERMIA

(Blass et al, 2004)

 INCREASED SUN SENSITIVITY

+

• Condition more prone when polypharmacy is practised 
• The Merk Manuals ONLINE MEDICAL MANUALS
• May result from NMS
• Damaged muscles release the protein myoglobin(myoglobinuria)
• Toxic to kidneys
• Urine turns brown

LIVER DAMAGE 

• Jaundice (yellowing of skin) may indicate liver damage (Ozcanli  et al 2006)

METABOLIC SYNDROME

This life threatening syndrome includes obesity, type 2 diabetes mellitus, hyperlipidaemia (high cholesterol) and diabetic ketoacidosis (Lieberman 2004, Usher et al 2006), abdominal obesity, insulin resistance and hypertension. A study by Heiskanen et al (2003) shows that metabolic syndrome with atypical and typical neuroleptics was  2-4 times higher than people who are not prescribed neuroleptics.

1. Obesity - Endocrine Effect

• ACTH deficiency Kutsky, (1973)
• Dysregulation of cortisol  causes excessive abdominal fat
• Decreased Thyroxine (T4) causes reduction in BMR slowing down the burning of body fat @ cholesterol for energy
• Shrinkage of adrenal glands creates decreased ability to use body fat for energy. 
• Increased appetite

2. Diabetes

• Excessive thirst is one symptom
• Cortisol imbalance - hyperglycaemia
• Increasing insulin resistance (Pao et al 2007)
• Duke University issued a report (2002) identifying:
• 289 cases of diabetes in patients who had been prescribed Olanzapine. These researchers stated: "Of the 289 cases of diabetes linked to the use of Olanzapine, 225 were newly diagnosed cases. 100 patients developed ketosis (a serious complication of diabetes).  22 patients developed pancreatitis – potentially life-threatening condition. 23 deaths, including that of a 15-year-old adolescent who died of necrotising pancreatitis, a condition where the pancreas breaks down and dies. 71 % occurred within six months of starting the drug and many cases were associated with moderate weight gain."
• 1994  Duke University team first reported a diabetes link with Clozapine.
• 2001 384 reports of diabetes were associated with Clozapine.

NASAL CONGESTION 

• Direct noradrenergic side effect

NEUROLEPTIC MALIGNANT SYNDROME (NMS)

Dysregulated sympathetic nervous system hyperactivity is responsible for NMS (Gurrera 1990).

This is a potentially fatal condition of neuroleptic prescribing and can be associated with rapid and large increases in neuroleptic dose and also in conjunction with other neuroleptics (polypharmacy). Occurs in 3% of people with a predominance towards men.  Mortality rates for NMS 6%. (Benzer 2002); 30% mortality rate (The Merk Manuals)

Clinical symptoms include:

• Hyperpyrexia
• Altered mental status
• Hypertension
• Hypotension       
• Tremor
• Incontinence                       Muscarinic Sign
• Generalised muscle rigidity Muscarinic Sign
• Sweating                            Muscarinic Sign
• Seizures
• Cardiac dysarrythmia
• Kidney failure
• Respiratory failure              Muscarinic Sign
• Sialorrhea (drooling)           Muscarinic Sign
• Dysarthria (difficulty in speaking)  Muscarinic Sign
• Elevated creatinine phosphokinase (CPK) enzymes. Caused by muscle & skeletal breakdown.  Known as rhabdomyolysis.
• Elevated  white blood cells
• All neuroleptics (typical and atypical) may precipitate NMS.
• Potent neuroleptics eg, Haloperidol, Fluphenazine, Modecate, Prochlorperazine, (Compazine), Promethazine (Phenergan), Clozapine (Clozaril), Risperidone (Risperdal, are associated with NMS.

 OSTEOPOROSIS

• Calcitonin deficiency
• Bone thinning (Meaney, A.M., et al 2004)
• Bone loss of strength 
• Bone pain
• Fractures

Osteoporosis has also been connected with hyperprolactemia and a vulnerability to hip fractures. Neurolepticed males have been found to have reduced bone density (Hummer et al 2005) and therefore have the potential for osteoporosis. Increased levels of cortisol (Annals of Internal Medicine 2005) was found in patients with osteoporosis and may possibly be the cause of neuroleptic induced osteoporosis.

Females have been found to have loss of bone mass. (Purificación Rey-Sánchez 2009)

SEIZURES

• Due to NMS
• Novartis Pharmaceuticals  UK Ltd - Clozapine

SEROTONIN SYNDROME

Potentially fatal condition resulting from excessive serotonin levels. Caused by:

• Excessive serotonergic activity from barely perceptible to fatal
• By raising the dose of one serotonin drug or combining with another serotonin drug
• Causes increased serotonin in central grey nuclei and brain stem
• Symptoms occur within minutes after change of dose
• Withdrawal of neuroleptics additionally creates a release/increase of 5HT 2A

Mild symptoms:

• Tachycardia (fast pulse rate)
• Diaphoresis (shivering)
• Mydriasis (dilated pupil)
• Tremor - intermittent
• Myoclonus (involuntary twitching)

Moderate symptoms:

• Hypertension (high blood pressure)
• Hypothermia (low body temperature)
• Hyperpyrexia - e.g. 40C
• Hyperactive bowel sounds

Severe symptoms:

• Hypertension
• Tachycardia
• Delirium
• High muscular tension
• Hyperpyrexia 41oC
• Metabolic acidosis - pH is low leading to diarrhoea coma and death
• Rhabdomyolysis - break down of muscle fibres, may lead to kidney damage
• Seizures
• Renal failure (Kidney failure)
• Disseminated intra vascular coagulation

Triad:

• Cognitive: mental confusion, hypomania, hallucinations, agitation, headache, coma
• Autonomic: shivering, sweating, fever, hypertension, tachycardia, nausea, diarrhoea
• Somatic: muscle twitching, hyperreflexia, tremor

Avoid foods containing tryptophan (Wikipedia)

39 fatalities with 21 fatalities from cardiovascular disorders

Quetiapine: period between 04.10.97 - 19.03.01

18 fatalities with 14 fatalities from cardiovascular disorders