Neuroleptic Awareness
Introduction > Neuroleptic Physical Side Effects

Neuroleptic Physical Side Effects


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

CARDIAC DEATH

  • Sudden risk of cardiac death (Straus et al 2004) 
  • Atypicals and Typicals caused sudden cardiac death rate compared with non neuroleptic patients (Kuehn 2009)

CONSTIPATION/ BOWEL OBSTRUCTION  
(Dome et al 2007)

(Hibbard et al 2009)


Physiology:

  • Intestine muscles have slower contractions   
  • Direct peripheral anticholinergic side effect  
DECREASED BASAL METABOLIC RATE (BMR)
  • Resulting from T 4 deficiency.  Erasmus, U. (1986,1993), Kutsky (1973)
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 also   prescribed 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
  • 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
  • TD is masked by atypicals but re-emerges after neuroleptic cessation.
  • 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

Dystonia seems to be caused by over-activity in the brain, particularly in the basal ganglia, thalamus, and cerebral cortex.

  • Sustained painful muscle spasms
  • Causes involuntary movement and abnormal posture
  • Torticollis - head and neck are twisted to one side
  • Retrocollis -  head and neck are pulled back between the shoulder blades
  • Blepharospasm - eyelids are forcefully squeezed shut 
  • Excessive arching of back

HEART FAILURE (Wayne et al 2009)
HEART ATTACK (MYOCARDIAL INFARCTION)

Likely cause:
  • Associated with increased cortisol level
  • Los Angeles Times January 15, 2009 Thomas H. Maugh II

 "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:
  • TSH deficiency
  • Body temperature unregulation
  • Resulting from disrupted and lowered BMR.  Erasmus (1986,1993)
  • 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
KIDNEY DAMAGE
  • 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 

(Oscanli et al 2006)

  • Jaundice (yellowing of skin) may indicate liver damage

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       
  • Tachycardia
  • 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)



PREMATURE AGEING

(Kirkpatrick et al. 2008)


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)



SEXUAL DYSFUNCTION FOR BOTH SEXES:

1. Hyperprolactinaemia
  • (Weick et al 2002)
  • Enlargement of male breast tissue - Gynaecomastia
  • Secretion of breast milk in both sexes  males & females - Galactorrhoea 15% (Windgassen 1996)
  • Associated with Pituitary Tumors  (Szarfman et al 2006)
  • Cause: elevated prolactin levels due to depletion of PRIF  Rex M., et al.


2. Females 


  • Infrequent or irregular periods - Oligomenorrhoea 45%
  • Absence of periods  - Amenorrhoea 45%
  • Cognitive difficulties (Mortimor 2007) 
  • Infertility
  • Cause: Oestrogen deficiency - resulting from reduced LHRF @ LH

3. Males

  • Impotence in males
  • Cognitive difficulties (Mortimor 2007) 
  • Infertility (Beumont 1980)
  • Caused by: Testosterone deficiency resulting from LHRF @ LH deficiency
  • Retrograde ejaculation  (Compton 2002) 
  • Results from reduced libido 
  • Sterility  -Northern Ireland Association for Mental Health & MIND
  • Hypogonadism (O'Keane 2005)
  • Low sperm counts
  • Small testicle
  • Reduced sperm quality





























































4. BIRTH DEFECTS
  • Damages DNA sperm (Aleem et al 2005) 

PREMATURE DEATH
(Braylet et al 2000)
  • Associated with high neuroleptic dose
  • Novartis Pharmaceuticals  UK Ltd –Clozapine
RESPIRATORY ARREST
  • Novartis Pharmaceuticals  UK Ltd - Clozapine
RESPIRATORY DISEASE
  • Neuroleptics increase Ach & decrease dopamine
  • Increased Ach causes excess lung mucous
  • Body unable to 'mop' up mucous because of insufficient dopamine 
  • Patients more prone to respiratory  diseases
  • In Ireland, within a ten year study of neuroleptics, there were 44% deaths usually from respiratory disease.  (Waddington et al 1998)


SHORTENED LIFE SPAN

(Waddington et al 1998)



STROKES
( Cerebro vascular Disease CVD) (Casey 1997)

A. (Douglas et al 2008)

  • Increased risk of stroke
  • Risk higher with atypical
  • Greater increase in Dementia 
B. "Antipsychotics and stroke:
the story to date. (Layton et al 2009)

Likely cause:

  • Dysregulation of fats
  • Increase in blood lipid and cholesterol
  • Caused by T4 deficiency

URINE RETENTION

  • Bladder Distension
  • Due to difficulty in urinating 
  • Direct peripheral anticholinergic side effect 


VENOUS THROMBOEMBOLISM  (Wolstein et al )
  • The formation of a blood clot in a vein.
  • Restricts blood flow  causing swelling and pain.
  • Usually occurs in the deep veins of the legs high and pelvis
  • May lead to pulmonary embolism if the clot fragments  
  • Potentially fatal 

Schizophrenia Association of Great Britain reports:
  • Clozapine: period 19.12.89 -7.03.01:
246 fatalities with 112 fatalities from cardiovascular disorder

  • Sertindole: period from 01.07.96 - 24.07.00
9 fatalities with 6 fatalities from cardiovascular disorders 
  • Amisulpiride: period between 26.01.98 - 23.03.01
5 fatalities with 5 fatalities from cardiovascular disorders

  • Olanzapine: period between 01.10.96 - 28.03.01
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

  • Risperidone: 
26 fatalities with 11 fatalities from cardiovascular disorders

  • Zotepine: period between 16.12.98 - 15.01.01
1 fatalities with 1 fatalities from cardiovascular disorders

  • Ziprasidone no reports