Story of the Brain

To be able to understand the multitude of adverse reactions and side effects of neuroleptics it helps to know a little about the brains' history, how different parts of the brain interact, the workings of the brain and how neuroleptics impact upon these structures and functions.  

The Evolving Brain

1. Brain Stem Brainstem

The ANS which is a part of the PNS, consists of the Sympathetic Nervous System and the Parasympathetic Nervous System  The Sympathetic Nervous System is the get-up-and-go system, whereas the Parasympathetic Nervous System takes over when resting or inactive. They complement each other.

The neurotransmitters acetylcholine and noradrenaline are used in the Sympathetic Nervous System and acetylcholine in the Parasympathetic Nervous System.

Sympathetic Nervous System
The Sympathetic Nervous System is on the ready for any potential emergency situation. To enable the natural 'fight and flight' responses the Sympathetic Nervous System works in conjunction with the endocrine or hormonal system though the hypothalamus gland (Parker 1997), which is above the brain stem.

The hypothalamus gland triggers the adrenal glands to produce adrenaline/epinephrine (a hormone) and via the ANS initiates the following for the preparation for fighting or fleeing:

1. Faster heart beat
2. Raises blood pressure
3. Increases respiration
4. Tenses muscles
   
5. Taps into to energy reserves 
6. Glucose released from liver to blood
   
7. Increases the metabolic rate
   
8. Dilates pupils 
9. Sweating 
10. Reduced urine output 
11. Dilation bronchioles in lungs
    

Dopamine is a precursor of adrenaline i.e. without dopamine adrenaline cannot be made. Neuroleptics therefore have the potential to cause adrenaline deficiency which will impede a person from responding normally in life threatening situations.

1. Lowered blood pressure
2. Decreased respiration
3. Deceased heart rate
   
4. Saliva and mucus increases, aiding digestion
   
5. Conservation of energy
6. Bladder sphincter relaxes  - urination
7. Anus sphincter relaxes  - defecation
8. Bronchioles in lungs constrict
9. Constricts pupils
   

2. Limbic System Limbic System
200 million years ago mammals developed an additional brain, known as the mammalian brain, mid brain or Limbic System. The Limbic System lies deep in the center of the brain and is the nerve formation which links the brain stem to the rational brain or cerebrum.

Social activities such as caring, playing, inquisitiveness and bonding with offspring stem from the Limbic System. (Sunderland 2005)

Other limbic functions include emotional response, mood, motivation, pain and pleasure sensations, feelings of desire and a process known as the 'reward system' which can provide us with a sense of well being. 

The negative symptomology of apathy, lack of motivation are likely to be an iatrogenic condition known as Neuroleptic Deficit Syndrome  (NIDS). The sense of well being disappears and is replaced by  negative emotions which supersede the natural 'reward system'. People may develop low functioning behaviour for their loss of well being.

NIDS includes feeling of indifference and therefore neurolepticed  people are vulnerable due to being unable to respond appropriately in times of danger.

The Limbic System is served by the dopamine mesolimbic pathway. It houses the amygdala and hippocampus.

Amygdala
The functions of the amygdala include storing memories of fear and the ability to connect these with the conscious memories in the cerebral cortex. This is important in order to be able to make an assessment of any current danger or potential threat. In normal functioning, a past memory of a situation greatly impacts a current assessment and response to a similar situation. Because the Limbic System has links with the brain stem and the cerebral cortex, (in the rational brain) when rage and fear is experienced in the amygdala, the link with the rational brain facilitates the decision to control the instinctive reptilian fight and flight responses. (Sunderland 2005). 

When people feel angry, frustrated or otherwise distressed, the amygdala communicates with the hypothalamus which releases Cortico Releasing Factor (CRF). This gears people up to respond to distressed feelings: the CRF stimulates the pituitary gland to release adreno-corticotrophic hormone (ACTH), which in turn triggers the adrenal gland to produce cortisol.

Cortisol has the following functions (stress.about.com/od/stresshealth/a/cortisol.htm):

• A quick burst of energy for survival reasons
• Heightened memory functions
• A burst of increased immunity
• Lower sensitivity to pain
• Helps maintain homeostasis in the body

Hippocampus
The hippocampus, although considered to be a part of the Limbic System, lies within the cerebral temporal lobe, which is either side of the head above the ears and cheek bone. Like the amygdala the hippocamapus is served by the dopamine mesolimbic pathway. The hippocampus is like a reservoir for the reception and conception of experiences, storage of memories and recall of memories.

Alzheimer's disease occurs as the neurons degenerate in the hippocampus: people are unable to recall short and long term memories such as being unable to retain and recall the names of people, places and what happened ten minutes ago. As the neurons in the hippocampus become increasingly thinner in density, there is a deterioration in the inability to solve new problems and assimilate new experiences. Interestingly when  the hippocampus is exposed to the oestrogen hormone, there is an increase of healthy synaptic functions which seems to indicate estrogen depletion plays a part in Alzheimer's disease.  

It would appear neuroleptic damage to the hippocampus causes memory deterioration, which is compounded by estrogen depletion.  This is a far cry from the healthy hippocampus which is essential for making and storing of new memories enabling us to live adequately in the present. People taking neuroleptics long term are grossly disadvantaged because of memory impairment. It is like inducing senility before ones natural allotted time span.

3. Cerebrum - the Rational Brain
Humans evolved 200,000 years ago and in addition to the reptilian  and mammalian brain eventually developed a rational brain which has the potential for reasoning, being imaginative, kind, empathic and have an ability to be self aware or reflective of our behaviour. This rational brain or cerebrum weighs 7/8ths of the total brain and occupies most of the skull. The mesocortical dopamine pathway serves the cerebrum.

The outer layer of the cerebrum, known as the cerebral cortex has 15 billion neurons with different areas of the cortex performing different functions.

Conscious facial and limb movements stem from the motor cortex which initiates muscles to contract.  The pre-motor cortex aids the motor cortex and also has nerve links with another important structure - the cerebellum at the back of the brain.

Speech stems from an area of the cortex which is called Broca's area. One symptom of NMS is slurred speech - the Broca's area, affected by neuroleptics, is likely to be the source of the difficulty.

Another area of the cerebrum is concerned with learning, planning and organisation skills, reading, interpretation and analysis of sensations and our conscious thinking and emotions.

There are five frontal lobes in each half of the cerebrum with social intelligence developing from the pre-frontal lobe which lies at the back of our eyes. The pre-frontal cortex, along with the hippocampus, is concerned with short term memory and sensory memory and is thought to be connected with our personality.

4. Hypothalamus

The Endocrine System - Hormone System
The hypothalamus is the primary structure that regulates the endocrine system. The hypothalamus releases 'releasing factors' which then trigger the pea size pituitary gland to release hormones which affect other glands in the body.

Neuroleptics interferes with the normal regulation of the endocrine system: all the hypothalamus releasing factors are affected, which in turn disrupts the pituitary gland functions, affecting the whole of the hormonal system. The following processes show how neuroleptics disrupts the endocrine system.

Prolactin Release Inhibiting Factor (PRIF)
Under normal circumstances the hypothalamus releases Prolactin Releasing Inhibiting Factor (PRIF), which regulates the release of the hormone prolactin.

Neuroleptics deplete PRIF, which leaves the pituitary to ooze masses of prolactin into the body. Excessive prolactin levels is called hyperprolactinemia. This causes breast enlargement and milk secretion in males and females. Hyperprolactinemia is associated with osteoporosis (Meany et al 2004).

Luteinising Hormone Releasing Factor (LHRF)
The LHRF from the hypothalamus triggers the release of the Luteinising Hormone (LH) and the Follicle Stimulating Hormone (FSH).

In females, the LH triggers the production of the female sex hormone, estrogen, which provides female characteristics. LH instigates ovulation. In males, it triggers the testes to produce the male sex hormone, testosterone.

Neuroleptics suppress LRHF which decreases the body's levels of estrogen and testosterone, causing sterility/infertility and is associated with  memory deterioration. (Mortimer 2007) In females estrogen deficiency causes irregular,  infrequent, or the absence of menstrual periods.

The FSH stimulates the production of sperm and ova.  Neuroleptics cause the suppression of  FSH which affects the ability of people to procreate. It has been shown that rats have reduced sperm quality and males have fewer litters when treated with a specific type of neuroleptic (Aleem et al 2005). Deficiency of FSH causes the testes to atrophy (waste) and become smaller.

Thryotropin Releasing Factor (TRF)
This releasing factor stimulates the pituitary gland to produce
Thyroid Stimulating Hormone (TSH),which travels to the thyroid gland. Here thyroxine (T4) and calcitonin hormones are released. 

Rinieris et al (1980) reports clozapine patients have decreased T4 and Baumgartner (2000) reports that neuroleptics suppress the release of TRH which follows through to the thyroid gland causing deficiencies of thyroxine and calcitonin hormones. 

a) Thryroxine deficiency

T4 is concerned with the body's metabolic rate, the rate of the heart and blood pressure, healthy functioning nervous system and body temperature regulation.

Thyroxine is necessary for life - without thyroxine - people die.

Thyroxine deficiency is associated with premature aging - people who take neuroleptics long term will look more aged than their parents.

Thyroxine deficiency causes a lowered basal metabolic rate (BMR) or lowered energy output, and is associated with weight gain and effects an increase in blood lipids and cholesterol.

When the external temperature drops the body responds by increasing TSH and thereby increasing T4 -  the body's metabolic rate rises and people feel warmer. And vise a versus.  However neuroleptics prevent the normal mechanism from occurring resulting in either hypothermia or hyperthermia.

Fever is the body's normal response to a bacterial or viral infection. Neuroleptics have the potential of preventing this normal response. A slight raise of body temperature could mislead a doctor into the severity of a viral of bacterial infection.   

        b) Calcitonin Deficiency

Calcitonin regulates calcium levels in the body and helps to build bone. Deficiency causes osteoporosis (loss of bone density and strength) which can cause pain from spinal compression and bone fractures (Howard et al 2007). Neurolepticed males have been found to have reduced bone density (Hummer et al 2005) which indicates neuroleptics cause osteoporosis.
   

Corticotropin Releasing Factor (CRF)
The hyothalamus Corticotropin Releasing Factor (CRF) stimulates the pituitary gland to release Adrenocorticotropin Hormone (ACTH). ACTH stimulates the adrenal glands to produce corticosteroids such as aldosterone and cortisol.  Functions of ACTH are regulation of ions in the blood and metabolism.

a) Aldosterone is necessary for muscle strength and tolerance of stress. ACTH partly controls the release of aldosterone, which is also produced from progesterone (a female hormone). Progesterone is suppressed by neuroleptics. When people age they loose their muscle power and become weaker.

Deficiency of aldosterone causes the adrenal glands atrophy (shrink) creating a decreased ability to use body fat as energy thereby causing weight gain. (Kutsky 1973) Long term neuroleptised patients experience similar difficulties due to deficiencies of progesterone and aldosterone.  

b) Cortisol

The functions of cortisol are:

• Proper glucose metabolism
• Regulation of blood pressure
• Insulin release for blood sugar maintenance
  
• Immune function
• Inflammatory response

It is also released in times of stress to help the body respond by increasing glucose into the blood circulation.

Popovic et al (2007) shows that typical neuroleptics increase cortisol levels whilst atypical neuroleptics decrease cortisol levels.  However each neuroleptic affects the brain differently and Moran (2006) depicts how the Metabolic Syndrome is prevalent in people taking Olanzapine and Clozapine; indicating that these neuroleptics do increase cortisol levels.

High levels of cortisol long term, - Cushing's Syndrome - means the body is in chronic stress which interferes with the brain functioning. Symptoms include (stress.about.com/od/stresshealth/a/cortisol.htm): 

• Brain damage 
• Euphoria
• Mania
• Psychosis
• Decreased ability to handle stress
• Decreased glucose tolerance
• Hypoglycemia
• Diabetes
  
• Impaired cognitive performance
• Suppressed thyroid function
• Blood sugar imbalances such as hyperglycemia
• Decreased bone density
• Decrease in muscle tissue, causing weakness
• Oedema
• Higher blood pressure
• Lowered immunity and inflammatory responses in the body, slowed wound healing, and other health consequences
• Increased abdominal fat, which is associated with a greater amount of health problems than fat deposited in other areas of the body. Some of the health problems associated with increased stomach fat are heart attacks, strokes, the development of , higher levels of “bad” cholesterol (LDL) and lower levels of “good” cholesterol (HDL), which can lead to other health problems

Sunderland (2005) reports that high cortisol levels result in people feeling 'the world can feel like a hostile, attacking place' which make us feel 'overwhelmed, fearful and miserable, colouring our thoughts, feelings, and dread as if everything we need to do is far too hard'. 

Growth Hormone Release Factor (GRF)
This hypothalamus factor triggers the pituitary to release the pituitary growth hormone (GH). It is well known that the GH affects growth in child hood. What is less well known is that GH deficiency in adults causes 'Depression, anxiety, poor memory, reduced vitality, social isolation, malaise, weakness, poor exercise tolerance, easy fatigue, weight gain: Central obesity, elevated waist:hip ratio, fine wrinkling around eyes, premature ageing (Kearney & Johnston 2000). These authors also state that studies have shown 'greater morbidity and mortality' with GH deficiency. 

5. Finally

Extrapyramidal System
The dopamine nigrostriatal pathway serves the extrapyramidal system in the basal ganglia and is involved with movement coordinations.  Neuroleptics cause Extrapyramidal Symptoms (EPS), Akathesia and Tardive Dyskinesia (TD). 

In order to alleviate Extrapyramidal Symptoms (EPS), anticholinergic drugs such as Procyclidine are prescribed. The side effects of these drugs induce blurred vision, dry mouth and constipation; in the Central Nervous System depleted acetylcholine causes confusion, drowsiness, poor short term memory and slowness in acquiring new learning skills. This occurs because the drugs reduce the acetylcholine to lower than required levels.

Several studies have indicated that long-term neuroleptic use is associated with both cognitive deterioration and atrophy of the brain. (Krausz 1999)