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
300 million years ago reptiles had a primitive reptilian brain, or brain
stem. It is concerned with the Autonomic Nervous System (ANS), which is vital
to sustain life. These are breathing, digestion, appetite, circulation,
physical movements and defence activities for fight or flight responses. All these functions are generally not in our conscious control.
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:
- Raises blood pressure
- Increases respiration
- Tenses muscles
- Taps into to energy reserves
- Glucose released from liver to blood
- Increases the metabolic rate
- Dilates pupils
- Reduced urine output
- 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. Parasympathetic Nervous System
The parasympathetic nervous system lies in the brain stem and takes
over when we are resting. the following is the bodies natural 'rest and digest' responses:
Dysregulation of the ANS, causing hyperactivity, has been associated with the potentially life threatening adverse reaction of Neuroleptic Malignant Syndrome (NMS) (Gurrera 1990).
- Lowered blood pressure
- Decreased respiration
- Deceased heart rate
- Saliva and mucus increases, aiding
- Conservation of energy
- Bladder sphincter relaxes - urination
- Anus sphincter relaxes - defecation
- Bronchioles in lungs constrict
- Constricts pupils
2. 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.
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
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
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
The outer layer of the cerebrum, known as the cerebral cortex has 15 billion
neurons with different areas of the cortex performing different
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
4. Hypothalamus The hypothalamus lies just above the brain stem. Its major functions are homeostasis and the endocrine (hormone) system.
The hypothalamus, served by the dopamine tuberoinfundibular
pathway, controls homoeostasis such as thirst, appetite and body
Neuroleptics prevent the hypothalamus gland from detecting whether the
body is too hot or cold which leave people in a vulnerable state. In hot
weather for example, people are unaware of the intense heat which can lead to
to hyperthermia and death.
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).
The normal amount of blood prolactin levels are <400 mU/l,
however long-term use of neuroleptics escalate blood levels to over 1000
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
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
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.
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
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
- Decreased ability to handle stress
- Decreased glucose tolerance
- Impaired cognitive performance
- Suppressed thyroid function
- Blood sugar imbalances such as hyperglycemia
- Decreased bone density
- Decrease in muscle tissue, causing weakness
- 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'. Increasing insulin resistance with some neuroleptics
(Poa et al 2007), is one likely factor which causes diabetes.
Decreased cortisol levels result in people experiencing muscle weakness, fatigue, weight loss with decreased appetite, low blood pressure, low blood sugar nausea and vomiting and diarrhoea.
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.
Extrapyramidal SystemThe 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.
studies have indicated that long-term neuroleptic use is associated with both
cognitive deterioration and atrophy of the brain. (Krausz 1999)