ADVANCED PSYCHOPHARMACOLOGY

Psychology 572                       	                 Spring, 2003
Dr. John M. Morgan                    Monday & Wednesday, 8am to 9:20
                                             Harry Griffith Hall, 117




 NEUROLEPTICS
Kathy Millwood


Neuroleptics are used to control symptoms experienced by people diagnosed 
with schizophrenia. These drugs do not cure the illness, but only treat the 
symptoms (Palfai, Jankiewicz, 2001). The symptoms of schizophrenia fall 
into two categories, positive symptoms that include thought disorders, 
hallucinations and delusions of grandeur, persecution and control, and 
negative symptoms that include flattened emotional response, poverty of 
speech, lack of initiative or persistence, anhedonia and social withdrawal 
(Carlson, 1998). Some evidence suggests that positive symptoms involve 
excess activity in the neural circuits that use dopamine, and negative 
symptoms have been correlated with damage to the medial temporal lobes, 
the frontal lobes, and the medial diencephalons (Carlson, 1998). One study's 
findings suggested that the negative symptoms are caused by damage to the 
dorsolateral prefrontal cortex, which is related to behavioral flexibility 
(Carlson, 1998). The severity of negative symptoms is positively correlated 
with the severity of brain abnormalities (Carlson, 1998). CT scans of the 
lateral ventricles found that these were more than two times the size in 
patients with schizophrenia compared with the control group (Carlson, 1998).  
Autopsies preformed on patients with schizophrenia also found enlarged 
ventricles thought to be the result of cell loss that developed over a long 
period of time (Palfai, Jankiewicz, 2001). There are two positive side effects 
to neuroleptics, they are not addictive and it is difficult to commit suicide 
using these drugs (Ray, Ksir, 2002). Symptom reduction is dependent upon 
continued treatment, forty percent of patients relapse within six months, and 
seventy percent relapse within a year of discontinuance of the medication 
(Spohn, Strauss, 1989). Standard neuroleptics are used to control the positive 
symptoms of schizophrenia and work by blocking the dopamine receptors, 
however the symptoms of up to one-third of the patients are not reduced 
(Carlson, 1998). There are three types of side effects experienced by those 
using standard neuroleptics; sedation, anticholinergic effects and 
extrapyramidal effects (Preston, Johnson, 2003). The extrapyramidal effects 
include drug-induced Parkinson disease symptoms, which are muscle rigidity, 
and tremors; akathisia, which is motor restlessness; and tardive dyskinesia, 
which includes rhythmic repetitive sucking and smacking of the lips, thrusting 
the tongue in and out, and involuntary movements of the arms, fingers and 
toes, and appears after years of neuroleptic treatment (Spohn, Strauss, 1989). 
Tardive dyskinesia appears in about twenty-five percent of the cases, it is 
considered untreatable but can be suppressed (Spohn, Strauss, 1989). It is 
believed to be caused by the super sensitivity of the dopaminergic receptors 
(Ray, Ksir, 2002). Super sensitivity develops in the postsynaptic neuron for 
dopamine to compensate for the decreased synaptic activity (Carlson, 1998). 
Dopamine agonists can intensify the symptoms of tardive dyskinesia as well 
(Carlson, 1998). The neuroleptics vary in the severity of movement disorders 
dependent on the amount of anticholinergic activity the drugs possess (Ray, 
Ksir, 2002). This side effect of movement disorders involves the nigrostrial 
dopamine pathway, and is a result of the blockade of dopamine receptors in 
the basal ganglia (Ray, Ksir, 2002). This is treated with anticholenergic 
drugs, which block receptors in the output pathways from the basal ganglia 
(Ray, Ksir, 2002). Another side effect of standard neuroleptics is an increase 
in prolactin, which is correlated with an increase in the incidence of cancer 
(Physician's GenRx, 1996). Studies show a gender difference in the use of 
neuroleptics, female patients experiencing a longer acting effect of the drugs, 
and there is a larger prevalence of Parkinson disease effects and tardive 
dyskinesia in female patients, but drug withdrawal symptoms are less severe 
(Spohn, Strauss, 1989).

The atypical neuroleptics are successful in treating the positive symptoms by 
blocking the dopamine D2 receptors, and also improve the negative 
symptoms by blocking a subtype of serotonin receptor (Ray, Ksir, 2002). The 
atypical neuroleptics, cloazpine, risperidone, olanzapine, quetiapine, and 
ziprasidone have a reduced incidence or lack of extrapyramidal symptoms 
and more benign side effects than standard neuroleptics (Preston, Johnson, 
2003). Clozapine became available in the US in 1990, and was used 
successfully with patients who did not respond to the standard neuroleptics. 
Clozapine's site of action is primarily on the nucleus accumbens (Carlson, 
1998). Clozapine interferes with the binding of dopamine at both D1 and D2 
receptor sites (Physician's GenRx, 1996), even though it only has about a 
10% affinity for the dopamine receptors compared with standard neuroleptics 
(Carlson, 1998). It also acts as an antagonist at the adrenergic, cholinergic, 
histaminergic and serotonergic receptors (Physician's GenRx, 1996). The use 
of clozapine does not produce Parkinsonian side effects (Carlson, 1998), and 
only a few cases of tardive dyskinesia have been reported (Preston, Johnson, 
2003). Clozapine and risperidone reduce movement disorders by blocking 
serotonin receptors (Ray, Ksir, 2002). Studies have shown that clozapine can 
increase the intensity and duration of REM sleep (Physician's GenRx, 1996). 
There are many reported side effects of clozapine; agranulocytosis, seizures, 
adverse respiratory effects, autonomic instability, altered mental status, 
muscle rigidity, drowsiness, sedation, dizziness, vertigo, headache, tremor, 
salivation, sweating, dry mouth, visual disturbances, tachycardia, syncope, 
hypotension, constipation, nausea, and fever (Physician's GenRx, 1996), The 
most dangerous side effect is agranulocytosis, which is a low white blood cell 
count, and can cause fatality by lowering the immune system's ability to fight 
diseases (Ray, Ksir, 2002). The incidence of occurrence is 1-2%, compared 
to 0.1% with other neuroleptics (Preston, Johnson, 2003). Because of the 
possibility of agranulocytosis, blood monitoring is necessary while using 
clozapine. 

The newest atypical neuroleptics, risperidone, introduced in 1994, 
olanzapine, introduced in 1996, quetiapine, and ziprasidone have a more 
benign side effect profile compared to standard neuroleptics and do not have 
a high incidence of agranulocytosis that clozapine has (Preston, Johnson, 
2003). Risperidone is a selective monoaminergic antagonist that has a high 
affinity for serotonin, dopamine, adrenergic and histaminergic receptors. Its 
many side effects include; insomnia, agitation, anxiety, aggressive reactions, 
extrapyramidal symptoms, headache, dizziness, constipation, nausea, 
dyspepsia, vomiting, abdominal pain, saliva increase, toothache, rhinitis, 
coughing, sinusitis, pharyngitis, dyspnea, back pain, chest pain, fever, skin 
rash, dry skin, seborrhea, upper respiratory difficulties, abnormal vision, 
arthralgia, and tachycardia (Physician's GenRx, 1996). Risperidone, 
olanzapine, and ziprasidone are all associated with extrapyramidal symptoms, 
whereas there is a lower incidence of these symptoms with quetiapine 
(Sussman, 2002). There is also a reduction in serum prolactin levels in 
patients who are using quetiapine (Sussman, 2002). Quetiapine has a 
normalizing effect on body weight, compared to the other neuroleptics, which 
have been shown to cause weight gain (Sussman, 2002). Because of the 
lower incidence of extrapyramidal symptoms, there is no requirement for 
liver, blood, or thyroid monitoring during treatment (Sussman, 2002).  High 
levels of patient satisfaction and compliance are reported when using 
quetiapine (Sussman, 2002).


References



Carlson, N.R.; (1998). Physiology of Behavior, 6th edition. Allyn& Bacon. 
MA
Mosby-year Book, Inc. (1996). Physician's GenRx, The Complete Drug 
Reference.
Palfai, T. & Jankiewicz, H. (2001). Drugs and Human Behavior, 2nd edition. 
McGraw-Hill Companies, Inc.
Preston, J.,Psy.D.& Johnson, J. M.D.; (2003). Clinical Psychopharmacology 
made ridiculously simple. 4th edition. MedMaster, Inc., FL.
Ray, O. & Ksir, C.; (2002). Drugs, Society, and Human Behavior. McGraw-
Hill Companies.
Spohn, H. E. & Strauss, M. E.; (1989). Relation of neuroleptic and 
anticholinergic medication to cognitive functions in schizophrenia. Journal of 
Abnormal Psychology. 98 (4), pp. 367-380.
Sussman, N.; (2002). Choosing an atypical antipsychotic. Int. Clinical 
Psychopharmacology. Aug. 17, 2002.

Copyright © 2003, Dr. John M. Morgan, All rights reserved - This page last edited 25-Nov, 2002
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