NAMI SCC WebsitePsych 421 Psychosis - C.D. Blaha
Drug Treatment of Psychotic and Neurological Disorders Part I
Categories of Psychosis
Psychosis is an impaired ability to perceive reality (impaired reality testing), which may result in delusions and hallucinations, among other symptoms. DSM-IV describes 9 major categories of psychotic disorders:
1. Schizophrenia - a disorder lasting at least 6 months, including two or more of the following: delusions, hallucinations, disorganized speech, severely disorganized or catatonic behavior, negative symptoms. The general category of schizophrenia includes the specific subtypes: paranoid, disorganized, catatonic, undifferentiated, and residual.
2. Schizophreniform Disorder - a disorder with symptoms similar to schizophrenia lasting less than 6 months and excluding a general reduction in functioning.
3. Schizoaffective Disorder - a disorder characterized by symptoms of schizophrenia (e.g., delusions, hallucinations, negative symptoms, disorganized speech, severely disorganized or catatonic behavior) and an episode of disordered mood, preceded or followed by at least 2 weeks of delusions or hallucinations without affective symptoms.
4. Delusional Disorder - a disorder in which "nonbizarre" delusions occur for at least 1 month, but without other schizophrenic symptoms.
5. Brief Psychotic Disorder - a psychotic disorder lasting more than 1 day but that subsides within 1 month.
6. Shared Psychotic Disorder - a disorder that develops as a result of contact with another individual who suffers from a delusion similar in nature.
7. Psychotic Disorder Due to a General Medical Condition - a disorder in which psychotic symptoms are a result of a general medical condition. Medical illnesses which can result in psychotic symptoms include CNS tumors, brain trauma as a result of head injury, dementias e.g., Alzheimer's disease, Huntington's disease, multiple sclerosis, and epilepsy.
8. Substance-Induced Psychotic Disorder - a disorder in which psychotic symptoms are a result of drug abuse, a prescribed medication, or a toxin. Drugs that can cause psychotic symptoms: cocaine, steroids, anti-Parkinsonian drugs, psychedelics, and hallucinogens.
9. Psychotic Disorder not Otherwise Specified - a psychotic disorder that does not fulfill the criteria for any of the previous psychotic disorders.
Schizophrenia
Distinction between 2 main types of schizophrenia:
Positive Symptoms - morbid and disordered behaviour (external):
Delusions - Strange beliefs, which cannot be shaken by logic or reason, e.g. aliens from inner space are invading the earth or belief they are a celebrity, a member of the royal family.
Hallucinations - Hears, sees, tastes or smells things which are not there. Most common is hearing voices which orders: to commit suicide.
Thought reading - Often believe their private thoughts can be read by others, or that thoughts are put into their heads to control them.
Negative Symptoms - absence of expected behaviour (internal):
Emotional vacancy - Feelings of emotional numbness.
Impoverished speech - Difficulty in communicating with others.
Amotivational - Lack of goal orientation or drive.
Overt apathy - Inability to care about everyday tasks such as getting out of bed in the morning, washing and dressing.
Agoraphobic - Withdrawal from social contact: cloistered mentality
Arhythmic - Changed sleep patterns so that sleeping and waking are disrupted.
Catatonia - Freezes like a statue, doesn't speak and will not eat or drink.
The following may be positive or negative symptoms: Ill at ease with people, difficulty in thinking so that what is said is hard to understand, paranoid beliefs that family, friends, or the whole work have become enemies plotting to harm the individual.
Debate as to whether these subtypes really exist, because many patients exhibit some positive and negative symptoms. Also, there is evidence that schizophrenia is generally associated with enlarged ventricles and focal brain damage therefore, both positive- and negative-symptom schizophrenia may be neurodegenerative disorders. Nonetheless, there is consensus that positive symptoms respond more effectively than negative symptoms to antipsychotic medication (Reynolds, 1992).
Drug Treatment for Psychosis
Antipsychotics are used mainly in treatment of psychotic illnesses. They may also be used as antiemetics (prevent vomiting), antinauseants, and antihistamines; they can potentiate the effects of analgesics, sedatives, and general anesthetics.
Their advent and application to the treatment of human psychosis has resulted in a major reduction in the number of patients held in psychiatric hospitals. ( see Fig. 1 )
There are 4 main classes of antipsychotics used to treat schizophrenias. The first 3 are:
phenothiazines (e.g., chlorpromazine, thioridazine)
butyrophenones (e.g., haloperidol), and
thioxanthines (e.g., flupentixol).
These 3 groups are referred to as classical antipsychotics. Because these drugs cause considerable extrapyramidal side-effects and sedation, they have been referred to as neuroleptics and sometimes as major tranquilizers.
The 4th class is atypical antipsychotics e.g.:
clozapine, sulpiride, remoxipride, risperidone
Pharmacokinetics
Behavioral Effects
Research Validation
( Fig. 4 )
In animals, low antipsychotic doses suppress operant behavior without any loss of spinal reflexes. Exploratory behavior decreases, responses become fewer and slower without any loss of the ability to discriminate between stimuli. Conditioned avoidance responses are inhibited, as is feeding behavior.
At high doses, antipsychotics induce catalepsy, a condition in which an animal becomes immobile but can be placed in any posture and will remain fixed in that position. Coma is not induced even by very high doses of antipsychotics. A variety of other effects on motor activity can be induced and are considered side effects (Baldessarini, 1991).
Antipsychotics affect most areas of the CNS. Most antipsychotic drugs have in common an ability to act as antagonists at the DA receptor. However, different antipsychotics act at different subtypes of DA receptor and other neurotransmitter receptors to differing extents (Reynolds, 1992).
Extrapyramidal side effects of antipsychotics are produced mainly by their action as DA receptor antagonists in the nigrostriatal pathway. The antagonistic action on the mesolimbic and mesocortical DA systems is considered to be at least partially responsible for their therapeutic effects in alleviating psychotic symptoms. However, it has also been suggested that the striatum may be important in the etiology of schizophrenia and that antipsychotic action in the nigrostriatal pathway may be important for the clinical therapeutic effects of these drugs (Miller, 1989). ( see Fig. 4 )
The endocrine side effects of antipsychotics (e.g., increase in prolactin secretion) are the result of their action on the tuberoinfundibular DA system (Baldessarini, 1991).
The hypothesis which has dominated schizophrenia research for decades is the Dopamine Hypothesis, which attributes schizophrenia to a hyperactivity of the DA systems, in particular an up-regulation of D2 receptors. Originally, this hypothesis was supported by several observations:
1. DA agonists or DA-releasing drugs like amphetamine were observed to induce a paranoid psychosis similar to paranoid schizophrenia.
2. Drugs that were antagonists for the D2 receptor had an antipsychotic action (e.g.,chlorpromazine).
3. Postmortem biochemical analyses of the brains of people with schizophrenia indicated an up-regulation of D2 receptors (see Reynolds, 1992).
The simple Dopamine Hypothesis has now been discredited (oh god no, say it ain't true!!) for several reasons as follows:
1. Drugs like phencyclidine (PCP, angel dust), glutamate NMDA antagonists receptors, induce schizophrenic symptoms but only facilitate dopamine transmission in subcortical regions.
2. Most antipsychotics have extensive actions on other transmitter receptors, including alpha-1 adrenoceptors, histamine receptors, 5-HT2 receptors, and muscarinic ACh receptors. Furthermore, some atypical antipsychotics like clozapine have a relatively low affinity for D2 sites and have greater action on 5-HT2, D1 and D4 receptors.
3. Positron emission tomography (PET) studies of untreated patients with schizophrenia have failed to show a substantial up-regulation of D2 receptors, suggesting that the earlier findings supporting D2 up-regulation were a result of drug treatment with antipsychotics (see, Seeman et al., 1993).
4. D2 blockade occurs very quickly following the initiation of treatment with antipsychotics and yet many of the therapeutic effects take weeks to develop (Reynolds, 1992).
5. Other neurochemical abnormalities such as a reduction in GABAergic neurons and a reduction in glutamate receptors have been documented (Reynolds, 1992). However, the relationship between these neurochemical abnormalities and pathological changes in brain structure is unclear.
Currently, the Dopamine Hypothesis is regarded as incomplete at best. Clearly, some of the initial empirical support for the hypothesis was flawed and it is now known that there are many neurochemical abnormalities in schizophrenia; whether changes in DA are the cause or the effect of other neurochemical changes remains to be elucidated (heck, I see it, at the very least, as another 10 years of grant funding for me and my lab from the ARC and NH&MRC in Australia) (see Davis et al., 1991).
Because PCP (an NMDA receptor antagonist) has been found to induce schizophrenic psychosis in normal humans, and because changes in glutamate have been documented in people with schizophrenia, a PCP model of schizophrenia has been proposed. Nonetheless, the current trend among theoreticians is to move away from "single-factor" hypotheses and recognize that neurochemical causes of schizophrenia are complex.
Uses of Antipsychotic Drugs
( Fig. 5 )
The particular antipsychotic that is chosen to treat psychosis depends to a large extent on the side effects that the patient can tolerate. The different antipsychotics available can be divided into low and high potency categories.
The choice between these different antipsychotics is often based on symptoms with which the patient presents (e.g., someone with marked agitation might receive a low potency drug with more sedative side effects; someone who is already withdrawn might be better treated with a high potency drug that has fewer sedative side effects).
Schizophrenic symptoms are classified into various categories, some of which respond more to antipsychotic medication than others:
( Fig. 6 )
1. ego dysfunctions - delusions and hallucinations, impaired judgment, anxiety, agitation, lack of emotional control.
2. characterological traits - alienation and isolation, reduced self-esteem, lack of social skills.
3. negative symptoms - flat affect, poverty of thought, anhedonia, lack of psychomotor activity, reduced perception (e.g., inability to sense pain).
It is mainly ego dysfunction (positive) symptoms that antipsychotics will alleviate. The negative symptoms are often resistant to antipsychotic treatment.
Low to moderate doses are first used and dose is "titrated" up until symptomatic relief is obtained. Although some psychiatrists start with very high doses - a procedure known as rapid neuroleptization.
Reasons why a patient may not benefit from antipsychotic medication:
1. Noncompliance. Patient may not be taking the medication as prescribed. Sometimes this is due to adverse side effects, sometimes due to the psychotic condition interfering with the cognitive processes necessary to keep track of medication. Noncompliant patients are sometimes given time-release IM antipsychotic medication (depot injections) in order to overcome these problems.
2. Dose may not be high enough to achieve symptomatic relief. Because the absorption, distribution, and metabolism (i.e., pharmacokinetics) of drugs vary between different individuals, it may be necessary to monitor blood plasma levels of the drug in order to ensure that the dose is adequate.
3. Patient is suffering from Type II, negative symptom schizophrenia. Type II patients often do not respond to the classical antipsychotics such as chlorpromazine. For these patients, atypical antipsychotics such as clozapine may be used. Some clinicians suggest that benzodiazepines can be useful in these cases.
The Best Choice Scenarios
( Fig. 7 )
Because of the adverse side effects produced by classical antipsychotics, and fact that about 30% of schizophrenics do not obtain symptomatic relief from them, the search for better antipsychotic drugs continues (Kane, 1993; Reynolds, 1992).
3 atypical antipsychotics that (in some cases) alleviate schizophrenic symptoms with fewer side effects, are clozapine (Clozaril), risperidone (Risperal), and remoxipride (Roxiam).
Clozapine
Risperidone
Remoxipride
Limitations and Side Effects
Antipsychotic drugs are relatively safe (i.e., they have a high therapeutic index) and can be used over a wide range of doses.
The 3 main categories of side effects experienced with antipsychotics, in general, are sedation, anticholinergic, and extrapyramidal side effects:
A. Anticholinergic side effects blockade of peripheral nervous system muscarinic receptors in the include: dry mouth, blurred vision, constipation, urinary retention, sometimes confusion and loss of memory, especially in the elderly.
B. Extrapyramidal side effects include the following:
1. Parkinson-like effects - muscularrigidity,tremor,bradykinesia(i.e.,slowness of movement), masklike facial expression. Sometimes anti-Parkinsonian drugs may be given to reduce these side effects.
2. Akathesia - a restlessness that is distinct from anxiety. This is treated with an anxiolytic drug such as a benzodiazepine (e.g., lorazepam) or an anti-Parkinsonian drug.
3. Acute dystonias - muscle spasms, especially of the head/neck. Anti-Parkinsonian drugs are often used to treat this side effect (e.g., benzotropine mesylate).
4. Tardive dyskinesia - a serious, irreversible condition that can develop late in antipsychotic therapy. Symptoms include: involuntary sucking and smacking lip and mouth movements, chorea of the limbs. Drugs such as baclofen (GABA-B receptor agonist) and benzodiazepines are used to treat tardive dyskinesia, but not very successfully. If tardive dyskinesia develops, antipsychotic treatment must stop (Reynolds, 1992).
The atypical antipsychotic, clozapine, was initially regarded as a breakthrough because of the low incidence of extrapyramidal side effects. Unfortunately it caused several deaths due to agranulocytosis (a reduced production of leukocytes in the bone marrow) and was withdrawn from the market. Although it is now used only with hematological monitoring, there are still occasional fatalities (Kane, 1993). Other side effects of clozapine include seizures (3% of patients), sedation, tachycardia, and dizziness.
Risperidone has a very low risk of extrapyramidal side effects; however, it may result in concentration difficulties and sedation.
Remoxipride also has a low risk of extrapyramidal side effects; however, it may cause tiredness, insomnia, tremor, concentration difficulties, and akathesia (Kane, 1993).
Tolerance develops to many of the sedative effects, although they are not regarded as having a high dependence liability, some physical dependence has been reported.
Drug Interactions (few and in between)
Antipsychotics can potentiate the actions of sedatives (including alcohol), analgesics, antihistamines and cold medications. Chlorpromazine increases drug-induced respiratory depression.
Baldessarini, R. (1991). Drugs and the treatment of psychiatric disorders. In A. Goodman Gilman, T. W. Rall, A. S. Nies, & P. Taylor (Eds.), The pharmacological basis of therapeutics (8th ed., Vol. 1, pp. 383-435). New York: Pergamon.
Davis, K. L., Kahn, R. S., Ko, G., & Davidson, M. (1991). Dopamine in schizophrenia: A review and reconceptualization. American Journal of Psychiatry, 148, 1474-1486.
Dolan, R. J., Fletcher, P., Frith, C. D., Friston, K. J., Frackowiak, R. S. J., & Grasby, P. M. (1995). Dopaminergic modulation of impaired cognitive activation in the anter-iorcingulate cortex in schizophrenia. Nature, 378, 180-182.
Edwards, J. G. (1994). Risperidone for schizophrenia. British Medical Journal, 308, 1311-1312.
Kane, J. M. (1993). New antipsychotic drugs. A review of their pharmacology and therapeutic potential. Drugs, 46, 585-593.
Olney, J. W., & Farber, N. B. (1995). Glutamate receptor dysfunction and schizophrenia. Archives of General Psychiatry, 52, 998-1007.
Reynolds, G. P. (1992). Developments in the drug treatment of schizophrenia. Trends in Pharmacological Sciences, 13, 116-121.
Seeman, P., Guan, H. C., & Van Tol, H. H. M. (1993). Dopamine D4 receptors elevated in schizophrenia. Nature, 365, 441-445.
Silbersweig, D. A., Stem, E., Frith, C. D., Cahill, C., Holmes, A., Grootoorik, S., Seaward, J., McKenna, P., Chua, S. E., Schnorr, L., Jones, T., & Frackowirk, R. S. J. (1995). A functional neuroanatomy of hallucinations in schizophrenia. Nature, 378, 176-179.
Waddington, J. L. (1993). Schizophrenia: developmental neuroscience and pathobiology. The Lancet, 341, 531-536.
Drug Treatment of Psychotic and Neurological Disorders Part II
Parkinson's Disease
( Fig. 8 )
Parkinison's disease is a degenerative disorder resulting in a severe impairment of normal motor control. It was first described by James Parkinson in 1817 as "paralysis agitans". Estimates suggest that about 3 million people in the United States alone are afflicted with Parkinson's disease.
The 3 major, characteristic symptoms of the disease are bradykinesia (slowness and poverty of movement), rigidity, and tremor (about 4-6 Hz and therefore distinct from the physiological 8 Hz tremor).
Parkinsonian symptoms do not appear until relatively late in the course of the disease; about 80% of the DA in the basal ganglia must be lost before obvious symptoms develop. Ultimately, loss of normal motor control may become so severe that movement is impossible. In addition to motor control impairment, about 1/3 of Parkinson's patients will develop dementia, although it is unclear whether this is a consequence of the disease itself or the drug therapy that is used to treat the disease. Patients often die from pneumonia caused by an accumulation of fluid in the lungs during long periods of immobility, or from severe bone breakage as a result of falls (Roberston, 1992).
It is important to distinguish between Parkinson's disease and other disorders that display Parkinson-like symptoms, for example, Parkinsonian side effects may appear with antipsychotic drug treatment; some people develop a familial tremor of about 4 Hz, without other Parkinsonian symptoms; poisoning with heavy metals such as manganese may cause Parkinsonian symptoms such as tremor.
20% to 60% of patients suffering from Parkinson's disease also suffer from dementia; the probablitity of dementia is increased in the elderly and those with advanced Parkinson's disease. Dementia in Parkinson's disease is characterized by memory impairment, a slowing of cognitive processes and motor performance, often accompanied by depression. In some cases, patients who suffer from Parkinson's disease and dementia are found to have the neuropathological signs of Alzheimer's disease at autopsy (Calne, 1994).
There are secondary types of parkinsonism which show atypical features in addition to those of classic Parkinson's, and are classified as Parkinson Plus Syndromes.
Parkinson Plus Syndromes include:
Progressive supranuclear palsy, multiple system atrophy or Shy-Drager syndrome, olivopontocerebellar atrophy (OPCA), cortical-basal ganglionic degeneration and diffuse Lewy body disease (Lewy bodies are 5-25 um spherical, eosinophilic structures found in dying cells and are considered a neuropathological hallmark of PD). Vascular parkinsonism, due to a multi-infarct state, represents an important group of parkinsonian disorders.
Here is a synopsis:
1. James Parkinson (1817); attacks ~1% of the pop. (~3 million US)
2. 80% of substantia nigra cells must die off
3. age of onset ~50-60 yrs.
4. tremors during inactivity and suppressed during voluntary movement and sleep
5. muscular rigidity (cogwheel movement) and postural instability
6. hypokinesis-decreased movement; hypertonia-increased muscle tone
7. bradykinesia - slowness in movement
8. on-off shuffling gate
9. usually no intellectual impairment, but can be accompanied by depression and dimentia
There are many potential causes of parkinsonism and these will require specific investigation.
Here are a few of the potential causes:
1. origin of PD is unknown, in some cases, specific causes include viral infections of the brain, strokes, certain toxins and drugs (typical antipsychotics or neurotoxins, Iatrogenic Parkinsonism), as well as some metabolic, degenerative and, yes, hereditary conditions (area of chromosome 4). (see appendix at end of lecture notes, APX-1)
2. neurotropic virus cohort disease? (see Oliver W. Sacks' book "Awakenings" describing Von Economo's Disease, encephalitis lethargica "sleeping sickness")
3. environmental toxin? herbicides; MPTP; Guam Palm Plant (~10% of pop. in Guam have Parkinson's)
Drug Treatment of Parkinson's Disease
( Fig. 9 )
Parkinson's disease results in a loss of DA neurons in the substantia nigra pars compacta (SNc), thus most of the drug therapies used attempt to compensate for the reduced DA.
Administration of DA itself is not possible because DA does not cross the blood brain barrier. Therefore, a DA precursor is administered, levodopa (L-Dopa), which penetrates the blood brain barrier and is converted to DA.
Levodopa
Pharmacokinetics
Behavioral Effects
Other Drug Treatments
( Fig. 10 )
DA Agonists
Some success has been achieved with selective D2 agonists, in particular bromocriptine. Approximately 50% of patients who receive bromocriptine as the only therapy do not benefit from it. However, those who do benefit do not suffer the long-term side effects of L-Dopa therapy. Often bromocriptine is given as a supplementary therapy to L-Dopa, especially as the effects of L-Dopa begin to wear off later in the course of the disease. When given as a supplement to L-Dopa, the usual starting dose is 2.5 mg/day (in divided doses), the maximal dose is 100 mg/day (Bianchine, 1991).
DA-Releasing Agents
Amantadine is a drug that is thought to release DA from DA-containing nerve terminals. Unfortunately, tolerance soon develops to its therapeutic effects. Nonetheless, some clinicians use amantadine as an occasional supplementary therapy (100 mg, twice daily).
MAO-B Inhibitors
Another strategy for increasing DA in the CNS of the Parkinsonian patient is to inhibit the enzyme that metabolizes DA. Selegiline specifically inhibits the MAO type-B that selectively metabolizes DA (but not norepinephrine or serotonin), thereby increasing DA concentrations in the brain.
Using selegiline, L-Dopa therapy may be reduced by about 30%. Evidence suggests that treatment with both selegiline and L-Dopa early in the course of Parkinson's disease may retard the development of the disease. However, the beneficial effects of selegiline are transient; it is not available for general prescription in the United States but is in Australia (see Appendix below, APX-2).
Muscarinic Cholinergic Antagonists
DA released by SNc nerve terminals in the striatum normally inhibits striatal neurons and reduces the excitability caused by cholinergic interneurons.
Following degeneration of SNc neurons a cholinergic hyperactivity develops in striatal neurons with muscarinic ACh receptors. If Parkinsonian symptoms are at least partly due to an uncontrolled striatal hyperactivity caused by ACh, ACh antagonists might be expected to help. Unfortunately, this is true mainly during the early stages of Parkinson's disease. Later, when the DA loss is severe, ACh antagonists are of little use.
The side effects of anticholinergic drugs (see below, limitations and side effects) limit their clinical utility; however, they are sometimes used as a supplement to L-Dopa and in patients who do not respond to L-Dopa or cannot tolerate its side effects. An example of an anticholinergic drug used in the treatment of Parkinson's disease is benzotropine mesylate (0.5-6.0 mg/day).
Research Validation
When DA is lost during substantia nigra degeneration, striatal function is disturbed by cholinergic excitation that is now unchecked by inhibitory DA. The result is a severe impairment of the extrapyramidal motor system that degrades both reflexive and voluntary movement.
The precise function of the extrapyramidal system in motor control is still poorly understood. The pyramidal motor system, which is concerned with voluntary movement, includes pyramidal tract neurons in the cortex, some of which project directly to the spinal cord (the corticospinal projection).
However, these pyramidal neurons also send collateral fibres to many other parts of the brain, including the striatum or basal ganglia (i.e., the caudate nucleus, putamen and globus pallidus, collectively referred to as the striatum). The striatum does not project directly to spinal motoneurons, but appears to serve some kind of integrative and coordinative role that is still not understood (Robertson, 1992). The pyramidal, extrapyramidal, and cerebellar motor systems can be thought of as highly integrated, parallel systems rather than a simple hierachical one.
The explanation for the degeneration of neurons in the SN is unknown. One peculiarity of SNc neurons is that they not only release DA from their axon terminals in the striatum but from their dendrites that extend into another part of the SN, the SN pars reticulata (SNr). Recent studies suggest that the DA that is released into the SNr by SNc neurons and that acts on presynaptic D1 receptors on axons descending from the striatum and terminating in the SNr, may be as important for Parkinson's disease as the DA that SNc neurons release in the striatum (Robertson, 1992).
The functions of D1 and D2 receptors in this complicated system are far from well understood, but it appears to be an oversimplification to suggest that anti-Parkinsonian drugs exert their therapeutic effects simply by providing DA to DA-deprived striatal neurons. The situation is made still more complicated by the fact that once deprived of DA from the SNc, striatal neurons become supersensitive to DA and the remaining SNc neurons increase their release of DA; such "compensatory" mechanisms may be one reason why Parkinsonian symptoms do not appear until relatively late in the course of the disease (Robertson, 1992). Exactly how anti-Parkinsonian drugs affect the up-regulation of DA receptors on striatal neurons is unclear.
The MPTP Story
One of the major difficulties for research into Parkinson's disease has been development of a realistic animal model of the disorder. Until recently, the best model has been the effects of 6-hydroxydopamine (6-OHDA), a selective DA cell neurotoxin that causes the death of DA neurons in the substantia nigra. Unfortunately, although this kind of experimental lesion produces akinesia (i.e., loss of normal movement) similar to Parkinson's disease in humans, in nonprimate species it does not produce rigidity or tremor (Caine, 1994).
Progress has been made in developing an animal model of Parkinson's disease as a result of the accidental synthesis of MPTP (methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by an illicit drug user. Exposure to MPTP left the drug users with permanent Parkinsonian symptoms as a result of a degeneration of their nigrostriatal systems. Researchers are now trying to determine why MPTP causes this degeneration and if the cause is related to the etiology of Parkinson's disease. (see appendix, APX-3, below)
An exciting therapy for Parkinson's disease is the use of cellular transplants (explants) that release DA into the striatum. In some cases, nonneural DA-producing tissue (e.g., adrenal tissue) has been implanted into the striatum, releasing uncontrolled amounts of DA. In other cases, DA-containing neural tissue has been Implanted; in the latter case, the implanted tissue sprouts neurites that make synaptic contact with target neurons in the striatum.
The major obstacle for transplantation therapy is the limited survival time of the transplanted tissue; however, development of immortalized DA cell (MES 23.5) may provide the answer (see APX-3, below).
Uses of Anti-Parkinson's Drugs
L-Dopa
The main drug therapy for Parkinson's disease is L-Dopa; other drug treatments such as bromocriptine and acetylcholine antagonists, if they are used at all, are typically used as supplements to L-Dopa therapy.
L-Dopa slowly loses its effectiveness over a period of years and, as well as having less effect on Parkinsonian symptoms, a single drug dose may exert a therapeutic effect for a shorter period of time (end-of-dose deterioration). After about 5 years, the treatment may begin to work inconsistently (the on-off effect). During this later phase of the disease, supplemental therapy with bromocriptine may be beneficial.
Limitations and Side-Effects
Drug Interactions
The efficacy of L-Dopa against Parkinsonian symptoms can be reduced by other drugs such as DA antagonists (e.g., phenothiazines) and pyridoxine (however, carbidopa prevents the latter interaction).
Other drugs such as clonidine, papverine, and phenytoin may also inhibit L-Dopa's therapeutic effect, but this is not clearly established.
MAOIs will induce a hypertensive response, which can be prevented by administration of carbidopa.
Antimuscarinic ACh antagonists such as benzotropine mesylate may increase breakdown of L-Dopa in the gastrointestinal tract, resulting in reduced blood plasma levels of L-Dopa. The use of more than one antimuscarinic drug may result in adverse anti-cholinergic effects such as blurred vision and urinary retention.
Bianchine,J. R. (1991). Drugs for parkinson's disease, spasticity,and acute muscle spasms. In A. Goodman Gilman, T. W. Rall, A. S. Nies, & P. Taylor (Eds.), The pharmacological basis of therapeutics (8th ed., Vol. 1, pp. 463-484). New York: Pergamon.
Calne, D. B. (1994). Is idiopathic parkinsonism the consequence of an event or a process? Neurology, 44, 5- 10.
Robertson, H. A. (1992) Dopamine receptor interactions: Some implications for the treat-
ment of Parkinson's disease. Trends in Neurosciences, 15, 201-206.
Appendix:
APX-1
Researchers link Parkinson's disease to gene mutation 03/17/98-
WASHINGTON - Researchers say they have found the first laboratory evidence that a flawed gene is linked to Parkinson's disease, a progressive brain disorder that affects a half-million Americans.
A mutation was found in an area of chromosome 4 by analyzing DNA from members of a Italian family that has had Parkinson's appear in generations going back to the 1700s, according to Dr. Mihael H. Polymeropoulos of the National Institutes of Health.
"The etiology (cause) of Parkinson's has been long debated - whether it is genetic or environmental," Polymeropoulos said in an interview. "This is the first evidence that a genetic factor can, in fact, be the cause."
Polymeropoulos is lead author of a study to be published Friday in the journal Science. The co-authors include other researchers from NIH, the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School in New Brunswick, N.J., and the Institute of Neurological Science in Naples, Italy. Finding the area of a chromosome where the genetic flaw exists, said Polymeropoulos, does not isolate a specific Parkinson's gene, but it narrows the search from the 3.3 billion base pairs that make up all of the human genes to about 6 million base pairs. Once the gene is located, it may then be possible to find the protein made by the gene and then to develop a drug to treat Parkinson's.
Parkinson's involves a progressive degeneration of the brain. Symptoms include tremors that led 19th century physicians to call it the "shaking palsy." The disorder also causes rigid muscles, a slow, shuffling gait and a characteristic stoop. It can cause a general weakening of organ systems that can hasten death. About 50,000 Americans annually are diagnosed with Parkinson's and more than a half-million are currently affected. The disease is treated with a drug that causes the body to make dopamine, a brain chemical. However, the drug has only a limited effect. To localize a gene related to Parkinson's, researchers got specimens from members of a family that can trace itself back to a common ancestor who had Parkinson's in the 18th century. The ancestor lived in Contursi, an Italian village near Salerno.
There are now more than 500 members of the family, said Polymeropoulos, with branches in Germany, Italy, the United States and Argentina. Researchers got specimens from 28 family members, nine with Parkinson's disease. "We developed a genetic signature for the family members and then compared the signature of the affected with that of those who are not affected," said Polymeropoulos. This isolated a gene mutation on the long arm of chromosome 4, he said.
Polymeropoulos said it will take more research to ascertain that the chromosome 4 gene is the only one associated with Parkinson's. "We want to see if Parkinson's in other families is linked to chromosome 4. If they do not link to chromosome 4, then we'd do the same type of study for those families to search for another gene," he said.
The finding does not eliminate the possibility that other factors contribute to Parkinson's. It is possible, said Polymeropoulos, that people inherit a susceptibility to Parkinson's, but that the disease is not triggered by an influence from the environment. However, he noted that studies so far show that 85% of the people with a gene mutation develop the disease, suggesting a very strong genetic effect.
The American Parkinson Disease Association said the discovery may speed work toward finding improved treatments for Parkinson's. "We applaud the discovery," Joel Gerstel, a director of the association, said in a statement. "Once they isolate the gene, then they can go after factors that cause the disease." Polymeropoulos said the study "opens a new door on Parkinson, but it is not a direct link to treatment." Improved treatment, he said, will come only when the gene is isolated and researchers learn what protein the gene makes. By The Associated Press
APX-2
Parkinson's Disease Medications Available in Australia
Anticholinergic Agents:
Anticholinergics block the action of the neurotransmitter acetylcholine, helping to regain balance between acetylcholine and the reduced supply of dopamine in the brain. Effective against early rigidity, drooling, and tremor, not against bradykinesia or akinesia. May be used alone early in treatment, or with Sinemet. Different people react differently to each drug so a poor response or side effects with one anticholinergic does not exclude a trial with another.
Orphenadrine Hydrochloride: Disipal, 50mg
Trihexyphenidyl HCL: Artane 2mg
Biperiden: Akineton 2mg
Dopaminergic agents:
Drugs used to replace or mimic the actions of dopamine:
Levodopa-Benserazide: Madopar
Madopar HBS: 100/25mg (Controlled Release)
Levodopa-Carbidopa: Sinemet 250/25mg
Sinemet: 100/25mg
Sinemet CR: 200/50mg (Controlled Release)
Dopamine Agonists:
Dopamine agonists mimic the effects of dopamine by directly stimulating the dopamine receptors. Agonists are most commonly used early in combination with Sinemet. They may also be started when patients are no longer responding to Sinemet satisfactorily. Agonists may smooth out the fluctuating effect (wearing off) or "on-off' often seen in Parkinson's patients on chronic levodopa treatment. They are started at low doses and built up gradually over several weeks before therapeutic results are achieved. If dyskinesias increase, then a reduction in levodopa is indicated.
Amantadine Hydrochloride: Symmetrel 100mg
Pergolide: Permax 0.05 mg, 0.25mg, 1mg
Bromocriptine Mesylate: Parlodel 2.5mg, 5mg
Other Medications:
An MAO B inhibitor. Increases effect of dopamine by blocking the enzyme MAO B that normally breaks down dopamine.
Selegeline: Eldepryl 5mg
Deprenyl: 5 mg
APX-3
MPTP
MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) a chemical which induces a selective dopaminergic sympathectomy that simulates ideopathic Parkinson's disease is the product of an innacurate attempted synthesis of MPPP (1-methyl-4-phenyl-4-propionoxypiperidine) from MPHP (1-methyl-4-phenyl-4-hydroxypiperide) - these are meperidine (Demerol) analoges and not amphetamine derivatives.
In 1983 a group of heroin users attempted a demerol synthesis and obtained instead a compound called MPTP. The product had a similar appearance and melting point, and they injected it expecting a demerol high. In the brain, MPTP decomposes to MPP+ which selectively bonds to and destroys dopamine receptors. These individuals thus prematurely gave themselves Parkinson's disease. MPP+ closely resembles paraquat, a defoliant used by the US government, outside US borders, against marijuana (a bit heavy handed and reckless).
In order to understand the development and behavior of central dopaminergic neurons and molecular mechanisms involved in the degeneration of such neurons in PD and MPTP-induced PD, several investigators have developed an immortalized dopaminergic cell line. The cell line is called MES 23.5 and is derived by fusion of rat embryonic mesencephalon cells with murine N18TG2 neuroblastoma cells. The cell line expresses a complex range of neural properties found in the dopaminergic neurons of the substantia nigra (Crawford et al, 1992), including tyrosine hydroxylase, dopamine synthesis, and conotoxin receptors (control of calcium channels). Only dopamine, and no other catecholamine, is synthesized by the cells. Levels of tyrosine and dopamine are elevated by 3-7 fold with the treatment of dibutyrl-cAMP. This cell line offers several advantages over other cell lines including greater homogeneity (providing more obvious and consistent observations), and susceptibility to both free radical-mediated cytotoxicity and calcium-dependent cell death.
It has been recently proposed that cerebrospinal fluid (CSF) from PD patients may possess substances which are neurotoxic for dopaminergic cells (Klawans et al, 1993; Hao et al, 1995). To define the selectivity, specificity, and property of these cytotoxic factors, investigators have employed MES 23.5 cell cultures to examine cytotoxicity of CSF from PD and non-PD patients. Preliminary studies from 5 of 7 CSF samples from PD patients, but none of 5 CSF samples from control subjects, have shown significant cytotoxic effects on MES 23.5 cells as determined by cell viability assays. The damaged cells demonstrate a pattern of apoptotic morphology including nuclear chromatin condensation and nuclear fragmentation. An approach to identify the cytotoxic factors is underway. These results raise intriguing possibilities for the etiology and pathogenesis of PD.
See:
Crawford, A.D., Le, W.D., Smith, R.G., Xie, W.J., Stefani, E., and Appel, S.H. (1992) A novel N18TG2 X mesencephalon cell hybrid expresses properties that suggest a dopaminergic cell line of substantia nigra origin. J. Neurosci., 12:3392-3398.
Klawans, H.L. (1993) Parkinson's disease ventricular CSF contains a growth-inhibitory factor directed at mesencephalic cultures. Neurology, 43(Suppl 2):A388.
Hao, R.Y. Norgren, R.B., Lau, Y.S. and Pfeiffer, R.F. (1995) Cerebrospinal fluid of Parkinson's disease patients inhibits the growth and function of dopaminergic neurons in culture. Neurology, 45:138-142.
