Therapy Outline

The Parkinson's-Reversing Breakthrough

Parkinson Disease Diet

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In 1952 reserpine, an alkaloid extract from the Indian snakewort plant, Rauwolfia serpentina, which had been used in that country to treat 'madness', was first tried in schizophrenia. The beneficial impact on patients and the hospital wards was dramatic, as was that a year later of chlorpromazine, a phenothiazine derivative and haloperidol, a butyrophenone. These latter two drugs and closely related derivatives remained the mainstay of therapy for almost 40 years.

Chlorpromazine had been shown to produce a tranquil state in animals and since it had a similar effect in humans it became known as a major tranquiliser but the term is rarely used today. Sometimes the drugs used to treat schizophrenia are called anti-psychotics but more commonly neuroleptics. Leptic means to activate (take hold of) and in animals these compounds produce a state of maintained motor tone known as catalepsy. This is an extrapyramidal effect and in schizophrenics the neuroleptics can cause a number of extrapyramidal side-effects (EPSs) including Parkinsonism. The new term 'neuroleptic' is unsatisfactory as a description of clinically useful drugs. It really describes a condition (catalepsy) seen in animals and is more indicative of a compound's ability to produce EPSs than to treat schizophrenia. 'Antipsychotic' is more descriptive but could imply a more general efficacy in psychoses than is the case. It would seem more appropriate to call a drug that is used to treat schizophrenia an 'antischizophrenic' just as we use the terms 'antidepressant' or 'antiepileptic' irrespective of how the drug works. Despite such personal reservations, the term 'neuroleptic' will be used in this text.

The ability of neuroleptics to produce EPSs immediately suggests that they reduce or antagonise dopamine (DA) function and this is supported by a number of other observations (Table 17.1).

Table 17.1

CNS effect

Known change in DA function

Neuroleptic effect

Presumed change in DA function

Parkinsonism

Reduced

Induction of Parkinsonism

Reduced

Elevated plasma prolactin

Reduced

Elevated proloctin

Reduced

Vomiting

Increased

Anti-emetic

Reduced

Hallucinations

Increased

Decrease hallucinations in

Reduced?

schizophrenics

Figure 17.1 The structures of some neuroleptic drugs

In addition, amphetamine causes hallucinations in humans similar to those in schizophrenia and in rats it induces stereotyped behaviour (rearing, grooming and sniffing). This is dependent on the release of DA and blocked by the neuroleptics, which are DA antagonists.

There is now a whole range of neuroleptics (Fig. 17.1) but their ability to block the Dj-receptor-mediated stimulation of adenylate cyclase does not correlate with clinical potency. By contrast, their potency in displacing DA or more commonly an appropriately (3H) labelled ligand, such as haloperidol, from D2 binding sites on striatal membranes shows a surprisingly good correlation with clinical efficacy (Fig. 17.2). Most effective neuroleptics are indeed dopamine D2-receptor antagonists. The importance of DA antagonism generally is underlined by the finding that while the thioxanthene flu-penthixol exists in two forms a (cis) and ft (trans) only the former is effective in schizophrenia and it is a hundred times more potent as a DA antagonist than the ft form.

This raises two obvious questions:

(1) If effective neuroleptics are DA antagonists, is there any evidence for increased DA function in schizophrenia?

(2) How can blocking DA-mediated activity overcome the symptoms of schizophrenia and which DA pathways are involved?

10 100 1000

Average daily clinical dose (mg)

Figure 17.2 Comparison between the clinical dose of some neuroleptic drugs in the therapy of schizophrenia and their affinity for D1 receptors, measured indirectly by inhibition (ki) of dopamine stimulated adenylate cyclase ((•) right-hand ordinate) or D2 receptors indicated as displacement of haloperidol binding ((x) left-hand ordinate). Data are given for only four selected compounds but many more neuroleptics fall on the regression line between clinical dosing and D2 antagonism (see Seeman 1980, 1992). The clinical doses used are based on those generally prescribed while K1 (nM) values are averaged from a number of published figures. SPIP — spiperone, FLU—fluphenazine, HAL—haloperidol, CPZ — chlorpromazine

10 100 1000

Average daily clinical dose (mg)

Figure 17.2 Comparison between the clinical dose of some neuroleptic drugs in the therapy of schizophrenia and their affinity for D1 receptors, measured indirectly by inhibition (ki) of dopamine stimulated adenylate cyclase ((•) right-hand ordinate) or D2 receptors indicated as displacement of haloperidol binding ((x) left-hand ordinate). Data are given for only four selected compounds but many more neuroleptics fall on the regression line between clinical dosing and D2 antagonism (see Seeman 1980, 1992). The clinical doses used are based on those generally prescribed while K1 (nM) values are averaged from a number of published figures. SPIP — spiperone, FLU—fluphenazine, HAL—haloperidol, CPZ — chlorpromazine

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