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Biological treatments of CNS disorders
von Jauregg in 1917 in Viennaused malaria as a treatment for syphilis-inducedparalysisthis was the first biological treatment for a major CNSdisorder
insulin shock therapyManfred Sakel, a German physicianin Vienna in 1933wanted to relieve morphine withdrawal by giving
. Anatomical View of the Brain
Emphasizing Dopamine Pathways
insulindecided it helpedgave it to other patientssaid it helped schizophrenics
employed in 1937 in Rome
developed by a Portuguese neurologist, Egas Moniz, in 1935
noted that animals became more docile after cutting away the frontal lobes
large number of operations performed in the 1940s
but patients loose ambition and imagination
Thus, situation did not look very promising for patientsin 1955 there were 560,000 patients in U.S. mental hospitalsat least half of these were schizophrenicthe number was increasing at the rate of 13,000/yrat this point drug therapy was introduced that started to reduce the hospital population
Current Drug Therapies
in the 1930s this class of compound was used for intestinal worms!promethazine
was found to be an antihistamine and a sedative
derivatives were made
one of these was chlorpromazine
sat on shelves of a French drug company for 10 years
Animal studies indicated it potentiated the effects of anesthetics and produced“artificial hibernation”a tendency to sleep and indifference to surroundingsHenri Laborit, a French surgeon, asked the drug company for their most sedatingantihistamine to use before surgical anesthesia. They gave him cpz. It calmed hispatients without putting them to sleep. He recommended its use in psychiatry.
In 1952 Jean Delay and Pierre Deniker reported the use of cpz for treating schizophrenicpatients. They reported that it calmed patients, but was not just a sedative. Somewithdrawn patients became more energetic, also reported that it did not help in treatingdepression. They noted development of akinesia and coined the term “neuroleptic”that which “seizes the neuron”
Successful treatment for schizophrenia reported in 1954actually had been reported in 1931 by Sen and Bose in IndiaThe shrub is also known as pagla-ka-dawa (“insanity herb”)but their report was ignored until reserpine treatment was “rediscovered” in 1954.
HALOPERIDOL (HLP) (HALDOL)
Success reported for hlp in 1958. A butyrophenone compound
A COMMON PROPERTY OF CURRENT DRUGS
Interfere with ability of sensory stimuli to “get through.”
Interfere with conditioned stimulus (bell) telling a rat to climb a pole to avoid a shock
without interfering with the shock-induced climbing itself. Implies that schizophrenia
associated with too many inputs coming in with insufficient screening? Similar to LSD?
implications: evidence for schizophrenia as a biochemical disorder
. A chemical
agent can relieve
symptoms (cpz, hlp, etc.). Chemical agents can produce
symptoms(amphetamine, LSD, PCP, etc.).
average expectancy of schizophrenia in general population: @. 1%
if one parent has it: @. 16%if one sibling or non-identical twin has it: @ 14%if one identical twin has it: @ 50%
Suggests that there is a strong genetic (i.e., biochemical) component, but thatenvironment must also come into play
DOPAMINE THEORY OF SCHIZOPHRENIA
Main line of support is that neuroleptics block DA receptors
in common with reserpine, can produce extrapyramidal side effects.
Produce a Parkinsonian symptomology upon acute administration: slowing of
volitional movement, rigidity, tremor at rest.
Block turning behavior in rats with a unilateral lesion of the nigrostriatal
pathway in response to either amphetamine or apomorphine.
Increase rate of DA formation in vivo
Increase rate of firing of nigrostriatal neurons in vivo
Block DA-induced stimulation of adenylyl cyclase
although weaker in this regard, presumably because this is a D response
Block labeled DA binding to striatal membranesIncrease prolactin blood levels (DA is inhibitory in this system)Ability to block DA receptors correlates
with clinical efficacy in treating
ANOTHER LINE OF EVIDENCE
Production of symptoms resembling paranoid schizophrenia with amphetamine
amphetamine is an effective releaser of DA in the CNS.
Metabolite studies are not consistent: some studies on receptors have reported an
increase in DA receptor number
but remember that neuroleptic treatment can produce this
effect in animal studies could there be a transmitter imbalance,
in which DA plays a part but is not necessarily the prime
NMDA system contributes tothe symptoms of the disease
Other drugs can also produce some of the symptoms of
(PCP) can produce both
type I and type II
symptoms, whereas amphetamine produces more of the type I symptoms . Since PCP isknown to block the NMDA receptor, this suggests a possible role for excitatory aminoacids
in the etiology of schizophrenia
more of the type I symptoms. Since LSD is a serotonin
receptor agonist, this
suggests a possible role for serotonin in schizophrenia.
Side effects of neuroleptic treatment
CNS-mediated decrease in blood pressurealpha blockadeboth of above can contribute to hypotension and reflex tachycardiamuscarinic blockadeconstipationdecreased sweating
Short-term: Parkinsonian symptoms. C
an treat with muscarinic blockers (e.g.,benztropine: Cogentin
) can potentiate CNS depressants such as alcohol and barbiturates
Longer-term: tardive dyskinesia
(TD). No generally effective treatment. May be relatedto DA receptor blockade in the striatum.
Is it possible to block DA receptors in other brain areas without blocking in the striatumand still get clinical improvement? Clozapine
(Clozaril) has a higher D /D blocking ratio
than classical neuroleptics. D is high in the frontal cortex; D is high in the striatum. D
is high in the accumbens and low in the striatum (also a target for clozapine?). Clozapine doesn’t produce as much TD as classical neuroleptics, and can treat about35% of patients who don’t respond clinically to the classics. Clozapine also blocks 5-HT2receptors; could this also relate to clinical profile?
(Zyprexa) is related to clozapine, but doesn’t lower white blood cells
(Risperdal) may also produce less TD: blocks 5-HT , D and H receptors
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