The action of drugs to treat mental illness

• Serotonin, noradrenaline and dopamine are involved in the control of many of our mental states, sometimes acting on their own and at other times acting together.

• These and other neurotransmitters are likely to play a pivotal role in the pathological basis of mental illness and diseases of the brain.

• Much of the evidence for this stems from the fact that most of the effective antidepressant drugs are thought to work by changing either serotonin and/or noradrenaline metabolism, or receptor sensitivity to these neurotransmitters

Definitions

• Ergotropic: Energy expending systems (sympathetic division of the PNS) “Fight or flight”

• Trophotropic: Nutrient accumulating systems (parasympathetic division of the PNS) “Rest and digest”

Neurotransmitter Too little leads to: Too much leads to: Acetylcholine Memory impairment

Depression Aggression Depression

Dopamine Dementia Depression

Psychosis Anxiety Confusion

Serotonin Depression Aggression

Anxiety

Norepinephrine Depression Dementia

Anxiety

GABA Anxiety Reduced Anxiety Reduced Aggression

Schizophrenia

• http://www.healthscout.com/animation/68/49/main.html

• http://www.abilify.com/abilify/channels/sch_content.jsp?BV_UseBVCookie=Yes&channelName=Schizophrenia%2fSch_Brain_Sch_Abilify&referrer=null

Historical: Drugs to treat schizophrenia

• http://www.pbs.org/wgbh/aso/databank/entries/dh52dr.html

• Histamine is a biogenic amine chemical involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter (Marieb, 2001, p.414). New evidence also indicates that histamine plays a role in chemotaxis of white blood cells.

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N NH2

Histamine

• Histamine is released as a neurotransmitter. The cell bodies of neurons which release histamine are found in the posterior hypothalamus, in various tuberomammillary nuclei. From here, these histaminergic neurons project throughout the brain, to the cortex through the medial forebrain bundle. Histaminergic action is known to modulate sleep.

• Classically, antihistamines (H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance.

• Finally, H3 receptor antagonists (which stimulate histamine release) increase wakefulness.It has been shown that histaminergic cells have the most wakefulness-related firing pattern of any neuronal type thus far recorded. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during REM and non-REM sleep. Histaminergic cells can be recorded firing just before an animal shows signs of waking.

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N NH2

Histamine

• Sexual response:• Research has shown that histamine is released as part of

the human orgasm from mast cells in the genitals, and the histamine release has been connected to the sex flush among women. If this response is lacking while a woman also has trouble achieving orgasm, this may be a sign of histapenia. In such cases, a doctor may prescribe diet supplements with folic acid and niacin (which used in conjunction can increase blood histamine levels and histamine release), or L-histidine. Conversely, men with high histamine levels may suffer from premature ejaculations.

Antibodies and the Immune Response

• Antibodies are manufactured by the lymph system. Antibodies are specialized proteins that the body produces in response to invasion by a foreign substance. The process of antibody formation begins when an antigen stimulates specialized lymphocytes, called B cells, into action. Antibodies then counteract invading

antigens by combining with the antigen to render it harmless to the body.

• Production of white blood cells and antibodies in reaction to an invading disease organism is called an immune response. This response is one of the body's primary and most efficient lines of defense. In most cases, once antibodies have been produced to fight a certain organism, it no longer poses a great threat to the body. That is why one attack of a disease often prevents that same disease from infecting the body again -- the first attack causes production of antibodies that protect the body against subsequent attacks. With measles, for example, antibodies are produced as a result of having the disease or of being immunized with the measles vaccine. These antibodies are able to resist a second attack of the disease.

Antibodies and the Immune Response• Antibodies are not always beneficial. For example, when tissue from

another body, such as a transplanted heart, is introduced, antibodies are produced to destroy the "invader." Transplants usually are made possible only by means of drugs that act against the body's natural immune response. Also, when blood is transfused from one person to another, it must be of a matching type; otherwise, the recipient's immune system will manufacture antibodies to destroy the transfused blood.

• Sometimes, the immune system causes reactions that make the body unusually sensitive to foreign material. When the immune response is disruptive to the body in this way, it is called an allergic reaction. Let's look at this important mechanism, and the types of allergens, in the next section.

Allergic Reaction

• An allergy is a state of special sensitivity to a particular environmental substance, or allergen. An allergic reaction is the body's response to exposure to an allergen.

• Although an allergy can be present almost immediately after exposure to an allergen, it usually develops over time, as the immune system forms antibodies against the foreign substance. Under normal conditions, such antibodies work to protect the body from further attack. In the case of an allergy, however, the antibodies and other specialized cells involved in this protective function trigger an unusual sensitivity, or overreaction, to the foreign substance.

• The antibodies stimulate specialized cells to produce histamine, a powerful chemical. Histamine causes the small blood vessels to enlarge and the smooth muscles (such as those in the airways and the digestive tract) to constrict. Histamine release can also cause other reactions, such as hives.

Allergic Reaction• No one knows why allergies develop, but it is known that an allergy

can appear, disappear, or reappear at any time and at any age. Allergic reactions rarely occur during the first encounter with the troublesome allergen because the body needs time to accumulate the antibodies. Also, an individual's sensitivity to certain allergens seems to be related to a family history of allergies. People who have a tendency to develop allergies are referred to as atopic.

• An allergic reaction can be so mild that it is barely noticeable or so severe that it is life-threatening. An extremely severe allergic reaction, called anaphylactic shock, is marked by breathing difficulties (from swelling of the throat and larynx and narrowing of the bronchial tubes), itching skin, hives, and collapse of the blood vessels, as well as by vomiting, diarrhea, and cramps. This condition can be fatal if not treated immediately.

Allergic reaction: Histamine and Antihistamines

• http://www.healthscout.com/animation/68/20/main.html

• http://pennhealth.com/health_info/animationplayer/allergies.html

Antihistamines to Antipsychotics?

• In the late 1930s, such dicyclic antihistamines as phenbenzamine, diphenhydramine, and mepyramine were in wide clinical use. The antihistamines' most striking clinical side-effect was CNS depression -- drowsiness.

CH2 N

NMe2

Phenbenzamine

ONMe 2

Diphenhydramine

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NMe 2

Mepyramine

O

H3C

Antihistamines to Antipsychotics?

• In common use, the term antihistamine refers only to H1-receptor antagonists, also known as H1-antihistamines. It has been discovered that these H1-antihistamines are actually inverse agonists at the histamine H1-receptor, rather than antagonists per se.

Antihistamines to Antipsychotics?• In the late 1930s, Paul Charpentier had synthesized

the first tricyclic antihistamine, promethazine, which had a strong sedative effect. He then synthesized a variety of promethazine analogues, including chlorpromazine.

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Promethazine(Phenargan)

(currently used as an anti-emetic)

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H3C NMe 2

N

Chlorpromazine

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Cl NMe 2

Antihistamines to Antipsychotics?• http://ajp.psychiatryonline.org/cgi/content/f

ull/160/10/1895?etoc

N

Promethazine(Phenargan)

(currently used as an anti-emetic)

S

H3C NMe 2

N

Chlorpromazine

S

Cl NMe 2

Antihistamines to Antipsychotics?• Chlorpromazine was the first antipsychotic drug,

used during the 1950s and 1960s. Used as chlorpromazine hydrochloride and sold under the tradenames Largactil and Thorazine, it has sedative, hypotensive and antiemetic properties as well as anticholinergic and antidopaminergic effects. It also has anxiolytic (alleviation of anxiety) properties. Today, chlorpromazine is considered a typical antipsychotic.

N

Promethazine(Phenargan)

(currently used as an anti-emetic)

S

H3C NMe 2

N

Chlorpromazine

S

Cl NMe 2

Antihistamines to Antipsychotics?• The drug had been developed by Laboratoires Rhone-Poulenc in 1950

but they sold the rights in 1952 to Smith-Kline & French (today's GlaxoSmithKline). The drug was being sold as an antiemetic when its other use was noted. Smith-Kline was quick to encourage clinical trials and in 1954 the drug was approved in the US for psychiatric treatment. The effect of this drug in emptying psychiatric hospitals has been compared to that of penicillin and infectious diseases.[1] Over 100 million people were treated but the popularity of the drug fell from the late 1960s as the severe extrapyramidal side effects and tardive dyskinesia became more of a concern. From chlorpromazine a number of other similar neuroleptics were developed (e.g. triflupromazine, trifluoperazine).

N

Promethazine(Phenargan)

(currently used as an anti-emetic)

S

H3C NMe 2

N

Chlorpromazine

S

Cl NMe 2

Antihistamines to Antipsychotics?• Previously used as an antihistamine and antiemetic its effects on mental

state were first reported by the French doctor Henri Laborit in 1951 or 1952 (different sources) as sedation without narcosis.

• It became possible to cause 'artificial hibernation' in patients, if used as a cocktail together with pethidine and hydergine.

• Patients with shock, severe trauma or burns, become, if treated so, sedated, without anxiety and unresponsive/indifferent to painful external stimuli like minor surgical interventions.

• The first published clinical trial was that of Jean Delay and Pierre Deniker at Ste. Anne H 冱 pital in Paris in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine.

• Drug treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behavior. Ironically, the antipsychotic properties of chlorpromazine appear to be unrelated to its sedative properties. During long term therapy some tolerance to the sedative effect develops.

Chlorpromazine

• Chlorpromazine substituted and eclipsed the old therapies of electro and insulin shocks and other methods such as psychosurgical means (lobotomy) causing permanent brain injury. Before the era of neuroleptics, starting with chlorpromazine, positive long-term results for psychotic patients were only 20%.

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Chlorpromazine

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Cl NMe 2