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Friday, May 15, 2009

PHARMACO THERAPY OF SCHIZOPHRENIA


PHARMACO THERAPY OF SCHIZOPHRENIA
C. Jovi John, Anil Babu
National College of Pharmacy, Manassery, Calicut

Cite this: C. Jovi John, Anil Babu, "PHARMACO THERAPY OF SCHIZOPHRENIA", B. Pharm Projects and Review Articles, Vol. 1, pp. 592-630, 2006. (http://farmacists.blogspot.in/)
 

 
INTRODUCTION

 

    Schizophrenia is found all over the world. The severity of the symptoms and long-lasting, chronic pattern of schizophrenia often cause a high degree of disability. Medications and other treatments for schizophrenia, when used regularly and as prescribed, can help reduce and control the distressing symptoms of the illness. However, some people are not greatly helped by available treatments or may prematurely discontinue treatment because of unpleasant side effects or other reasons. Even when treatment is effective, persisting consequences of the illness - lost opportunities, stigma, residual symptoms, and medication side effects - may be very troubling.

 
DEFINITION

 

    Delusions are false personal beliefs that are not subject to reason or contradictory evidence and are not explained by a person's usual cultural concepts. Delusions may take on different themes. For example, patients suffering from paranoid-type symptoms - roughly one-third of people with schizophrenia - often have delusions of persecution, or false and irrational beliefs that they are being cheated, harassed, poisoned, or conspired against

 

MIOLOGY

 
    Schizophrenia is a chronic, severe, and disabling brain disease. Approximately 1 percent of the population develops schizophrenia during their lifetime - more than 2 million Americans suffer from the illness in a given year. Although schizophrenia affects men and women with equal frequency, the disorder often appears earlier in men, usually in the late teens or early twenties, than in women, who are generally affected in the twenties to early thirties. People with schizophrenia often suffer terrifying symptoms such as hearing internal voices not heard by others, or believing that other people are reading their minds, controlling their thoughts, or plotting to harm them. These symptoms may leave them fearful and withdrawn. Their speech and behavior can be so disorganized that they may be incomprehensible or frightening to others. Available treatments can relieve many symptoms, but most people with schizophrenia continue to suffer some symptoms throughout their lives; it has been estimated that no more than one in five individuals recovers completely.

 
ETIOLOGY

 
ENVIRONMENTAL FACTORS

 
    Some aspects of the behavior, personality or attitudes of one or both parents or of specifying modes of family interactions play an etiological role in schizophrenia.

 
NEUROLOGICAL FACTORS

 
    Cranical CT Scan, MRI Scan and post mortem studies show enlarged ventricles and mild cortical atrophy or some patients with schizophrenia. PET (Positron Emission Tomography) show hypofrontality and decreased glucose utilization in the dominant temporal lobe. Patients with chronic temporal lobe epilepsy have an increased risk of developing schizophrenia symptoms and so do patients with Hurelington's chorea. Compared with normal people schizophrenia patients generally gave increased amounts of theta activity, fast activity and paroxysmal activity in their EEG.

 
PRECIPITATING FACTORS :-

 
  1. STRESS : Increased number of stressful events in life before the onset or relapse probably has a triggering effect on the onset of schizophrenia, in a vulnerable person.

 
  1. PHYSICAL ILLNESS :
    When schizophrenia follows closely on physical illness or child bearing, the association seems usually to be due to general stressful psychological and physiological factors rather that due to any specific causative agent.

 
PERPETUATING FACTORS :

 
  1. SOCIAL FACTORS
    Although the prevalence of schizophrenia is quite uniform across cultures, it was found to be more common in lower socioeconomic status. This is now explained due to a downward social drift which is a result of schizophrenia rather than its cause.

     
    High rates of schizophrenia have been reported among migrants. This may be probably due to a disproportionate migration of people, who are unsettled because they are becoming mentally ill. Effect of new environment may also play a part in provoking illness in predisposed people.

     
    Retrospective study comparing schizophrenics with controls suggested that social isolation is living alone, unmarried and with few friends also contributed to the disease.

     

     

     
  2. FAMILY INFLUENCES

 
  1. Deviant Role Relationships

     
    Two types of abnormal family pattern were reported. (i) Marital skew in which one parent yielded to the other's eccentricities, which dominated the family (ii) Marital schism in which the parents maintained contrary views so that the chills had divided loyalties.

 
  1. Disordered Family Communication
    Studies proved that children of parents having amorphous communications (vague, indefinite, loose) and fragmented communications (early disrupted, poorly integrated and lacking closure) have more chance of developing schizophrenia.

 

 
    There is no known single cause of schizophrenia. Many diseases, such as heart disease, result from an interplay of genetic, behavioral, and other factors; and this may be the case for schizophrenia as well. Scientists do not yet understand all of the factors necessary to produce schizophrenia, but all the tools of modern biomedical research are being used to search for genes, critical moments in brain development, and other factors that may lead to the illness.

 
PATHOPHYSIOLOGY
    Computerized axial tomography (CAT) scans and magnetic resonace imageing(MRI) Show increased ventricular size,particularly in the third and lateral ventricles, in subtypes of schizophrenias.recent studies also shows a small but definite decreased in brain size as compared to matched controls. This changes appears to be consistent with brain asymmetry,the ventricular enlargement being most pronounced in the left temporal horn,and the decreased cortical size being most obvious in the left temporal lobe. These changes appears to correspond with changes in neuropsychologicial testing, and these patiant may have poor response with tradional antipsychotic medications. Decreased cortical thickness reflects a decreased in the space between nurons rather than a decreased in the number of nurons in the prefrontal lobe cortex. This may reselted in decreased number of axonal and dendritic a communication between cells and there fore, a loss of connectivity that could be important with respect to neuronal adaptivity and CNS homeostasis .this changes are likely consistent with the effidence for abnormal neuronal pruning.

 
    Serotonergic receptor are present on dopaminergic axon and it is known that stimulation of these receptors will decreased DA release, at least in the striatum.although some what more diffuse the distibution of serotonergic nurons is similar to that of dopaminergic nurons thus allowing these two neurotransmitter systems to innervrate the same area .serotonin and D4 receapter have been found to be colocalized in the cortex.

 
    Schioprenia patients with abnormal brain scans have higher whole blood 5HT concentration, and these concentration are correlated with increased ventricular size. A typical antipsychotics with potent 5HT2 receptor antagonist effects reverse worsening of symptomatology induced by 5HT antagonist in schizophrenic patients.

 
    Increasing evidence supports the prescence of a DA receptor defect in schizophrenia. Numerous positron emission tomography(PET) studies have shown regional brain upnormalities, included increased glucose metabolism in the frontal lobe and left temporal lobe. This may indicate dopaminergic hypofunction in the head of the nucleus and dopaminergic hypofunction in the frontal emporal regions.PET studies assessing difunction suggested that sub population of the sehizorphernic may have decreased densities of D1 recepetor in the croted nucleus and pre fontal cortex. The hetrogenicity in the classical presentation of schizophrenia it has also been suggested that the DA hypothesis may be more applicable to nurolepetic response psychosis,with masteble different etiologies possible being responsible for casing schizophrenia.

 
    It is currently belived that the antipsychotic drugs block dopeamin reseptors which are mainly presented in the mesolimbic systems,which accounts for the antipsychotic activity while the blockade of D2 receptor in the extrapyramidal side effects. The newer or a typical antipsychotic particularly act on SHT2 receptors. Typical antipsychotic are effective in treating positive symptoms of schizophrenia where as a typical drugs are effective in treating both positive and negative systems with lesser side effects. Clozapine is effective in the manegement of treatment of resistant schizophrenia.

 
    Scientists are studying genetic factors in schizophrenia. It appears likely that multiple genes are involved in creating a predisposition to develop the disorder. In addition, factors such as prenatal difficulties like intrauterine starvation or viral infections, perinatal complications, and various nonspecific stressors, seem to influence the development of schizophrenia. However, it is not yet understood how the genetic predisposition is transmitted, and it cannot yet be accurately predicted whether a given person will or will not develop the disorder.
    Several regions of the human genome are being investigated to identify genes that may confer susceptibility for schizophrenia. The strongest evidence to date leads to chromosomes 13 and 6 but remains unconfirmed.
    Basic knowledge about brain chemistry and its link to schizophrenia is expanding rapidly. Neurotransmitters, substances that allow communication between nerve cells, have long been thought to be involved in the development of schizophrenia. It is likely, although not yet certain, that the disorder is associated with some imbalance of the complex, interrelated chemical systems of the brain, perhaps involving the neurotransmitters dopamine and glutamate. This area of research is promising.

 
    Developmental neurobiologists funded by the National Institute of Mental Health (NIMH) have found that schizophrenia may be a developmental disorder resulting when neurons form inappropriate connections during fetal development. These errors may lie dormant until puberty, when changes in the brain that occur normally during this critical stage of maturation interact adversely with the faulty connections. This research has spurred efforts to identify prenatal factors that may have some bearing on the apparent developmental abnormality.

 

SIGNS AND SYMPTOMS
    The first signs of schizophrenia often appear as confusing, or even shocking, changes in behavior. Coping with the symptoms of schizophrenia can be especially difficult for family members who remember how involved or vivacious a person was before they became ill. The sudden onset of severe psychotic symptoms is referred to as an "acute" phase of schizophrenia. "Psychosis," a common condition in schizophrenia, is a state of mental impairment marked by hallucinations, which are disturbances of sensory perception, and/or delusions, which are false yet strongly held personal beliefs that result from an inability to separate real from unreal experiences. Less obvious symptoms, such as social isolation or withdrawal, or unusual speech, thinking, or behavior, may precede, be seen along with, or follow the psychotic symptoms.

 
    The individual with "chronic" schizophrenia, or a continuous or recurring pattern of illness, often does not fully recover normal functioning and typically requires long-term treatment, generally including medication, to control the symptoms.
SCHIZOPHRENIA
DSM IV TR DIAGNOSTIC CRITERIA FOR SCHIZOPHRENIA
  1. CHARACTERISTIC SYMPTOMS : Two or more of the following each persisting for a significant portion of at least a 1 month period
1)DELUSIONS
2)HALLUCINATION
3) DISORGNIZED SPEECH
4)GROSSLY DISORGANIZED OR CATIONIC BEHAVIOR
5)NEGATIVE SYMPTOMS

 
  1. SOCIAL/OCCUPATIONAL DYSFUCTION:
For a significant portion of the time since onset of the disorder;one or more major areas of functioning such as work interpersonal relations;or self care are significantly below the level prior to onset.

 
  1. DURATION:Continuous signs of the disorder for at least 6 months. This must include at least 1 monthof symptoms fulfilling criterion . this 6 months may include prodromal or residual symptoms.

 

D)Disorder is not due to medical disorder or substence use.

 

E)Schizoaffective or mood disorder has been excluded

 

F) If a history of a pervasive developmental disorder is present,there must be
Symptoms of hallucinations or delusion present for at least 1 month

 

TREATMENT
How is schizophrenia treated
    Since schizophrenia may not be a single condition and its causes are not yet known, current treatment methods are based on both clinical research and experience. These approaches are chosen on the basis of their ability to reduce the symptoms of schizophrenia and to lessen the chances that symptoms will return.
What about antipsychotic drugs for schizophrenia?

 
    Antipsychotic medications have been available since the mid-1950s. They have greatly improved the outlook for individual patients. These medications reduce the psychotic symptoms of schizophrenia and usually allow the patient to function more effectively and appropriately. Antipsychotic drugs are the best treatment now available, but they do not "cure" schizophrenia or ensure that there will be no further psychotic episodes. The choice and dosage of medication can be made only by a qualified physician who is well trained in the medical treatment of mental disorders. The dosage of medication is individualized for each patient, since people may vary a great deal in the amount of drug needed to reduce symptoms without producing troublesome side effects.
    The large majority of people with schizophrenia show substantial improvement when treated with antipsychotic drugs. Some patients, however, are not helped very much by the medications and a few do not seem to need them. It is difficult to predict which patients will fall into these two groups and to distinguish them from the large majority of patients who do benefit from treatment with antipsychotic drugs.
    A number of new antipsychotic drugs (the so-called "atypical antipsychotics") have been introduced since 1990. The first of these, clozapine (Clozaril®), has been shown to be more effective than other antipsychotics, although the possibility of severe side effects - in particular, a condition called agranulocytosis (loss of the white blood cells that fight infection) - requires that patients be monitored with blood tests every one or two weeks. Even newer antipsychotic drugs, such as risperidone (Risperdal®), olanzapine (Zyprexa®), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify) are safer than the older drugs or clozapine, and they also may be better tolerated. They may or may not treat the illness as well as clozapine, however. Several additional antipsychotics are currently under development.
    Antipsychotic drugs are often very effective in treating certain symptoms of schizophrenia, particularly hallucinations and delusions; unfortunately, the drugs may not be as helpful with other symptoms, such as reduced motivation and emotional expressiveness. Indeed, the older antipsychotics (which also went by the name of "neuroleptics"), medicines like haloperidol (Haldol®) or chlorpromazine (Thorazine®), may even produce side effects that resemble the more difficult to treat symptoms. Often, lowering the dose or switching to a different medicine may reduce these side effects; the newer medicines, including olanzapine (Zyprexa®), quetiapine (Seroquel®), and risperidone (Risperdal®), appear less likely to have this problem. Sometimes when people with schizophrenia become depressed, other symptoms can appear to worsen. The symptoms may improve with the addition of an antidepressant medication.
    Patients and families sometimes become worried about the antipsychotic medications used to treat schizophrenia. In addition to concern about side effects, they may worry that such drugs could lead to addiction. However, antipsychotic medications do not produce a "high" (euphoria) or addictive behavior in people who take them.
    Another misconception about antipsychotic drugs is that they act as a kind of mind control, or a "chemical straitjacket." Antipsychotic drugs used at the appropriate dosage do not "knock out" people or take away their free will. While these medications can be sedating, and while this effect can be useful when treatment is initiated particularly if an individual is quite agitated, the utility of the drugs is not due to sedation but to their ability to diminish the hallucinations, agitation, confusion, and delusions of a psychotic episode. Thus, antipsychotic medications should eventually help an individual with schizophrenia to deal with the world more rationally.
How long should schizophrenic patients take antipsychotic drugs?
    Antipsychotic medications reduce the risk of future psychotic episodes in patients who have recovered from an acute episode. Even with continued drug treatment, some people who have recovered will suffer relapses. Far higher relapse rates are seen when medication is discontinued. In most cases, it would not be accurate to say that continued drug treatment "prevents" relapses; rather, it reduces their intensity and frequency. The treatment of severe psychotic symptoms generally requires higher dosages than those used for maintenance treatment. If symptoms reappear on a lower dosage, a temporary increase in dosage may prevent a full-blown relapse.
    Because relapse of illness is more likely when antipsychotic medications are discontinued or taken irregularly, it is very important that people with schizophrenia work with their doctors and family members to adhere to their treatment plan. Adherence to treatment refers to the degree to which patients follow the treatment plans recommended by their doctors. Good adherence involves taking prescribed medication at the correct dose and proper times each day, attending clinic appointments, and/or carefully following other treatment procedures. Treatment adherence is often difficult for people with schizophrenia, but it can be made easier with the help of several strategies and can lead to improved quality of life.
    There are a variety of reasons why people with schizophrenia may not adhere to treatment. Patients may not believe they are ill and may deny the need for medication, or they may have such disorganized thinking that they cannot remember to take their daily doses. Family members or friends may not understand schizophrenia and may inappropriately advise the person with schizophrenia to stop treatment when he or she is feeling better. Physicians, who play an important role in helping their patients adhere to treatment, may neglect to ask patients how often they are taking their medications, or may be unwilling to accommodate a patient's request to change dosages or try a new treatment. Some patients report that side effects of the medications seem worse than the illness itself. Further, substance abuse can interfere with the effectiveness of treatment, leading patients to discontinue medications. When a complicated treatment plan is added to any of these factors, good adherence may become even more challenging.
    Fortunately, there are many strategies that patients, doctors, and families can use to improve adherence and prevent worsening of the illness. Some antipsychotic medications, including haloperidol (Haldol®), fluphenazine (Prolixin®), perphenazine (Trilafon®) and others, are available in long-acting injectable forms that eliminate the need to take pills every day. A major goal of current research on treatments for schizophrenia is to develop a wider variety of long-acting antipsychotics, especially the newer agents with milder side effects, which can be delivered through injection. Medication calendars or pill boxes labeled with the days of the week can help patients and caregivers know when medications have or have not been taken. Using electronic timers that beep when medications should be taken, or pairing medication taking with routine daily events like meals, can help patients remember and adhere to their dosing schedule. Engaging family members in observing oral medication taking by patients can help ensure adherence. In addition, through a variety of other methods of adherence monitoring, doctors can identify when pill taking is a problem for their patients and can work with them to make adherence easier. It is important to help motivate patients to continue taking their medications properly.
    In addition to any of these adherence strategies, patient and family education about schizophrenia, its symptoms, and the medications being prescribed to treat the disease is an important part of the treatment process and helps support the rationale for good adherence.

 
  1. MONOGENIC THEORY
    This theory states that due to a single gene that is recessive, dominant or intermediate, schizophrenia is a specific inherited disease. It is further hypotherised that the genotype is characterized by an undiscovered metabolic error that leads to schizophrenia illness.

     
  2. TWO GENE THEORY
    A two gene theory has been proposed, in which each gene is distinct, is inherited independently and has a mutant counterpart. An different combinations, these two genes and their counterparts may lead to a normal or creative person, or a mentally retarded or autistic child.

     
  3. POLYGENIC THEORY
        This theory is based on concept that several genes located at different parts of chromosomes may express themselves in a like manner and may act in a cumulative fashion. Of persons have too many of these genes, they are liable to have schizophrenia traits.

 

 
THE MAIN NEUROCHEMICAL THEORIES ARE
  • DOPAMINE THEORY
  • GLUTAMATE THEORY
  • TRANSMETHYLATION

 
DOPAMINE THEORY
    This was proposed by Carlsson. Dopamine over activity can produce behavioural syndrome seen in schizophrenia. Potent D2 receptor against (Apomorphere, Bromocripine) can exacerbate the symptoms of schizophrenia patients. There are reports of increased Dopamine receptor density in the caudate nucleus, putamen and nucleus accumbens, of increased concentration of dopamine in the amygdale of the left hemisphere. The best evidence for increased dopamine release in schizophrenia patients comes from imaging studies.

 
GLUTAMATE THEORY

 
Another transmitter implicated in the pathophysiology of schizophrenia is glutamate. The glutamate NMDA receptor antagonists, such as phencyclidine, Retamine and dizocilpine produce psychotic symptoms (eg: hallucination, thought disorder) in humans and reduced glutamate concentrations and glutamate receptor densities have been reported in post mortem brains of schizophrenics.

 

 
TRANSMETHYLATION

 
    Mesclaine, a hallucinogen is a methylated substance with a chemical relationship to dopamine and nor adrenaline. Osmond suggested that abnormal methylated metabolites might be formed in the brain and might produce the psychological symptoms of schizophrenia. Some support for this theory appeared to be provided by the finding of methylated substance in the urine of some schizophrenia.

 
Dopaminergic receptor and dopaminergic neuron.
There are two main receptor type.
D1     –    which increases adenyl cyclare activity.
D2     –    which medicate main presynaptic and post synaptic inhibitory         action of dopamine.
D3 and D4 receptors belong to the same group as D2. The antipsychotic drug probably owe their therapeutic effect mainly to blockade of D2 receptors.

 
    As stated above antipsychotic effect require about 80% block of D2 receptors. Antagonism at D2 receptors can be measuered in experimental antigen by various tests. Such as inhibition of amphetamine induced stereotypic behaviour or of apomorpheine induced turning behaviour in animals with unilateral strial lesion and in vitro by ability to inhibit the binding of radioactive D2 antagonist. (eg: speroperidof) to brain membrane fragments. The main groups phenothiazeries, thioxanthenes and butyrophenones show same preference for D2 over D1 receptors. Some of the newer agents (eg: salpiride, remoxioride) are highly selective for D2 receptors where as clozapine is relatively nonselective between D1 and D2 that has high affinity for D4.

 
All antipsychotic drugs have been found initially to increase the rate of production of dopamine in regions containing dopaminergic nerve terminals. This is detected by an increase in tyrosme hydroxylase activity and an increase in the concentration of dopamine metabolites, homoranillic acid and DOPAC. At the same time electrical activity recording has shown that the activity of midbrain dopaminergic neurons in the substantia nigra and ventral tegmentum is initially increased by these drugs. Effect on the latter as believed to correlate with antipsychotic effect whereas effect on the former are responsible for the unwanted motor effect produced by antipsychotic drugs. Thus haloperidol a classical drug with market unwanted motor effects acts on both sides of dopamine neurons whereas dozapine an atypical drug which lack motor effects affects only the ventral segmental neurons.

 
Antipsychotic drugs like many neuroactive compounds, takes several weeks to take effect eventhough their receptor blocking action is immediate. When antipsychotic drugs are adiministered chronically the increase in activity of dopaminergic neurons is transient and given way after about 3 weeks to inhibition at which time both the biochemical and electrophysiological markers of activity decline.

 
Another delayed effect seen with chronic administration of antipsychotic drugs in proliferation of dopamine receptors detectable as an increase in haloperidol binding and also a super sensitivity to dopamine some what akin to the phenomenon of denervation sensitivity. At present neither the mechanism of the delayed effects nor their relationship to the chemical response is at all well understood.

 
Antipsychotic drugs show varying pattern of selectivity in their response blocking effects. Some having high affinity for 5-HT and / or D4 receptors. The connection between their receptor specificity and their functional and therapeutic effects despite a wealth of fine argument, remain hidden where it understood, we should not have to fall back in disperation on words like atypical to hide our uncertainty.

 

 


 


 

ANTIPSYCHOTIC DRUGS USED IN SCHIZOPHRENIA:-

 


 


 

Category 
Drugs 


Typical antipsychotics 


Chlorpromazine
Loxapine
Penfluridol
Fluphenazine
Trifluperidol
Triflupromazine
Haloperidol
Thioridazine
Trifluoperazine
Pimozide
Zuclopenthixol
Prochlorperazine
Flupenthixol


Atypical antipsychotics 


Clozapine
Olanzapine
Risperidone
Ziprasidone
Quetiapine


Deport preparations  


Fluphenazine decanoate
Haloperidol decanoate
Flupenthixol decanoate
Zuclopenthixol decanoate
Penfluridol
Pimozide

 


 

MECANISM OF ACTION OF ANTIPSYCHOTIC DRUGS

 
    The exact mechanism of action of antipsychotic remains unclear.however it is corrently belived that the antipsychotic drugs block dopamine(D2) receptors(antidopaminergic activity)which are mainly presented in the mesolimbic system,which accounts for the antipsychotic activity while the blocked of D2 reseptors in the extrapyramidal system accounts for the extrapyramidal side effects the newer or a typical a antipsychotic particularly act on 5HT 2 receptors typical antipsychotic are effective in treating positive symptoms of schizophrenia where as a typical drugs are effective in treating both positive and negative symptoms with lesser side effects CLOZAPINE is effective in the manegement of treatment resistant schizophrenia .

 

WHAT ABOUT DRUG SIDE EFFECTS?
    Antipsychotic drugs, like virtually all medications, have unwanted effects along with their beneficial effects. During the early phases of drug treatment, patients may be troubled by side effects such as drowsiness, restlessness, muscle spasms, tremor, dry mouth, or blurring of vision. Most of these can be corrected by lowering the dosage or can be controlled by other medications. Different patients have different treatment responses and side effects to various antipsychotic drugs. A patient may do better with one drug than another.
The long-term side effects of antipsychotic drugs may pose a considerably more serious problem. Tardive dyskinesia (TD) is a disorder characterized by involuntary movements most often affecting the mouth, lips, and tongue, and sometimes the trunk or other parts of the body such as arms and legs. It occurs in about 15 to 20 percent of patients who have been receiving the older, "typical" antipsychotic drugs for many years, but TD can also develop in patients who have been treated with these drugs for shorter periods of time. In most cases, the symptoms of TD are mild, and the patient may be unaware of the movements.
Antipsychotic medications developed in recent years all appear to have a much lower risk of producing TD than the older, traditional antipsychotics. The risk is not zero, however, and they can produce side effects of their own such as weight gain. In addition, if given at too high of a dose, the newer medications may lead to problems such as social withdrawal and symptoms resembling Parkinson's disease, a disorder that affects movement. Nevertheless, the newer antipsychotics are a significant advance in treatment, and their optimal use in people with schizophrenia is a subject of much current research.
SUBSTANCE ABUSE
    Substance abuse is a common concern of the family and friends of people with schizophrenia. Since some people who abuse drugs may show symptoms similar to those of schizophrenia, people with schizophrenia may be mistaken for people "high on drugs." While most researchers do not believe that substance abuse causes schizophrenia, people who have schizophrenia often abuse alcohol and/or drugs, and may have particularly bad reactions to certain drugs. Substance abuse can reduce the effectiveness of treatment for schizophrenia. Stimulants (such as amphetamines or cocaine) may cause major problems for patients with schizophrenia, as may PCP or marijuana. In fact, some people experience a worsening of their schizophrenic symptoms when they are taking such drugs. Substance abuse also reduces the likelihood that patients will follow the treatment plans recommended by their doctors.
  • Schizophrenia and Nicotine: The most common form of substance use disorder in people with schizophrenia is nicotine dependence due to smoking. While the prevalence of smoking in the U.S. population is about 25 to 30 percent, the prevalence among people with schizophrenia is approximately three times as high. Research has shown that the relationship between smoking and schizophrenia is complex. Although people with schizophrenia may smoke to self medicate their symptoms, smoking has been found to interfere with the response to antipsychotic drugs. Several studies have found that schizophrenia patients who smoke need higher doses of antipsychotic medication. Quitting smoking may be especially difficult for people with schizophrenia, because the symptoms of nicotine withdrawal may cause a temporary worsening of schizophrenia symptoms. However, smoking cessation strategies that include nicotine replacement methods may be effective. Doctors should carefully monitor medication dosage and response when patients with schizophrenia either start or stop smoking

 
WHAT ABOUT PSYCHOSOCIAL TREATMENTS FOR SCHIZOPHRENIA?
    Antipsychotic drugs have proven to be crucial in relieving the psychotic symptoms of schizophrenia - hallucinations, delusions, and incoherence - but are not consistent in relieving the behavioral symptoms of the disorder. Even when patients with schizophrenia are relatively free of psychotic symptoms, many still have extraordinary difficulty with communication, motivation, self-care, and establishing and maintaining relationships with others. Moreover, because patients with schizophrenia frequently become ill during the critical career-forming years of life (e.g., ages 18 to 35), they are less likely to complete the training required for skilled work. As a result, many with schizophrenia not only suffer thinking and emotional difficulties, but lack social and work skills and experience as well.
    It is with these psychological, social, and occupational problems that psychosocial treatments may help most. While psychosocial approaches have limited value for acutely psychotic patients (those who are out of touch with reality or have prominent hallucinations or delusions), they may be useful for patients with less severe symptoms or for patients whose psychotic symptoms are under control. Numerous forms of psychosocial therapy are available for people with schizophrenia, and most focus on improving the patient's social functioning - whether in the hospital or community, at home, or on the job. Some of these approaches are described here. Unfortunately, the availability of different forms of treatment varies greatly from place to place.

 
REHABILITATION
    Broadly defined, rehabilitation includes a wide array of non-medical interventions for those with schizophrenia. Rehabilitation programs emphasize social and vocational training to help patients and former patients overcome difficulties in these areas. Programs may include vocational counseling, job training, problem-solving and money management skills, use of public transportation, and social skills training. These approaches are important for the success of the community-centered treatment of schizophrenia, because they provide discharged patients with the skills necessary to lead productive lives outside the sheltered confines of a mental hospital.
INDIVIDUAL PSYCHOTHERAPY
    Individual psychotherapy involves regularly scheduled talks between the patient and a mental health professional such as a psychiatrist, psychologist, psychiatric social worker, or nurse. The sessions may focus on current or past problems, experiences, thoughts, feelings, or relationships. By sharing experiences with a trained empathic person - talking about their world with someone outside it - individuals with schizophrenia may gradually come to understand more about themselves and their problems. They can also learn to sort out the real from the unreal and distorted. Recent studies indicate that supportive, reality-oriented, individual psychotherapy, and cognitive-behavioral approaches that teach coping and problem-solving skills, can be beneficial for outpatients with schizophrenia. However, psychotherapy is not a substitute for antipsychotic medication, and it is most helpful once drug treatment first has relieved a patient's psychotic symptoms.

 
FAMILY EDUCATION
    Very often, patients with schizophrenia are discharged from the hospital into the care of their family; so it is important that family members learn all they can about schizophrenia and understand the difficulties and problems associated with the illness. It is also helpful for family members to learn ways to minimize the patient's chance of relapse - for example, by using different treatment adherence strategies - and to be aware of the various kinds of outpatient and family services available in the period after hospitalization. Family "psychoeducation," which includes teaching various coping strategies and problem-solving skills, may help families deal more effectively with their ill relative and may contribute to an improved outcome for the patient.
SELF-HELP GROUPS
    Self-help groups for people and families dealing with schizophrenia are becoming increasingly common. Although not led by a professional therapist, these groups may be therapeutic because members provide continuing mutual support as well as comfort in knowing that they are not alone in the problems they face. Self-help groups may also serve other important functions. Families working together can more effectively serve as advocates for needed research and hospital and community treatment programs. Patients acting as a group rather than individually may be better able to dispel stigma and draw public attention to such abuses as discrimination against the mentally ill.
    Family and peer support and advocacy groups are very active and provide useful information and assistance for patients and families of patients with schizophrenia and other mental disorders. A list of some of these organizations is included at the end of this document.

 
WHAT CAN OTHERS DO TO HELP SOMEONE WITH SCHIZOPHRENIA?
    A patient's support system may come from several sources, including the family, a professional residential or day program provider, shelter operators, friends or roommates, professional case managers, churches and synagogues, and others. Because many patients live with their families, the following discussion frequently uses the term "family." However, this should not be taken to imply that families ought to be the primary support system.
    There are numerous situations in which patients with schizophrenia may need help from people in their family or community. Often, a person with schizophrenia will resist treatment, believing that delusions or hallucinations are real and that psychiatric help is not required. At times, family or friends may need to take an active role in having them seen and evaluated by a professional. The issue of civil rights enters into any attempts to provide treatment. Laws protecting patients from involuntary commitment have become very strict, and families and community organizations may be frustrated in their efforts to see that a severely mentally ill individual gets needed help. These laws vary from State to State; but generally, when people are dangerous to themselves or others due to a mental disorder, the police can assist in getting them an emergency psychiatric evaluation and, if necessary, hospitalization. In some places, staff from a local community mental health center can evaluate an individual's illness at home if he or she will not voluntarily go in for treatment.
    Sometimes only the family or others close to the person with schizophrenia will be aware of strange behavior or ideas that the person has expressed. Since patients may not volunteer such information during an examination, family members or friends should ask to speak with the person evaluating the patient so that all relevant information can be taken into account.
Ensuring that a person with schizophrenia continues to get treatment after hospitalization is also important. A patient may discontinue medications or stop going for follow-up treatment, often leading to a return of psychotic symptoms. Encouraging the patient to continue treatment and assisting him or her in the treatment process can positively influence recovery. Without treatment, some people with schizophrenia become so psychotic and disorganized that they cannot care for their basic needs, such as food, clothing, and shelter. All too often, people with severe mental illnesses such as schizophrenia end up on the streets or in jails, where they rarely receive the kinds of treatment they need.
    Those close to people with schizophrenia are often unsure of how to respond when patients make statements that seem strange or are clearly false. For the individual with schizophrenia, the bizarre beliefs or hallucinations seem quite real - they are not just "imaginary fantasies." Instead of "going along with" a person's delusions, family members or friends can tell the person that they do not see things the same way or do not agree with his or her conclusions, while acknowledging that things may appear otherwise to the patient.
    It may also be useful for those who know the person with schizophrenia well to keep a record of what types of symptoms have appeared, what medications (including dosage) have been taken, and what effects various treatments have had. By knowing what symptoms have been present before, family members may know better what to look for in the future. Families may even be able to identify some "early warning signs" of potential relapses, such as increased withdrawal or changes in sleep patterns, even better and earlier than the patients themselves. Thus, return of psychosis may be detected early and treatment may prevent a full-blown relapse. Also, by knowing which medications have helped and which have caused troublesome side effects in the past, the family can help those treating the patient to find the best treatment more quickly.
    In addition to involvement in seeking help, family, friends, and peer groups can provide support and encourage the person with schizophrenia to regain his or her abilities. It is important that goals be attainable, since a patient who feels pressured and/or repeatedly criticized by others will probably experience stress that may lead to a worsening of symptoms. Like anyone else, people with schizophrenia need to know when they are doing things right. A positive approach may be helpful and perhaps more effective in the long run than criticism. This advice applies to everyone who interacts with the person.

 
WHAT IS THE OUTLOOK FOR SCHIZOPHRENIA?
    The outlook for people with schizophrenia has improved over the last 25 years. Although no totally effective therapy has yet been devised, it is important to remember that many people with the illness improve enough to lead independent, satisfying lives. As we learn more about the causes and treatments of schizophrenia, we should be able to help more patients achieve successful outcomes.
    Studies that have followed people with schizophrenia for long periods, from the first episode to old age, reveal that a wide range of outcomes is possible. When large groups of patients are studied, certain factors tend to be associated with a better outcome - for example, a pre-illness history of normal social, school, and work adjustment. However, the current state of knowledge, does not allow for a sufficiently accurate prediction of long-term outcome.
    Given the complexity of schizophrenia, the major questions about this disorder - its cause or causes, prevention, and treatment - must be addressed with research. The public should beware of those offering "the cure" for (or "the cause" of) schizophrenia. Such claims can provoke unrealistic expectations that, when unfulfilled, lead to further disappointment. Although progress has been made toward better understanding and treatment of schizophrenia, continued investigation is urgently needed. As the lead Federal agency for research on mental disorders, NIMH conducts and supports a broad spectrum of mental illness research from molecular genetics to large-scale epidemiologic studies of populations. It is thought that this wide-ranging research effort, including basic studies on the brain, will continue to illuminate processes and principles important for understanding the causes of schizophrenia and for developing more effective treatments.

 


 
CHARACTERISTIC OF ANTIPSYCHOTIC DRUG

 

 

 
DRUG                    RECEPTOR AFFINITY

D1D2X-Adr.H1M Ach5 HT2CLASSICAL :-

CHLORPROMAZINE
THIORIDAZINE
HALOPERIDOL
FLUPENTHIXON

++
+
+
++

+++
++
+++
+++

+++
+++
++
++

++
+
-
++

++
++
+
-

++
++
+
+++


ATYPICAL :-

SULPIRIDE
CLOZAPINE
RISERIDONE
SERTIDONE
QUETIAPINE

-
++
-
-
-

+++
++
++
++
+

-
++
++
++
+++

-
++
++
-
-

-
++
++
-
+

-
+++
+++
+++
+

D1, D2        -    Dopamine receptors
X –adr        -    Adrenoreceptor
M-Ach        -    Muscarinic acetylcholine
Manza
Brings back happiness





Excellent tolerability profile offering high patient acceptability.
 

 
  • Appropriate treatment choice in patients who do not respond to prior anti-psychotic therapy.

 

  • Well tolerated and reduced prolaction when compared to Haloperidol.


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 


 


 


 


 


 


 


 


 


 

 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 



 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 

CLINICAL TYPES AND DIAGNOSTIC CRITERIA FOR SCHIZOPHRENIA

 

    According to international statistical classification of Disease and Related Health Problems, tenth division, (ICD-10) WHO, Geneva, 199244, Schiophernia can be classified into paranoid, hebephrenic, catatonic, undiffernetialted, residual, post schizophrenia and other schizophrenia, schizophrenia unspecified. The history of the diagnosis of schizophrenia is often misunderstood, which hs lead t erroneous conclusions about the validity of the diogonostic process45. Throughout most of the teentieth century, there have been international difference among the diagonosticians throughout the world, in the recognition of the typical cases or schizophrenia.

 
    The diagnosis of schizophrenia is more difficult because symptoms of schizophrenia can be similar at times to other major brain disorders such as bipolar disorder or even depression47. Like many mental illness, the diagnosis of schizophrenia is based upon the behaviour of the person, who is being assessed. There are lists of diagnostic criteria which must be met for a person to be diagnosed as having the condition. This depends both on the presence of certain signs and symptoms as well as their duration. The diagnostic instruments of schizophrenia include standardized diagnostic criteria, structured interviews and psychiatric rating scales. The ICD-10 diagnostic criteria published by WHO and diagnostic and statistical manual of mental disorders (DSM-IV), fourth edition, American Psychiatric Association are the two main types of diagnostic criteria which provide characteristic signs and symptoms of schizophrenia and its subtypes. The structured interview such as present state examination (PSE), composite international diagnostic interview (CIDI) schedule for affective disorders and schizophrenia (SADS), diagnostic interview schedule (DIS) and comprehensive assessment of symptoms and history (CASH) are designed to provide comprehensive information base concerning past psychopathlogy and functioning relevant to evaluation of diagnosis, prognosis, overall severity for the symptomatological assessment of the psychiatric illness.

 
    Although the structured interviews and diagnostic criteria are used to make diagnosis to identify broad range of symptoms in patients, rating scales are usually be used in order to measure changes in clinical status overtime. The brief psychiatric rating scale (BPRS), which is the prototype of rating scale, contains scales for rating different symptoms such as conceptual disorganization, blunted affect, emotional withdrawal, distorted thinking, depressed mood and psychic anxiety. The scale for assessment of thought, language and communication, (TLC) was developed to evaluate formal thought disorder in schizophrenia. The scale for assessment of negative symptoms (SANS) was developed in order to provide a comprenhensive method for evaluating negative symptoms and and the scale for assessment of positive symptoms (PANS) for assessing the positive symptoms for schizophrenia. The scale for emotional blunting (SEB) is another scale developed to rate abnormality in affect.

 

 
CLINICAL FEATURES

 
    Schizophrenia is characterized by disturbancesin thotht and verbal behaviour, perception, affect, motor behaviour and relationship to the external world. the diagnosis is entirely clinical and is based on the following clinical features, none of which are pathogomonic alone. The clinical features are thought and speech disorders (autistic thinking, loosening of associations, thought blocking, neologisms, mutism, poverty of speech, enchoalia, preservation, variegation, delusions and ambivalence), disorders of perception (auditory and visual hallucinations), disorders of affect (apathy, emotional blunting and anhedonia), disorders of motor behaviour (either decrease or increase in psychomotor activity) and negative symptoms which include alogia, affective flattening, inattentiveness, anhedonia and avolition-apathy. Delusion, hallucinations and thought disorder are called positive symptoms because these phenomenas are not present in normal individuals.

 
NEUROCHEMICAL BASIS FOR SCHIZOPHRENIA

 
    The major investigation of neurochemical basis for schizophrenia have focused on the deficiency in monomine oxidase (MAO) activity, impairment of noradrenergic function (NA), impairment of neuroactive pepdide systems, impairment of gamma-amino butyric acid (GABA)system function, impairment of serotonergic function, excitatory amino acid systems. The most widely replicated biochemical finding in schizophrenia has been the low peripheral MAO activity in chronic schizophrenics. A low MAO activity has been found in the examination of platelet MAO activity and amine metabolites in cerebrospinal fluid (CSF) of 22 schizophrenia patiets. Owen et al. reported decrease in MAO activities in seven regions of post mortem brains form 39 patients with schizophrenia and 44 control subjects. Stein et al. postulated that a degeneration of the cortical noradrenergic system could account for the lack of goal directed behaviour observed in schizophrenics. They strengthenes this hypothesis by reporting a significant reductionin the activity of dopamine beta hydroxylase (DBH) activity in post modern brain samples form schizophrenics. Hartmann et al. elaborated on the phpotheis of stein and wise by suggesting that a deficit in cortial DBH activity could lead to an increased concentraton of NA in cortical region and that this imbalance in dopamine and NA may be involved in the pathogenesis of schizophrenia.
    
    However, the evidence of a central noradrenergic deficit in schizophrenics is not strong. Cross et al. assessed DBH activity in 6 brain regions form 12 control and 12 schizophrenics and reported no significant difference in DBH activity between controls and schizophrenics in any brain region. There have been several attempts to assess central noadrenergic function in schizophrenia using peripheral body fluids and tissues such as plasma serum and lymphocytes. The results, in general have been equivocal and often of dubious relevance to control noradrenegic function.

 
    The role of neurophetides in schizophrenia, abnormal metabolism of brain opioids, and possibility of altered levels has been extensively studied. Terenius et al. from Sweden reported an increase in endogenous opiod peptide concentration in CSF of schizophrenia patients. Lindstorm et al. investigated schizophrenics and reported two of nine chronic schizophrenia patients, four of six acute schizophrenia patients had elevated CSF fraction of the neuro peptide. However, Naber et al reported significant reduction in CSF opioid activity using a radioreceptor assay in male schizophrenics. This proposal of schizophrenia may be associated with an activity of opioid system has also proved difficult to substantiate clinically. The administration of beta endorphins to schizophrenics has proved inconclusive results. Roberts postulated the reduction of GABA in schizophrenics and suggested that it could be readily verified by measuring the activity of glutamate decarboxylase (GAD), the enzyme that calalases the decarboxylation of glutamate to from GABA and is marker for GABA-ergic neurons.

 
    Subsequently, Bird et al. reported significant reduction in GAD activity in protmorten barin samples from schizophrenics. The CSF level of 87 subjects, 29 normal control subjects, 11 patients with schizophrenia, 26 with depression, 6 with mania and 15 with anorexia nervosa was examined and findings suggested lower GABA level. However, cross et al. found the concentrations of GABA in the brain regions to be similar in control and schizophrenics. Pharmacological evidence does not support a significant reduction in GABA agonists such as baclofen and muscimol does not ameliorate the symptoms.

 
    Reduced plasma concentration of tryptophan, the precursor of 5-hyfroxy tryptamine (5-HT), have been reported in acute schizophrenics, but the therapeutic effectiveness of administrated oral doses of tryptophan, to correct this apparent deficit, has produced equivocal results. A direct investigation of central 5-HT metabolism in schizophrenics was carried out by Joseph et al., who measured the concentration of 5-HT, 5-hydroxy indle acetic acid (5-HIAA) and their precursor tryptophan, in three getions of post mortem brain tissue from 23 controls and 15 schizophrenics, reported that there was no generalized change in 5-HT metabolism in the brain of schizophrenics. Investigation of the concentration of homovanillic acid (HAV-the major end product of dopamine metabolism) in the CSF reveled higher levels of HVA in schizophrenics with family history of schizophrenia. Dopamine receptors have been studied extensively in the brain of schizophrenics, and in general there is a consensus that D2 receptors are at increase in the basal ganglia. Post-mortem studies of dopamine receptors in 15 schizophrenic brains and 15 control brains revealed elevated D2 receptor densities in schizophrenic brains.

 
    Post mortem studies in patients with schizophrenia have revealed variety of abnormalities in glutamate transmission. For example, an increased cortical expression of N-methyl-D-asparate (NMDA) receptor units and glutamate reuptake if frontal cortex, decreased cortial glutamate release and altered concentration of glutamate in schizophrenics are evidenced. In contrast, lateralized changes in glutamate uptake sites have also been observed in other brain regions including the amygdala.

 

 
MANAGEMENT OF SCHIZOPHRENIA

 
    Schizophrenia can be managed by pharmacological intervention, electroconvulsive therapy (ECT), psychosocial treatments like psycho education, group psychotherapy, individual psychotherapy, family therapy and psychosocial psychotherapy. Electroconvulsive therapy involves the induction of a seizure ofr therapeutic purpose by the administration of a variable frequency electrical stimulus shock via electrodes applied to the scalp. The effects of its use in people with schizophrenia, it is less promising. ECT can be tried in patient whose response is poor with antipsychotic drugs. Antipsychotic medication should be administered during and following ECT treatment. Patients should first receive the trials of antipsychotic medications and if these medication arte ineffective, acutely ill patients can be terted with ECT. Thus, ECT is mot offted to persons who have failed to respond to pharmacotherapy, defining a relatively treatment refractory population for ECT.

 
    Most psychotherapy, by themselves, has not been shown to be helpful for treating schizophrenia. Therapies directed at improving family interactions, in conjunction with ongoing medication therapy, however can decrease relapse rate in schizophrenia. Psychoeducation educates the family as well as the patient regarding the nature of illness, its course and treatment, which helps in establishing a good relationship between patient and family. Family therapy is aimed to improve communication, reduce conflict and distress between family members and improve family functioning such as to alleviate the problems that led to the disorder in the identified patient. Several or all of the family members take part in the treatment. Individual psychotherapy is used with the intention of bringing about substantial change in symptoms, identifying personal problems, overcome difficulties in interpersonal relationships or to encourage limited adjustments to specific problems including those of disability physical or mental illness. Other psychosocial therapy includes activity therapy, occupational therapy and psychosocial rehabilitation services.
PHARMACOLOGICAL INTERVENTION:

 
    Prior to 1952, there was no generally applicable, effective pharmacological treatment of schizophrenia. Reserpine (Rauwolfia serpentine extract) had been used with some limited success in india by Sen and Bose and electroconvulsive therapy (ECT) was important in reducing symptoms in most acutely disturbed cases. Lithium, antidepressants and antianxiety drugs have also been used to treat the symptoms of schizophrenia. However these drugs have not proved to be effective alternative to antipsychotic therapy. The discovery of phenothiazine, chlorpromazine, in the early 50's may be the most important single contribution to the treatment of psychiatric illness. Antipsychotics were discovered by Delay andDeniker in 1952 and since their introduction, antipsychotics remain the mainstay of drug treatment of schizophrenia. The main therapeutic uses of antipsychotic drugs are to reduce hallucinations, delusions, agitation and psychomotor excitement in schizophrenia and psychosis secondary to a medical condition or mania. The antipsychotic drugs used to treat schizophrenia have a wide variety of mechanism of action, but all share the capacity to occupy postsynaptic dopamine receptors in the brain. Antipsychotic drugs can be categorized into typical antipsychotics or dopamine antagonists and atypical antipsychotics or serotonindopamine antagonists.

 
    Dopamine (DA) antagonists appear to reuduce psychotic symptoms through inhibition of dopamine-to-dopamine binding receptors. X-ray crystallographic data have demonstrated that the molecular configuration of chlorpromazine is similar to that of dopamine, which may explain its ability to block this neurotransmitter's receptors, preferentially D2 receptor sites. The x-ray structures of different antipsychotic drugs have been examined in detail in an attempt to rationalize their structural activity relationship (SAR) with respect to their ability to block DA receptors in the brain. It was found that antipsychotics are able to block DA receptors because of a conformational complementarity between certain portions of these drugs and dopamine. Serotonin-dopamine antagonists also called as newer, novel or more broadly atypical antipsychotics, which have fewer neurological adverse effects than dopamine antagonists and is effective against positive and negative symptoms of schizophrenia. They differ in having effects related to their ratio of dopamine (D2) and serotonin (5-hydroxy tryptamine, 5-HT2) antagonism.

 
Depot antipsychotics

 
    Since schizophrenic patiens are notoriously non compliant with antipsychotic medications, due to various reasons such as lack of insight, adverse effects, discontinuation of medications, often leads to release of the disease. Long acting (depot) preparations of antipsychotics which are given either intramuscular or administered orally are valuable in such cases. Although reduction in relapse and assured compliance are merits of depot preparations, the demerit is, if side effects (e.g. dystonia, neuroleptic malignant syndrome) develop, it is difficult to alter the dose.

 
ALTERNATE PATHWAYS OF DRUG DEVELOPMENT:

 
    Phencyclidine (PCP), an antagonist at NMDA subclass of the glutamate receptor complex, can induce both positive and negative symptoms of schizophrenia. This observation has led to the proposal of a glutaminergic deficiency in the pathophysiology of schizophrenia suggesting that glutaminergic drugs might have therapeutic potential in schizophrenia. Disturbances of NMDA receptor mediated glutaminergic transmission may play an important role in the pathophysiology of schizophrenia. The NMDA receptor has a number of binding sites for glutamate, glycine and the polyamine, spermidine. The glycine modulatory site has become the target for drug development. Increasing NMDA transmission by increasing glycine binding has been hypothesized to reduce symptoms of schizophrenia. Several studies using glycine site modulators including glycine, d-serine and cycloserine have shown effectiveness in small scale clinical trials. However, a major difficulty with increasing NMDA neurotransmission is its narrow range of physiological responsivity. If NMDA stimulation is too high, seizures or neurotoxicity can develop.

 
ADVERSE EFFECTS OF ANTI-PSYCHOTICS

 
System affected  
Adverse effects 
Autonomic nervous system Dry mouth, constipation, cycloplegia, mydriasis, urinary retention, postural hypotension, impaired ejaculation, ventricular fibrillation and impotence
Extrapyramidal systems Pseudo parkinsonism, acute dystonia, akathisia, tardive dyskinesia, rabbit syndrome (peri-oral tremor) and neuroleptic malignant syndrome 
Metabolic/Endocrinal side effects Weight gain, galactorrhoea, gynaecomastia and hypothermia
Central nervous system
Allergic side effects 
Seizures, sedation and pseudo depression
Cholestatic jaundice and agranulocytosis 
Dematological side effects Contact dermatitis, photosensitivity reactions and hyper pigmentation 

 
    The presynaptic dopamine receptors in the prefrontal and cingulated corlex of the dopamine nerve terminals have been reported to inhibit dopamine synthesis and regulate dopamine release and neuronal firing. Neuroleptics produce supersensitivity of presynaptic receptor for dopamine release. The concept of presynaptic receptor for dopamine that monitors its release by feedback inhibition offers an appealing method for reducing dopaminergic activity. This indicates that there is a potential for clinical use of dopamine agonists at presynaptic receptors as therapeutic agents in schizophrenia. Aripiprazole, a presynaptic dopamine receptor against, was found to be effective in positive and negative symptoms with fewer neurological side effects. However, clinical evidence supporting an antischizophrenic effect related to presynaptic receptor stimulation is far from conclusive, ranging from transient improvement in some patients to absolutely no effects. Levodopa, in small doses and bromocriptine in substantial doses, has been used to treat schizophrenia with unimpressive results. Although presynaptic DA receptor agonists may be efficacious in the treatment of schizophrenia, they might also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors.

 
    Alteration in dopamine (DA) and/or cholecystokinin (CCK) transmission in the CNS may be of relevance for schizophrenia, since CCK and dopamine coexist within mesolimbic and mesocortical dopaminergic neurons. This has focused interest on the possible role of CCK in schizophrenia. Several lines of research, indicate a CCK deficit in schizophrenic patients, and the administration of CCK to schizophrenics appears to have therapeutic implications. Two types of CCK receptors have been idenfitied as CCKA and CCKB, of which CCKB predominates the brain. The administration of CCKB agonists to redents resulted in behavioural effects analogous to those of antipsychotic drugs. Mato et. all suggested that CCK tetrapeptide, a cCKB receptor agonist in rat diminishes rat explaratory behaviour in the fre exploration paradigm. Based on human studies of altered CCK levels in schizophrenia, initial open studies suggested antipsychotic activity following systemic administration of the CCK analogue caerulin. However, controlled, double-blind crossover studies showed no significant effect with systematically administered caerulin.

 
    Unmade (schizophrenia) is the most elaborately discussed manasavyadhi (mental disorders) in ayurveda. Various herbal drugs have been mentioned in ancient ayurvedic literatures for the management of unmade. Some of the clinical studies are reviewed here. Fozedar used the indigenous drug Acorus calamus in 75 schizophrenic patients and reported 7 patients showed improvement over 75% and 9 patients showed improvement over 50%. Ramu et. al. carried out a pilot study using brahmyadiyoga, a herbal compound consisting Centella asiatica, Acorus calamus, Rauwolfia serpentine, Saussurea lappa, Nymphoides macropermum and Nardostachys jatamansi in 41 patients suffering from chronic schizophrenia and reported improvement in 7 out of 10 patients who completed the course. Dash et. al. in a preliminary study used a compound formulation of five potent drugs, Convolvulus pluricaulis, Nardostachys jatamansi, Bacopa monnieri, Withania somnifera, Acorus calamus, to evaluate its clinical efficacy in patients suffering from unmade. The patients were treated for a period of 6 weeks and observed a notable shift of grades of psychotic symptoms and the trial indicated the effectiveness of the compound in unmade. Kale used siledin an herbal compound formulation in 112 schizophrenic patients and reported improvement rate of 59.9% with no serious side effects. There is a need to take up further studies to assess the relative efficacy of various compound preparations as well as individual drugs. Modern drugs are already known to have neurotoxic side effects especially movement disorders. If herbal drugs are demonstrated to be free from such adverse effects even on long term use, it may open ewer vistas in psychopharmacology.

 

 

 

 
THE WORLD OF PEOPLE WITH SCHIZOPHRENIA

DISTORTED PERCEPTIONS OF REALITY
    People with schizophrenia may have perceptions of reality that are strikingly different from the reality seen and shared by others around them. Living in a world distorted by hallucinations and delusions, individuals with schizophrenia may feel frightened, anxious, and confused.
    In part because of the unusual realities they experience, people with schizophrenia may behave very differently at various times. Sometimes they may seem distant, detached, or preoccupied and may even sit as rigidly as a stone, not moving for hours or uttering a sound. Other times they may move about constantly - always occupied, appearing wide-awake, vigilant, and alert.
HALLUCINATIONS AND ILLUSIONS
    Hallucinations and illusions are disturbances of perception that are common in people suffering from schizophrenia. Hallucinations are perceptions that occur without connection to an appropriate source. Although hallucinations can occur in any sensory form - auditory (sound), visual (sight), tactile (touch), gustatory (taste), and olfactory (smell) - hearing voices that other people do not hear is the most common type of hallucination in schizophrenia. Voices may describe the patient's activities, carry on a conversation, warn of impending dangers, or even issue orders to the individual. Illusions, on the other hand, occur when a sensory stimulus is present but is incorrectly interpreted by the individual.
DELUSIONS
    Delusions are false personal beliefs that are not subject to reason or contradictory evidence and are not explained by a person's usual cultural concepts. Delusions may take on different themes. For example, patients suffering from paranoid-type symptoms - roughly one-third of people with schizophrenia - often have delusions of persecution, or false and irrational beliefs that they are being cheated, harassed, poisoned, or conspired against. These patients may believe that they, or a member of the family or someone close to them, are the focus of this persecution. In addition, delusions of grandeur, in which a person may believe he or she is a famous or important figure, may occur in schizophrenia. Sometimes the delusions experienced by people with schizophrenia are quite bizarre; for instance, believing that a neighbor is controlling their behavior with magnetic waves; that people on television are directing special messages to them; or that their thoughts are being broadcast aloud to others.

 
DISORDERED THINKING
    Schizophrenia often affects a person's ability to "think straight." Thoughts may come and go rapidly; the person may not be able to concentrate on one thought for very long and may be easily distracted, unable to focus attention.
    People with schizophrenia may not be able to sort out what is relevant and what is not relevant to a situation. The person may be unable to connect thoughts into logical sequences, with thoughts becoming disorganized and fragmented. This lack of logical continuity of thought, termed "thought disorder," can make conversation very difficult and may contribute to social isolation. If people cannot make sense of what an individual is saying, they are likely to become uncomfortable and tend to leave that person alo At times, normal individuals may feel, think, or act in ways that resemble schizophrenia.

 
NORMAL VERSUS ABNORMAL :-
     Normal people may sometimes be unable to "think straight." They may become extremely anxious, for example, when speaking in front of groups and may feel confused, be unable to pull their thoughts together, and forget what they had intended to say. This is not schizophrenia. At the same time, people with schizophrenia do not always act abnormally. Indeed, some people with the illness can appear completely normal and be perfectly responsible, even while they experience hallucinations or delusions. An individual's behavior may change over time, becoming bizarre if medication is stopped and returning closer to normal when receiving appropriate treatment.ne.
WHAT ABOUT SUICIDE AND SCHIZOPHRENIA?
    Suicide is a potential danger in those who have schizophrenia. If an individual tries to commit suicide or expresses plans to do so, he or she should receive immediate professional help. People with schizophrenia appear to have a higher rate of suicide than the general population. Unfortunately, the prediction of suicide in schizophrenic patients may be especially difficult. For more, please read the Suicide article.

 

 

 
CONCLUSION

 
  • Schizophrenia is an extremely puzzling condition, the most chronic and disabling of the major mental illnesses. Approximately 1 percent of the population develop schizophrenia during their lives.
    • With the sudden onset of severe psychotic symptoms, the individual is said to be experiencing acute schizophrenia. "Psychotic" means out of touch with reality, or unable to separate real from unreal experiences.
    • There is no known single cause of schizophrenia. As discussed later, it appears that genetic factors produce a vulnerability to schizophrenia, with environmental factors contributing to different degrees in different individuals.
    • There are a number of various treatments for schizophrenia. Given the complexity of schizophrenia, the major questions about this disorder, its cause or causes, prevention, and treatment, are unlikely to be resolved in the near future. The public should beware of those offering "the cure" for (or "the cause" of) schizophrenia.
BIBLIOGRAPHY

 

 
  1. Robins pathological basis of disease edited by Cotran, Kumar, Collins, 6th edition, Saunders, an imprint of Elsevier science, the curtiscentre independent squir west, Philadelphia, Pennsylvania,.
  2. Clinical pharmacy and therapeutics edited by Roger Walker, Clive Edward, 3rd edition, Churchil Livingstone.
  3. Goodman and Ginmans pharmaceutical basis of therapeutics by Joel. G. Hardman, Lee E. Limbard 10th edition, McGraw Hill, New York,
  4. Pharmacology and Pharmaco therapeutics by R.S. Sathoskar and S.D. Bhandarkar, 13th edtion, Popular Prakasan, Mumbai,
  5. Essentials of medicinal pharmacology by K.D. Tripathi, 5th edition, Jay Pee Brothers Medical Publishers Pvt. Ltd.,.pg no 381-397
  6. Robins pathological basis of disease edited by Cotran, Kumar, Collins, 7th edition, Saunders, an imprint of Elsevier science, the curtiscentre independent squir west, Philadelphia, Pennsylvania,
  7. Text book of pathology, 5th edition, Harsh Mohan, Jay Pee Brothers Medical Publishers Pvt. Ltd., New Delhi,
  8. Pathology and therapeutics for pharmacists (basis for clinical pharmacy practice) by Russel J. Greene and Normann D. Harris,
  9. General pathology and pathology of systems by S.G. Deodhare, Popular Prakasan, Mumbai,
  10. Basic and clinical pathology by Bertram G. Kazung, 9th edition, Prentice Hall International,
  11. Pharmacotherapy a pathophysiologic approach by Joseph T. Dipiro, Robert L. Talbert, Garry C. Yee, Gary R. Matzte, Barbara G. Well, L. Michel Posey, 5th edition McGraw Hill, New York, 1967-1969.
  • Hoffman S, Diagnosis, treatment and prevention of schizophrenia Med. Clin. North Am 76:, 1992.
  • Sharma UP, Re-emergence of schizophreniaIndia, Indian J Med Res. 103: 26-45, 1996.
  • Indian journal of pharmaceutical science March April 2004,66(2): 137-258
  • URL://http//www.cleveland clinicmeded.com
  • URL://http//www.healthreserve.com
  • URL://http//www.cleveland clinic.org






Cite this: C. Jovi John, Anil Babu, "PHARMACO THERAPY OF SCHIZOPHRENIA", B. Pharm Projects and Review Articles, Vol. 1, pp. 592-630, 2006. (http://farmacists.blogspot.in/)
 

2 comments:

Sacha Neville said...

"Medications and other treatments for schizophrenia, when used regularly and as prescribed, can help reduce and control the distressing symptoms of the illness." Many meds are available and treatments are there but few focus on an approach that involves the family and community to help better create a system of healing for the one with schizophrenia.
Sacha Neville
sacha.neville@gmail.com
http://www.drugrehab.org

kanaksoni said...

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