A REVIEW ON PHARMACOLOGICAL AND ADJUVANT THERAPIES FOR SCHIZOPHRENIA

Schizophrenia is a psychological disorder, diagnosed by observed behavior and patient reported experiences. Antipsychotic medication mainly works by suppressing dopamine activity. Neuroleptics are also called as antipsychotic drugs. There is a increased risk of extrapyramidal side effects with typical antipsychotics. Atypical antipsychotics refers to newer antipsychotics that confer to less risk of extrapyramidal side effects. Along with these Neuroleptic treatment other adjuvant treatments like Insulin shock, Electroconvulsive, Oestrogen, Glycine, Cox 2 and Antioxidant therapies are also used for Schizophrenia. Insulin is a hormone that maintain blood sugar level. Repeated injections with large doses of insulin causes daily comas over several weeks during which the patient lost psychotic thoughts. In electroconvulsive therapy controlled electric currents pass through the brain, altering brain chemistry and reducing depression and schizophrenic symptoms. Repeated applications of electric current alter the neurotransmitter level in central nervous system. In oestrogen therapy epidemiological, clinical and animal studies exploring the protective effect of oestrogen against schizophrenic symptoms. Psychoprotective action of oestrogen appears to be mediated by central dopaminergic and serotonergic mechanisms. Glycine(amino acid) , antioxidants and vitamins are potential treatments for the negative symptoms of Schizophrenia. There is an imbalance between the type 1 and type 2 immune systems in patients with psychosis, this imbalance can be restored by Cox 2 inhibitors.


INTRODUCTION
Schizophrenia is a psychological disorder characterized by disintegration of thought processes and of emotional responsiveness. 1 It most commonly manifests as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social or occupational dysfunction. The onset of symptoms typically occurs in young adulthood, with a global lifetime prevalence of about 0.3-0.7%. 2 Diagnosis is based on observed behavior and the patient's reported experiences. Genetics, early environment, neurobiology, and psychological and social processes appear to be important contributory factors; some recreational and prescription drugs appear to cause or worsen symptoms. Current research is focused on the role of IJBR 2 [3] [2011]192-203 www.ijbr.ssjournals.com neurobiology, but this inquiry has not isolated a single organic cause. The many possible combinations of symptoms have triggered debate about whether the diagnosis represents a single disorder or a number of discrete syndromes. 3 The mainstay of treatment is antipsychotic medication, which primarily works by suppressing dopamine activity. Psychotherapy and vocational and social rehabilitation are also important. In more serious cases-where there is risk to self and others-involuntary hospitalization may be necessary, although hospital stays are now shorter and less frequent than they were. 4 The disorder is thought mainly to affect cognition, but it also usually contributes to chronic problems with behavior and emotion. People with schizophrenia are likely to have additional (comorbid) conditions, including major depression and anxiety disorders; the lifetime occurrence of substance abuse is almost 50%. 5 Social problems, such as long-term unemployment, poverty and homelessness, are common. The average life expectancy of people with the disorder is 12 to 15 years less than those without, the result of increased physical health problems and a higher suicide rate (about 5%). 2

DRUG TREATMENT
Effective pharmacologic treatment of schizophrenia has been available since the 1950s. In the early 1950s, the term "neuroleptic" was introduced to denote the effects of chlorpromazine (Thorazine; brand no longer available in the United States) and reserpine on laboratory animals. It was intended to distinguish their effects from those of sedatives and other central nervous system depressants. 6 Although "neuroleptic" is still used synonymously with "antipsychotic," the term now usually refers to first-generation antipsychotics that confer an increased risk of extrapyramidal side effects, such as dystonic reactions (e.g., fixed upper gaze, neck twisting, facial muscle spasms), parkinsonian symptoms (e.g., rigidity, bradykinesia, shuffling gait, tremor), and akathisia (e.g., inability to sit still, restlessness, tapping of feet). Tardive dyskinesia, which is a chronic disorder of the nervous system characterized by involuntary jerking movements (primarily of the face, tongue, and jaw), often is considered an extrapyramidal side effect. However, it is actually a separate and mechanistically different phenomenon. The term "atypical antipsychotic" refers to newer antipsychotics that confer less risk of extrapyramidal side effects than traditional antipsychotics. Table 1 lists antipsychotic agents currently available in the United States. Nonadherence to medications is a significant problem; in a recent study, 74 percent of patients discontinued their medication within 18 months. 7 Nonadherence often leads to relapse of symptoms. Atypical antipsychotics were initially thought to help with adherence because of their lower rate of neurologic side effects. However, meta-analyses have found that drop-out rates and relapse prevention are no better with atypical antipsychotics than with neuroleptics. 8,9 Meta-analyses also have found that in terms of symptom scores and drop-out rates, atypical antipsychotics are better than high dosages (i.e., more than 12 mg per day) of haloperidol (Haldol); there was no advantage when the dosage of haloperidol was less than 12 mg per day. 8 In other words, many of the perceived benefits of atypical antipsychotics actually were a result of the excessive doses of firstgeneration antipsychotics that were used for comparison in randomized trials. 8

Mechanism of action
There are different types of DAreceptors 12 and it appears that antipsychotic drugs probably owe their therapeutic effects mainly by blocking the D2 receptors.The main groups, phenothiazines, thioxanthines and butyrophenones, show preference for D2 over D1 receptors. Some newer agents (e.g. remoxipride) are highly selective for D2 receptors, whereas clozapine is relatively non-selective between D1 and D2, but has high affinity for D4 dopamine receptor. The naturally occurring agonist interacts with D1 and D2 receptors, and both receptors are found in high density in the corpus striatum and nucleus accumbens. It has been observed that mostly striated neurons exhibit D1 responses whereas accumben neurons exhibit D2 responses. 13

Insulin shock therapy
Insulin shock therapy or insulin coma therapy was a form of psychiatric treatment in which patients were repeatedly injected with large doses of insulin in order to produce daily comas over several weeks. 14 A standardized treatment protocol was developed. Insulin injections led to two to three hours of low blood sugar levels.
(Insulin is a hormone that drives sugars from the blood to storage in the liver.) When blood sugar levels fall precipitously, the brain cannot sustain consciousness and the patients become stuporous. When the patients developed stupor or coma, they lost their psychotic thoughts.
Insulin coma therapy was a labourintensive treatment that required trained staff and a special unit. 15 Patients, who were almost invariably diagnosed with schizophrenia, were selected on the basis of having a good prognosis and the physical strength to withstand an arduous treatment. 16 There were no standard guidelines for treatment; different hospitals and psychiatrists developed their own protocols. 16 Typically, injections were administered six days a week for about two months. 14 The daily insulin dose was gradually increased to 100-150 units until comas were produced, at which point the dose would be levelled out. 14 Occasionally doses of up 450 units were used. 17 After about 50 or 60 comas, or earlier if the psychiatrist thought that maximum benefit had been achieved, the dose of insulin was rapidly reduced before treatment was stopped. 16,18 Courses of up to 2 years have been documented. 18 After the insulin injection patients would experience various symptoms of decreased blood glucose: flushing, pallor, perspiration, salivation, drowsiness or restlessness. 18 Sopor and coma-if the dose was high enough-would Insulin shock therapy follow. 18 Each coma would last for up to an hour and be terminated by intravenous glucose. 14 Seizures sometimes occurred before or during the coma. 19 Many would be tossing, rolling, moaning, twitching, spasming or thrashing around. 16 Some psychiatrists regarded seizures as therapeutic and patients were sometimes also given electroconvulsive therapy or cardiazol/metrazol convulsive therapy during the coma, or on the day of the week when they didn't have insulin treatment. 18 20 Patients required continuous supervision as there was a danger of hypoglycaemic aftershocks after the coma. 15 In "modified insulin therapy", used in the treatment of neurosis, patients were given lower (subcoma) doses of insulin.

Electroconvulsive therapy
During electroshock therapy, controlled electric currents pass through the brain, altering brain chemistry and reducing depression and schizophrenia symptoms. When schizophrenia patients don't respond to antipsychotic medication, doctors may recommend electroshock therapy. 21 Early electroshock therapy methods exposed fully conscious patients to dangerously high levels of electricity, sometimes resulting in death. Although electroshock therapy has become significantly safer over the years, public opinion continues to view it as cruel and dangerous. Electroshock therapy is rarely the first choice for schizophrenia treatment. Schizophrenia symptoms are generally treated with antipsychotic medication first. If this method fails, doctors may then consider electroshock therapy. Electroshock therapy works faster than antipsychotic medication, which can take several weeks to alleviate schizophrenia symptoms. In certain circumstances, the fast-acting nature of electroshock therapy may make it a preferable first line of schizophrenia treatment. People suffering from exceptionally severe schizophrenia symptoms may experience relief after two or three sessions of electroshock therapy. Schizophrenia patients who are a threat to themselves or others may also benefit from electroshock therapy before taking antipsychotic medication. An electroshock therapy session lasts approximately fifteen minutes, plus preparation and recovery time. During the procedure, the patient is under general anesthetic, so she feels nothing. As the electric current stimulates a seizure, a muscle relaxant prevents convulsions. Electrodes are positioned on the head and a controlled electric current is sent through the electrodes and into the brain. 22 The patient's heart rate, blood pressure and breathing are carefully monitored during an electroshock therapy session. The patient may also wear a protective mouth guard during the induced seizure. Electroshock therapy usually lasts two to four weeks, with two to three treatments a week. Since schizophrenia symptoms often return after electroshock therapy, patients may require "maintenance" sessions to prevent relapse. The exact mechanisms by which ECT exerts its therapeutic effect are not known, but studies show that repeated applications have effects on several kinds of neurotransmitters in the central nervous system. ECT seems to sensitize two subtypes of serotonin (5-HT) receptor, thereby strengthening signaling. ECT also decreases the funtioning of norepinephrine and dopamine inhibiting auto-receptors in the locus ceruleus and substantia nigra, respectively, causing more of each to be released 23 .

Complications
Electroshock therapy requires general anesthetic, which can cause an increase in blood pressure and heart rate.

Oestrogen therapy
The oestrogen protection hypothesis proposes that oestrogen has a protective effect against onset of schizophrenia. In support of this: o Epidemiological studies have shown that young women are less likely to develop schizophrenia than men of the same age, and women are more likely to develop late-onset schizophrenia after menopause. o Clinical studies have shown higher psychotic symptoms in perimenopausal women, and women at the low oestrogen phase of the menstrual cycle. Animal studies provide further evidence in support of the oestrogen protection hypothesis. One of the most compelling hypotheses to emerge in the understanding of the possible causes and potential new treatments for schizophrenia is the oestrogen protection hypothesis. 24,25 The hypothesis is described in two parts: • In women, oestrogen "protects" women from developing severe schizophrenia at an early age. • Fading oestrogen secretion at menopause in vulnerable women leads to relapse of schizophrenia symptoms or new, lateonset schizophrenia.
There are three main areas of support for the oestrogen protection hypothesisepidemiological findings, clinical evidence and animal studies exploring the effects of oestrogens on key neurotransmitters that are implicated in producing psychotic symptoms. Randomised controlled trials are providing evidence for the use of oestradiol to ameliorate the symptoms of schizophrenia.

Epidemiological evidence
Epidemiological sex differences in schizophrenia have been reported for over a century. In 1910, Kraepelin described a later age of first admission for women with schizophrenia compared with men 26 . A review of over 50 studies showed the same sex difference in the age of admission and onset of the first episode of schizophrenia 27 . In a population-based sample of 232 first-episode schizophrenia presentations, there was a steep early increase in the age of schizophrenia onset in men between the ages of 15 and 25 years. 28 In women, the rates of onset were less steep and had a broader age of onset between the ages of 15 and 30 years plus a smaller, second peak between the ages of 45 to 50 years. 27

Clinical support
A clinical study has shown that perimenopausal women with schizophrenia required increased antipsychotic drug doses to maintain remission. 25 This study strongly suggested that due to the declining oestrogen levels during menopause and beyond, the "protective" or "antipsychotic" effect of oestrogen is diminished, leading to the patient requiring a greater dose of antipsychotic medication to treat symptoms of schizophrenia. A small study of 32 women found that psychotic symptoms were worse during the lowoestrogen phase of their menstrual cycles. 30 This suggests that higher circulating oestradiol levels provide an antipsychotic effect for women with schizophrenia. 31

Animal studies
Many animal studies have demonstrated several neuroprotective effects of oestrogens. Dopamine and serotonin are key neurotransmitter systems involved in the formation of the main symptoms of schizophrenia, and oestrogen has a psychoprotective action that appears to be mediated by central dopaminergic and serotonergic mechanisms. 32 The effects of oestrogen are broadly classified into the slower, classical, intracellular "genomic" and the more rapid, direct, non-genomic actions. 33 Both the genomic and direct effects of oestrogen on the central nervous system are thought to contribute to oestrogen's antipsychotic properties.

Glycine therapy
Glycine (an amino acid ) has been a subject of research for over 15 years as a potential treatment for the negative symptoms of schizophrenia. One hypothesis of schizophrenia pathology suggests that NMDA-receptor disfunction (a special kind of glutamate receptor in the brain) may contribute to disordered synapses and brain atrophy, which ultimately result in the visible symptoms. Glycine may turn out to be a very beneficial supplemental treatment (when added to standard antipsychotic medications) for some people with schizophrenia. We hope to see longer and larger trials for glycine supplemental treatments.
The clinical trials have shown that Glycine did not help people who are taking Clozapine, but it did help (in reducing negative symptoms) in people who were taking risperidone (Risperdal), and olanzapine (Zyprexa). The clinical trials suggest that the optimal dosage may be in the range of 30 grams to 60 grams a day. The biggest downside to taking glycine seems to be upset stomach and nausea which, researchers tell us, is quite common in people who take 60 grams of glycine a day for a month or two. Approaches used by the researchers to minimize this problem have been to start at lower doses (e.g. 5 to 10 grams split into two doses per day) and then to slowly phase up to higher doses over a period of weeks. 34 Also -taking it after meals may assist in reducing side effects.

Cox-2 Inhibitors as an Adjunctive Treatment for Schizophrenia
Recently, increased attention has been paid to the interface between the immune system and the treatment of schizophrenia. Historically, it has been noted that in patients with typhus, there appears to be decreased rate of infection in those afflicted with mental illness when IJBR 2 [3] [2011]192-203 www.ijbr.ssjournals.com compared with a control group. It was also noted that when the mentally ill group was afflicted with an infection, half showed improvements in their psychotic symptoms. Today, it is believed that there may be an imbalance between the type 1 and type 2 immune systems in patients with psychosis. Schizophrenic patients who are treatment-resistant appear to have an increase in interleukin-6 levels, which is part of the type 2 system. It is felt that in schizophrenic patients, there is relative decrease in activity in the type 1 immune system. Cox 2 inhibitors inhibit the synthesis of IL-6 and also inhibit prostaglandin E2 synthesis, which ordinarily increases IL-6 levels. Celecoxib, as an inhibitor of prostaglandin E2, is felt to restore the balance between the type 1 and 2 systems. In a doubleblind, prospective, placebo-controlled, randomized study, 35 50 schizophrenic patients were evaluated, with half of them receiving risperidone 6 mg/day plus celecoxib 400 mg/day while the other half received placebo instead of celecoxib for a 5-week trial. During weeks 2-4, the PANSS (Positive and Negative Schizophrenia Symptoms) total score was reduced in the risperidone plus celecoxib group. In addition, benzodiazepine usage was decreased for this group. Drug interactions between the risperidone and celecoxib did not appear to explain this finding. It will be interesting to note whether the above study will be replicated, showing celecoxib to be a useful adjunct in the acute treatment the schizophrenia.

Antioxidant &Vitamin therapy
Researchers have found a positive correlation between superoxide generation and the negative symptoms of schizophrenia, indicating a possible role for oxidative stress in the development of the disease (and the potential for antioxidants to help in decreasing the risk or severity of the disease). "There are several lines of evidence to support the contribution of oxygen free radicals in schizophrenia, including increased lipid peroxidation, fatty acids, and alterations in blood levels of antioxidant enzymes. 36 Higher than normal intake of foods known to have a high content of antioxidants, as well as supplements of high antioxidant vitamins (Alpha Lipoic Acid, Vitamin E, Vitamin C) may have some beneficial impact on the incidence and progression of the disease.