Prophylaxis In Psychiatry Research Paper

In the absence of current curative treatments in psychiatry, the use of maintenance therapy—which is associated with long-term control of symptoms and illness-episodes—is especially important. Some of the current drug-prophylactic-maintenance strategies will be described that are used to control abnormal behavior and symptoms in three major psychotic disorders: schizophrenia, major depression, and bipolar illness. Since a knowledgeable choice of a proper maintenance drug treatment necessitates a set of predictors for the success or failure of a given drug, this issue will be exemplified below while discussing maintenance treatment for bipolar illness.

Drug therapy, whether preventive or maintenance, depends on patient compliance. This in turn depends on several variables and certain measures can be taken to maximize compliance. This issue will be discussed as well.

Finally, future directions in prophylactic medication treatment for psychiatric disorders will be discussed focusing on strategies for primary prevention.

1. Primary Prevention In Schizophrenia

There is as yet no consensus as to the nature of a subgroup of individuals carrying a high risk for the development of schizophrenia. Research designs used toward this aim involve both retrospective and prospective methods.

Prospective research projects mainly apply long-term follow-up of selected high-risk groups of subjects. Such prospective strategies assume that biological and psychological data obtained from subjects who will later develop the disease will help to identify markers associated with this disease. This, it is hoped, will enable a knowledgeable prediction as to who will develop a schizophrenic illness. One example of such a prospective approach is the follow-up of offspring of schizophrenic patients or their family members (Mednick et al. 1987, Weintraub et al. 1987, Asarnow et al. 1988, Erlenmeyer-Kimling et al. 1993). Another is the examination of psychomotor and neuropsychological variables in large cohorts of individuals while identifying variables associated with later development of psychotic illness and schizophrenia. Yet, another prospective strategy is the study of a variety of factors and early symptoms associated with a transition phase—that is, the phase leading from ‘normal’ into a psychotic state—in order to identify relevant risk factors. All the above strategies require long-term follow-up. Interestingly, there is also a suggestion for a short-term prospective strategy employed by Yung et al. (1998) aiming at identifying a very high risk group of subjects for the development of psychosis. This strategy utilizes a 6–12 months follow-up of selected subgroups of individuals demonstrating high risk for a manifestation of a schizophrenic episode.

In general, retrospective and prospective studies have identified a host of markers increasing the risk for future psychosis including a family history of schizophrenia, distressed family functioning, early separation and institutional rearing, neurobehavioral deficits, delivery complications, maternal exposure to influenza during the second trimester of pregnancy, along with certain behavioral and personality patterns. The latter are mainly reported by teachers and caregivers. Also, a variety of biological findings were identified, all of which still need to be verified in further research. An example of a biological finding is that of small amygdala-hippocampal complex or thalami in people at high risk of developing schizophrenia (Lawrie et al. 1999). Another finding is that of increased plasma homovanillic acid that is negatively correlated with performance in arithmetic tasks in a group of subjects demonstrating prodromal phase of schizophrenia (Shimushi et al. 2000). All the markers discussed above should be taken at the moment with caution until further research is done. Also, it is our opinion that the use of certain combinations of the above markers for the initiation of antipsychotic treatment in high-risk individuals—although suggested by some (Phillips et al. 1999)—is not recommended at this time as routine treatment.

2. Maintenance Treatment In Schizophrenia

Maintenance therapy in schizophrenia is provided by long-term treatment. Based on accumulated experience, it was suggested that schizophrenic patients could be looked at as two groups. One in which maintenance therapy seems to play a ‘suppressive role,’ and its discontinuation leads to a rapid reappearance of psychotic symptoms, and another group in which the treatment has more of a ‘prophylactic’ role. In this last group discontinuation of treatment leads to a more gradual and remote in time relapse of symptoms (see Gelenberg et al. 1991).

It is estimated that about 10 percent of remitted medication free schizophrenic patients will relapse in any given month. That means that after 6 months roughly about half of these patients will relapse whereas after 12 months about 70 percent will do so and only a small portion of these patients will not relapse at the end of 2 years.

Several strategies of maintenance treatment are suggested for these patients. The first consists of a continuous maintenance treatment. This strategy applies relatively lower doses of antipsychotic treatment as compared with that used for acute exacerbation.

The second maintenance strategy includes ‘drug holidays,’ that is, treatment periods interrupted by drug free periods. This strategy was suggested in order to lower the incidence of side effects while retaining drug efficiency. However, such a strategy is not recommended nowadays since research studies could not support its effectiveness. A third strategy suggests ‘intermittent’ treatment or ‘targeted dose’ for chronic schizophrenic patients. In this case, patients are treated during the acute episode only, while monitored for the appearance of prodromal symptoms (first symptoms anticipating the appearance of an exacerbation). Once prodromal symptoms appear, pharmacological treatment is initiated.

In general pharmacological treatment in schizophrenia includes the use of a group of drugs collectively called ‘antipsychotic drugs.’ These drugs have the ability to block neurons using the neurotransmitter dopamine to transmit messages to other neurons.

In the 1980s, a second generation of drugs came into use. The prototype was clozapine, a drug that besides its ability to block some types of dopaminergic neurons can also exert a blocking effect on certain serotonergic neurons—(labeled as 5HT-2 neurons) in the central nervous system. This drug was shown to have a lower side-effect profile compared to the more traditional drugs, especially it had minimal extrapyramidal signs (a set of abnormal motoric signs that interfere with daily activities) and it did not elevate plasma levels of prolactin (the lactating hormone). However, clozapine also has several distressing side effects including the lowering of white blood cell count that may expose these subjects to severe infections. Clozapine seems to affect not only the positive illness symptoms but also the negative symptoms of schizophrenia (a set of symptoms characterized by impaired volition and motivation, apathy and paucity of speech) and it may also improve some neurocognitive impairments demonstrated in this disease (see Kane et al. 1988). Beside clozapine, other second-generation antipsychotic drugs were also developed of which mainly olanzepine and risperidone are in use. However, there is still a question whether all these second generation antipsychotic drugs or only some of them can mimic clozapine’s effect and if so to what extent.

3. Maintenance In Bipolar Illness

This illness course is characterized by the appearance of manic episodes with or without the occurrence of depressive episodes. It is estimated that the majority of patients who had a manic episode will have one or more recurrences. Since both manic and depressive episodes may be associated with progressive deterioration of interpersonal and occupational functioning and may also carry the risk of harming oneself or others, an adequate maintenance drug treatment for bipolar illness is of utmost importance. Several mood stabilizers—that is, drugs designed for maintenance of the euthymic (normal) state while preventing the appearance of both manic and depressed episodes—are now available. The first mood stabilizer to be used was lithium, a drug still considered by many to be the gold standard treatment for bipolar illness. Other commonly used mood stabilizers are valproic acid and its derivatives, and carbamazepine whereas newer drugs such as the anticonvulsants lamotragine, gabapentin, and topiramate are still under study. This research paper will mainly address data published for lithium.

Three open trials suggested that lithium may be effective in the prophylaxis of bipolar disorders (Baastrup 1964, Hartigan 1963, Baastrup and Schou 1967). During the 1970s, a series of double blind studies were conducted to examine the possible efficacy of lithium in the prophylaxis of bipolar disorder. Goodwin (1994) summarized these studies calculating the recurrence rates over a one year period for placebo (a nonactive treatment) to be 81 percent, but only 34 percent for lithium. These reports included two types of studies. Prospective studies treating patients with either lithium or placebo and discontinuation studies where one group of patients continues with lithium treatment for a given period of time, whereas the other discontinues treatment for a similar time period.

From the 1980s and on more prospective and discontinuation studies were conducted. These studies basically confirmed lithium’s efficacy as maintenance treatment for bipolar disorder. They also suggested that there may be an advantage in keeping maintenance lithium blood levels at about 0.6 meq L as it may lead to less side effects and increase compliance (Coppen et al. 1983) and that lithium plasma levels of 0.8–1.0 meq L seem to be associated with less relapse (Gelenberg et al. 1989). In general, although many authors still suggest that lithium is an efficient drug for bipolar illness, especially in the classic bipolar patient (Grof 1999), some authors now point to the fact that there is a group of patients who are less responsive to this drug or that demonstrate a decreased response throughout the years.

One important issue associated with long-term maintenance therapy is the finding of predictors for a beneficial, or lack of, response for a given drug. Several predictors of lithium response were offered. Grof et al. (1983a, 1983b, 1999) suggested a better response to lithium treatment in a group of patients demonstrating a course of illness with periods of euthymia (normal range of mood), followed by mania, depression, and then euthymia. These authors also suggested that the absence of rapid cycling (four and more illness episodes per year), the absence of personality disorder, and the diagnosis of primary bipolar disorder (i.e., not secondary to street drugs or organic cause) predict a good prophylactic response to lithium. Faedda et al. (1991) in agreement with Grof suggested that maniadepression-euthymia course is associated with a good response to lithium. Others suggested that good response to lithium in relatives and a family history of mood disorders carry a good response. Aagaard and Vestegaard (1990) suggested that bipolar patients tend to demonstrate decreased response to lithium treatment when they have a lengthy episode, they are young or of female gender. Abou-Soleh and Coppen (1990) suggested that positive prophylactic response to lithium over 6–12 months predicts further good response in the future. Patients with dysphoric and mixed mania (manic episode associated with some depressive symptomatology) were suggested to respond less to lithium treatment and some studies suggest this is also true for rapid cycling bipolar disorder. Hopefully, a knowledgeable use of predictors may help the physician to choose selected subgroups of patients, which will benefit from lithium maintenance treatment.

4. Maintenance In Major Depression

Depression is a serious illness. It carries high suicidal risk. It is estimated that the recurrence of major depression is between 70–85 percent. Two types of studies report the efficacy of antidepressants to prevent relapse in the first year after remission from a depressive episode. The first is that of a cross-over design, whereas the second is that of a continuation design. In the first design patients are first brought into remission with a given medication and are then maintained on this medication for a period of 2–3 months. Patients who respond are then entered into a double blind design for up to another year, in which they receive randomly either the same antidepressant or placebo. In the continuation design, acutely depressed patients are assigned randomly to either active drug or placebo. Patients who respond continue with the same treatment. Eighteen studies compared a group of antidepressants collectively called tertiary amine tricyclics (this name describes the common molecular structure characterizing this group of drugs), finding that while 50 percent relapsed on placebo only 23 percent relapsed on the active drugs. Three studies compared another group of newer antidepressants collectively called selective serotonin reuptake inhibitors (SSRIs) (this name describes the hypothesized mechanism of action of this group of drugs) finding that the relapse rate for the active drug was between 13–26 percent whereas for placebo it was 46–57 percent (see Janicak et al. 1997).

In general, it is agreed that prevention of relapse in major depressive illness is of major importance and every effort must be taken to address this. Contrary to previous reports that supported the use of low doses in the prophylactic treatment of major depression, several authors now recommend that the full dose be used, that is, a similar dose to that used for the acute treatment of a major depressive episode.

In general, it is recommended to continue maintenance treatment after a first episode of major depression for about 6 months and then to taper the drug gradually. If another episode occurs the recommendation is to continue treatment for several years and after a third episode a lifetime maintenance treatment is recommended.

5. The Issue Of Compliance And Its Importance In Prophylactic Drug Treatment

Compliance to drug treatment is defined as adherence to an agreed treatment schedule between a physician and the patient. It is estimated that no more than 50 percent of patients fully comply with their treatment and we suspect that the magnitude of non-compliance may be even greater in the case of long-term maintenance treatment. Various factors seem to influence compliance including the nature of the patient-physician relationship, the patient’s set of beliefs and expectations as well as the occurrence of side effects. Issues relevant to compliance in psychiatric disorders are: (a) the occurrence of delusions and severe cognitive distortions about the index drug, its effect and side effects, (b) the patient’s cognitive functioning and motivation, which may be impaired in certain psychiatric disorders, and (c) the patient’s general attitude toward mental illness. Especially important in this context is the level of stigma felt by the patient; the greater the stigma, the less compliant the patient will be.

Several remedies can be offered to enhance compliance and they should be tailored according to the patient’s condition and level of understanding. First, an empathic approach, one that builds basic trust with the patient and their family is of utmost importance. Second, whenever possible, the patient with the guidance of their physician should be an active participant in decisions made for the treatment plan. This does not mean that the patient decides or guides such decision making, but that they are presented with several treatment alternatives and an educated decision is agreed upon with the guidance of the physician. Third, the patient should be educated as to side effects and ways to cope with them once they appear (i.e., lower the drug by a certain degree and contact your physician). Treatment diaries and involvement of family members whenever necessary can also be of help. Since maintenance treatment is a long-term treatment, it is our opinion that a responsible physician should renew such a drug treatment ‘agreement’ at least every several months, discussing it with the patient and perhaps with relevant family and community members if needed. The physician should also actively ask in each meeting with the patient about side effects as well as examine whether there is any change in the patient’s set of beliefs about the drug and its action that may need renewed education.

6. Future Directions For Primary Prevention Of Psychiatric Disorders

Genetic epidemiological studies have shown that genes play a major role in several psychiatric disorders including schizophrenia, bipolar illness, and major depression. It is now believed that these disorders are not related to a single gene, but rather are determined polygenetically. In general, it seems that geneenvironment interactions are involved in the causation of many psychiatric disorders. Interestingly, the vulnerability to environmental influences may also be genetically determined (see Owen et al. 2000 for review).

The human genome project, now completed, is expected to contribute to the finding of genes responsible for the susceptibility, occurrence, and maintenance of these disorders. The sorting out of genetic variations in the population, which are related to these psychiatric disorders, may open new avenues to genetic medical interventions prior to the manifestation of these diseases. Such interventions may alter the course or even prevent these diseases from occurring. Although this project is still far off, one cannot ignore it at the dawn of this new era, which started with the recent completion of the decoding of the human genome.

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