Serotonin and Schizophrenia

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Support for the involvement of the serotonergic system in schizophrenia has been gathering in the literature since it was first observed almost forty years ago that lysergic acid diethylamide (LSD) causes a syndrome evocative of schizophrenia in normal controls and that the structure of LSD shares similarities with serotonin (Gaddum and Hameed 1954). Although the dopamine hypothesis dominated the literature for the next three decades, further evidence to reassert serotonergic abnormalities in patients with schizophrenia came when clozapine, the first antipsychotic in forty years to show clinical superiority to chlorpromazine (Thorazine, a dopamine antagonist), was found to have potent serotonin receptor antagonism (Meltzer et al. 1989; Canton et al. 1990).

Because the serotonergic system is functionally interactive (Kelland et al. 1990) and anatomically closely connected (Tork 1991) with the dopaminergic system, there is good reason to view these two neurotransmitter systems in tandem, as opposed in isolation. The serotonin system inhibits dopaminergic function at both its origin in the midbrain and its termination in the forebrain (Kapur and Remington 1996). Thus, it may be desirable to augment the dopamine antagonist effect of classic antipsychotics with a serotonin agonist. Serotonin modulation may be beneficial in reducing the negative symptoms of schizophrenia (Leysen et al. 1993). It should be noted, however, that many of the newer antipsychotics are serotonin antagonists. This is a complex area of study. There are many different receptor subtypes of both serotonin and dopamine, and there are likely several modes of interaction between these two systems (Kapur and Remington 1996). Also confounding are the changes that take place in the brain when doses of serotonin and dopamine antagonists (for example, antipsychotics) are administered over the long term (versus the immediate effects seen with acute agonists of these same neurotransmitter systems, as is seen with MDMA).

The coexistence of illnesses known to respond to the antidepressants that are selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), lends support to the idea that serotonin is involved in the pathophysiology of schizophrenia. The prevalence of depression in people with schizophrenia is quite high and is seen throughout the course of the disease. Approximately 25 percent of schizophrenic patients experience depression after an acute psychotic episode ("post-psychotic depression"), and as many as 60 percent experience a major depressive episode during the course of their illness (Bartels and Drake 1989). One study found the baseline incidence of depression to be 22 percent, and the incidence over a five-year follow-up period was 26 percent (Koreen et al. 1993). The suicide rate for schizophrenic patients (10 to 13 percent) is ten times the national average (1 percent), and suicide is the leading cause of premature death in these patients (Caldwell and Gottesman 1990). A general population study showed that people with schizophrenia have the highest relative risk of attempted suicide, with a risk ratio of 23:1 (Dyck et al. 1988). Mann (1987) notes that a low level of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) measured in the cerebrospinal fluid correlates with suicidal behavior in depression and in schizophrenia. One cerebrospinal fluid 5-HIAA study noted low levels in schizophrenic patients, with a further reduction seen in those patients who had attempted suicide (Cooper et al. 1992). Clozapine treatment of neuroleptic-resistant patients resulted in markedly less suicidal behavior and was accompanied by improvements in depression and hopelessness (Meltzer and Okayli 1995).

Schizophrenia and obsessive-compulsive disorder show a high rate of coexistence, perhaps reflecting the involvement of the serotonergic system in both of these psychiatric diseases. One study listed the occurrence of significant obsessive-compulsive symptoms in schizophrenic patients as 25 percent (Berman et al. 1995). Schizophrenia and autism also share similar features (withdrawn behavior, self-stimulation stereotypes, inappropriate or flattened affect, poor eye contact). Some of these features of autism have been shown to respond to treatment with fenfluramine (Geller et al. 1982; Ritvo et al. 1983), a modified amphetamine with serotonin-agonist actions

in behavioral models and serotonin-depleting actions in biochemical models (Clineschmidt et al. 1978) similar to MDMA.

Clinical Studies: Giving Serotonin Agonists to Schizophrenics

Several studies have used serotonin reuptake inhibitors, particularly fluoxetine, as adjunctive treatment for medicated patients with schizophrenia. Fluoxetine has been shown to improve negative symptoms significantly though blood levels of antipsychotics were elevated. (Spina et al. 1994; Goff et al. 1995); fluvoxamine (Luvox) also has been shown to ameliorate negative symptoms (Silver and Nassar 1992). In one study comparing the effects of fluvoxamine with those of maprotiline (Ludiomil, a non-serotonergic antidepressant) in medicated schizophrenic patients, the patients given fluvoxamine showed significant improvement in motor retardation, emotional withdrawal, and affective blunting compared with the group given maprotiline (Silver and Shmugliakov 1998). This effectively factors out the possibility that it is merely an antidepressant effect and suggests that it is specifically the serotonergic effect that is responsible for the improvement in negative symptoms.

In a study in which medicated schizophrenic patients received fenfluramine, three of eight subjects showed statistically significant improvement in negative symptoms, and three other patients showed significant improvement in positive symptoms (Stahl et al. 1985). Fenfluramine has properties similar to MDMA, and rats trained to discriminate between fenfluramine and placebo also tended to generalize to MDMA 90 percent of the time (Schecter 1997). Another study using long-term fenfluramine treatment, however, showed that it worsened negative symptoms in schizophrenic patients (Soper et al. 1990). An open trial (patients and doctors knew what patients were receiving) of sertraline (Zoloft) administered to patients stabilized on antipsychotics noted some amelioration of both positive and negative symptoms (Thakore et al. 1996), while a double-blind study (neither patients nor doctors knew whether patient was receiving experimental drug or placebo) found no statistically significant improvement (Lee et al. 1998).

Studies have been done using the serotonin agonist metachlorophenyl-piperazine (mCPP) as a challenge test (single dose) in schizophrenic patients in an effort to test the assumption of serotonergic involvement in schizophrenia. They have produced mixed results. In normal subjects, mCPP mfu-

sion leads to an increase in body temperature, anxiety, and release of growth hormone, Cortisol, ACTH, and prolactin (Murphy et al. 1986, 1991). In a 1991 Yale study of unmedicated schizophrenics, mCPP caused a larger anxiety response in patients than in controls (Krystal et al. 1991). Furthermore, it was shown to exacerbate psychotic symptoms in the patient group (Krystal et al. 1991). Iqbal and associates (1991) corroborated the finding of psychotogenesis in schizophrenic patients exposed to an mCPP challenge (0.25 mg/kg taken by mouth [PO]). Kahn (1992), however, measured an improvement in symptoms (by the Brief Psychiatric Rating Scale) of those schizophrenics undergoing an mCPP challenge (0.35 mg/kg PO).

What can be understood from all of these results? Clearly, there is no simple answer. What was once a theory of too much dopamine or serotonin is now a theory of imbalance: too much in some areas and not enough in others. A few theorists go one step further to match the levels of neurotransmitters with symptoms. Positive symptoms represent an abundance of dopamine turnover, and negative symptoms represent the opposite (Rao andMoller 1994). Because some people with schizophrenia have more positive symptoms and others have more negative symptoms, some do better with certain medications, and others respond to different medications. There are some researchers who think that schizophrenia is a syndrome, or a group of illnesses, and not simply one disease. This may mean that research conducted on large groups of subjects may not be studying the same phenomenon. Many studies now try to focus on either positive-symptom- or negative-symptom-predominant groups. Perhaps the only thing that can be generalized from all these data is that decreasing available dopamine and serotonin in the synapse seems to improve positive symptoms. It is possible, though not nearly as certain, that enhancing available serotonin and dopamine in the synapse improves negative symptoms.

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