The neurophysiology of schizophrenia: Etiology and Psychopharmacological treatment
Authors note - I am adding this paper for only one reason, some students might find it useful. This was my very first paper. I strongly believe that I would do a much better job of it if I was doing it today. I don't know what format I was using for the references but it isn't APA.
Also, in this
article I refer to a new antipsychotic currently being tested called Olanzopine.
I do know that this atypical antipsychotic is now in successful use in Canada.
As well, at least in Canada, risperidone has primarly taken over the role as
the primary atypical antipsychotic (mainly due to the higher costs of Clozapine
and the risk of agranulocytosis)
Schizophrenia is a major debilitating illness that strikes 1% of our population. It is found in every society, from the most primitive and isolated to the largest and most technologically advanced. In this paper I will briefly describe the symptoms that characterize this illness. I will then conduct a detailed discussion of the current research into the mechanisms and controls of schizophrenia. These are the dopamine studies, the serotonin studies, GABA studies and norepinephrine studies. Finally I will outline the historically significant and current approaches used in the treatment of this devastating crippler of men and women.
Schizophrenia most often strikes adolescents and young adults and is found to have a higher prevalence in first-degree biologic relatives of people with schizophrenia. For many people afflicted with the illness, schizophrenia results in chronic disabilities. The disorder involves dysfunctions in a persons primary areas of functioning. It usually embodies interpersonal relations, work or education, or self care. A combination of positive and negative symptoms characterizes it. Positive symptoms are an excess or distortion of normal functioning. These symptoms include delusions, hallucinations, disorganized speech and grossly disorganized or catatonic behavior. Negative symptoms reflect a loss of normal functioning, including restrictions in range intensity of emotion fluency and productivity of thought and speech, and goal-directed behavior (American Psychiatric Association, 1994).
Schizophrenia involves disturbances in some, but not all, brain functions. This led to the determination that specific areas of the brain, involving a series of neural circuits, were involved. Schizophrenia involves alterations of physiological processing, which reflect altered cytoarchitectural, biochemical and electro-physiological properties of neural systems (Kaplan & Sadock, 1995). Schizophrenia is generally considered a biochemical disorder of the brain. This assumption has led researchers to the study of those chemicals and chemical pathways involved in brain function.
The Dopamine Studies
Scientists have noted the role of dopamine in schizophrenia since they uncovered the chemical reactions behind the first antipsychotics. The exact nature of its role, however, has long been and remains in dispute.
The first model of dopamine's role schizophrenia was the dopamine hyperactivity hypothesis. This hypothesis asserts that hyperactivity of the brains dopaminergic systems is directly responsible for the symptoms of schizophrenia (Hemmings & Hemmings, 1978). In the period since its inception, this hypothesis has been accepted, studied and supported by both practitioners and researchers.
One supportive observation involves the actions of drugs that antagonize the activity of dopaminergic systems. Amphetamine is one such drug. When introduced in chronic amounts amphetamines can induce symptoms virtually identical to those of a paranoid psychosis (Hemmings & Hemmings, 1978). The secondary administration of a post-synaptic dopamine receptor antagonist will reduce the effects of the amphetamine, and eliminate the psychotic symptoms it created. The researchers also see this symptom reduction when they administer an antagonist to a schizophrenic subject (Kaplan & Sadock, 1995). The similarities of the two results suggest that reactions to amphetamines and schizophrenic psychosis are alike. This supports the belief that post-synaptic dopamine blockade is, at the very least, an initiating factor in a cascade of events correcting the abnormal excess in dopamine levels responsible for the symptoms of psychosis (Kaplan & Sadock, 1995).
Biochemical research, also, supports the belief in the association of increased dopamine concentrations and symptoms of schizophrenia. All the clinically effective antipsychotics, presently in use, are Dopamine2 (D2 )-like receptor antagonists (Nestler, 1997). When they are administered, a positive correlation is demonstrated between the potency of an antipsychotic and the levels in which dopamine's principle breakdown product, homovallinic acid (HVA), are present in urine, plasma and cerebrospinal fluid (CSF). Increased potencies of antipsychotics lead to both an increased dopamine breakdown into HVA and a lessened presentation of the positive symptoms of schizophrenia (Kaplan & Sadock, 1995).
Brain imaging techniques have provided much evidence indicating abnormal dopamine levels in schizophrenic patients. In the basal ganglia, increased densities of D2-like receptors are evident in the caudate and putamen (Kaplan & Sadock, 1995). Such abnormalities of the basal ganglia fit in well with the symptomology of schizophrenia. Peculiarities in motor functioning and normal frontal lobe modulatory activities are evident in schizophrenia and are believed to be basal ganglia controlled activities in normal subjects (Kaplan & Sadock, 1995). A second abnormality has been seen in the limbic system, an area long thought to be involved in schizophrenia because of its role in modulating the emotional aspects of behavior. Raised levels of both dopamine and HVA, particularly in the left amygdala have been found in many case studies (Kaplan & Sadock, 1995).
Both the limbic system and basal ganglia, are interconnected via the nucleus accumbens. This area is dense with dopaminergic innervation, and like the two systems it interconnects, increased numbers of D2-like receptors have been observed in cases of schizophrenia (Kaplan & Sadock, 1995).
Increases in D2-like receptor concentrations are also evident in the substantia nigra, thalamus and striatum. Overall, two studies have shown that there is a two to threefold increase in D2-like receptor concentrations in cases of schizophrenia (Kaplan & Sadock, 1995).
Recent studies, however, have shown that both dopamine and dopamine receptors are not at increased levels in all parts of the brain. In fact they are clearly at significantly reduced levels in some areas (Kaplan & Sadock, 1995). While D2-like receptors do seem to follow the pattern of increased concentration, there are several areas of the brain that have reduced D1-like receptor levels. PET scans have shown that D1-like receptors are at reduced levels in the prefrontal cortex. This occurrence explains certain cognitive deficiencies and is thought to be responsible for the negative symptoms of schizophrenia (Nestler, 1997).
Somatic therapy has provided further evidence for the existence of dopaminergic activities in schizophrenic illness. Typical antipsychotics induce behaviors and neurochemical changes through their affinities for striatal D2-type receptors (Ereshefsky & Lacombe, 1993). For a long time many people were convinced that this constituted proof that schizophrenia symptoms were the result of dopamine hyperacitvity. However, this idea was brought into question with the introduction of atypical antipsychotics. These drugs are much less efficacious at striatal D2 receptors, yet they are equally or more effective then typical neuroleptics.
These facts have led to the conclusion that D2 receptor antagonists, such as typical antipsychotics, which block the striatal targets of the nigrostriatal system are more likely responsible for motor disorder symptoms and extrapyramidal side effects of antipsychotics. The mesolimbic dopamine system, which all antipsychotics target, now seems responsible for changes in psychotic features (Kaplan & Sadock, 1995).
The Serotonin Studies
The dopamine hyperactivity hypothesis appears still to be a viable explanation for the psychosis (positive) symptoms of schizophrenia and is useful in explaining the actions of typical antipsychotics. However, this still raises the question of the relationship between the negative symptoms of schizophrenia and a new breed of psychiatric medications, known as atypical antipsychotics. This new class of medications, which I will later discuss in detail, has proven more effective than the older antipsychotics in controlling the negative symptoms of schizophrenia. The study of serotoninergic activity may provide the answer to the unexplained elements of schizophrenia, the predominance of negative symptoms and the actions of antipsychotics.
Serotonin (5-hydroxtryptamine, 5-HT) is an essential neurotransmitter synthesized from dietary tryptophan ( Kaplan & Sadock, 1995). Serotonin's possible role in schizophrenia was first recognized in the 1950's, when researchers noticed serotonin's similarity to lysergic acid diethylamide (LSD). LSD competes for and occupies serotonin's receptor sites with very high potency, resulting in psychosis like symptoms (Hemmings & Hemmings, 1978). These observations eventually led to a hyper serotonin hypothesis for schizophrenia.
Like dopamine, evidence for serotonin's actions in schizophrenia lies in observations of brain-behavior relationships, neurotransmitter systems, drug mechanisms and postmortem studies. Several studies have found elevated serotonin levels in blood platelet's (Kaplan & Sadock, 1995). Though these studies are suggestive, CSF levels of both serotonin and its primary metabolite 5-hydroxyindolacetic acid (5-HIAA) are considered more reflective of brain serotonin transmission. Unfortunately, reports of CSF levels are quite conflicting. Interpreting the data has been problematic with some researchers identifying raised prolactin and growth hormone levels, both of which central serotoninergic input directly regulates (Kaplan & Sadock, 1995).
Though these studies may be suggestive of serotonin's role in the hyperactivity associated with schizophrenia, the only consistently reported findings are that levels of serotonin are raised in the putamen, caudate, globus pallidus and prefrontal cortex (Kaplan & Sadock, 1995). These sites show a reduction of serotonin uptake sites, a possible explanation for findings of consistently increased levels of serotonin (Kapur & Remington, 1996).
The strongest evidence of serotonin's role in schizophrenia, by far, is the mechanism of atypical antipsychotic drugs like clozapine and risperidone. These drugs, which have provided dramatic improvements in patients that were resistant to other medications, interestingly enough, show a weak direct dopaminergic antagonist effect. They are, also, very selective of where and on which receptors they act (Kaplan & Sadock, 1995). One could conclude, therefore, that the principal mechanism of symptom relief with atypical antipsychotics is from something other then dopamine antagonism. This mechanism is probably serotonin antagonism. This hypothesis was confirmed when they combined typical antipsychotics with a 5-HT2 antagonist such as ritanserin. When used in combination they resulted in a substantial relief of patients negative symptoms and motoric side effects (Kaplan & Sadock, 1995).
Though serotonin does appear to have a role in schizophrenia, the assumption that it is directly responsible is still in question. Scientists have shown that serotoninergic projections for the dorsal raphe project directly to the substantia nigra. These projections inhibit dopamine neurons, which may provide neural modulation of a secondary set of dopaminergic systems outside the prefrontal cortex and surrounding systems (Kaplan & Sadock, 1995). Many have now theorized that increased levels of serotonin in the prefrontal cortex will result in lower dopamine levels in the area. These reduced dopamine levels, which may be responsible for the negative symptoms of schizophrenia, appear to lead to increased levels of dopamine in secondary dopaminergic systems. The increased dopamine levels are most likely responsible for the positive symptoms of schizophrenia.
The theory of a serotonin-dopamine interaction as the mechanism behind schizophrenia is beginning to gain wide acceptance. Serotonin's exact role, however, is still not clear. Its effects on dopamine aside, serotonin has a great deal of direct inhibitory effect on prefrontal neurons. One cannot ignore the possible role of such actions on schizophrenia and further investigation is warranted.
The GABA Studies
A second neurochemical that appears to have effects on dopamine levels is gamma-aminobutyric acid (GABA), an inhibitor amino acid. It is synthesized by the action of glutamic acid decarboxylase (GAD), which removes the alpha-carboxyl group of glutamate in an irreversible reaction. Dopamine production in dopaminergic cells is under the direct control of GABAergic neurons that produce GABA. An abnormally low amount of GAD, which by that lowers the effective GABA concentrations, promotes dopamine production (Kaplan & Sadock, 1995).
Pyridoxal-5'-phosphate (vitamin-B6) is an essential cofactor to GABA synthesis. An individual with a genetic pyridoxine metabolism abnormality or one who is taking a pyridoxine antagonist (i.e. isoniazid) may experience inadequate GAD activity and will have significant GABA deficiency leading to symptoms of irritability and confusion (Kaplan & Sadock, 1995). Confusion and irritability are symptoms often associated with schizophrenia (American Psychiatric Association, 1994).
Two very separate GABA receptors have been identified, GABAA and GABAB. Extensive testing of the GABAB receptor has shown that it is unrelated to schizophrenia. The GABAA receptor, however, has shown consistent and significant relevance to schizophrenia. This receptor is a member of the ligand-gated channel family of synaptic receptors.
Each GABAA receptor has three functional domains. The first domain is the GABA-recognition site. Each time GABA binds to this site a chloride channel, the second functional domain, opens and a one to 10-ms current flow occurs (Kaplan & Sadock, 1995). The third functional domain, the benzodiazepine receptor site, is found only on the GABAA receptors in the central nervous system (CNS). To this site pharmacologically induced agonists, such as diazepam (Valium) and clonazepam (Klonopin), will bind and by that increase GABA's affinity for its own binding sites. These benzodiazepines (BDZ), which I will discuss in detail later, are one of many significant treatments that, when used alone or as an augmenting agent, have successfully alleviated many of schizophrenias' symptoms (John & Mahableshwarkar, 1995).
Abnormalities of GABA activity in schizophrenia have been consistently shown in the last ten years. Schizophrenia is associated with both decreased numbers and abnormalities in the distribution of GABAergic neurons in the cortex, particularly in the cortical laminae (Kaplan & Sadock, 1995). In the most recent postmortem studies of schizophrenics, antipsychotic naive schizophrenics, and non schizophrenic controls, they found that there was a significant decrease in the number of GABA containing inter neurons, and a lessened amount of GABA production within these inter neurons in both of the schizophrenic groups (Nestler, 1997). The results of this study support the findings of abnormal GABA previously recorded.
GAD, the GABA precursor, has also been shown to have decreased activity in schizophrenics. This decreased activity has been found in the nucleus accumbens, putamen, amygdala and the hippocampus. Interestingly, a lowered concentration of GABA and GAD is a primary physiological factor in Huntington's Chorea. This disorder displays several schizophrenia type symptoms in its early stages (Hemmings & Hemmings, 1978). This suggests that loss of neuroinhibitory control of GABA, in specific regions of the brain, may be responsible for some of schizophrenias' symptoms.
One precursor to GABA production is glutamate, one of the brains most prevalent neurotransmitters. The presence of glutamate affects almost every neuron in the brain. Three main classes of glutamate receptors exist. They think two are unrelated to schizophrenia. The third class is the N-methyl-D-asparate (NMDA) receptor. This receptor has a substantial role in long term potentiation (a memory process) in the hippocampus. The NMDA-receptor density is highest in hippocampus and prefrontal cortex regions, two areas continually implicated in schizophrenia (Kaplan & Sadock, 1995).
Glutamate's role in the pathophysiology of schizophrenia was first brought to light in studies conducted on phencyclidines (a.k.a. PCP and angel dust) reactions at the NMDA-receptor complex. They have shown PCP to cause toxic effects that mimic both the positive and negative symptoms of schizophrenia, and exacerbate these symptoms in schizophrenic subjects. This PCP action occurs because of its antagonistic role on NMDA-receptors (Kaplan & Sadock, 1995).
Normally, binding of glycine or D-serine activates NMDA receptors. They recognize them as endogenous ligands, at the primary modulator site. This opens the calcium channels permitting cationic flux, which reduces membrane potential, excites post synaptic neurons and by that leads to glutamate transmission. PCP's antagonize glutamate transmission by binding to a modulator site that is only available when the ion channel has been activated. This binding blocks any further ionic flux (Coyle, et al., 1996).
The fact that NMDA-receptor abnormalities may produce psychotic symptoms is due to their effects on striatal and limbic dopaminergic neurotransmission. They have shown that NMDA-receptors mediate glutamate transmission. Glutamate transmission inhibits dopamine production that, in turn, inactivates glutamatergic transmission once the dopamine levels are significantly lowered (Kaplan & Sadock, 1995).
It makes sense that abnormalities in such a negative feedback loop could create an imbalance of certain neurotransmitters. Some current theorists believe that insufficient activation on NMDA subtypes of glutamate receptors may be a possible mechanism underlying several symptoms of schizophrenia (Coyle, et al.).
Many studies have confirmed that some form of a glutamate dysfunction does occur in schizophrenia. Dysfunctions of the glutamate system and increased levels of both glutamate and NMDA receptors have been seen in the amygdala and hippocampal region (Kaplan & Sadock, 1995). Psychopharmacological studies show that glutamate transmission agonists, which act on the glycine modulator site, typically reduce the amount negative symptoms (Coyle, et al.). Though it seems unlikely that glutamate transmission abnormalities can fully explain schizophrenias entire symptomology, its role in dopamine level regulation and the production and exacerbation of negative symptoms seems well founded.
The Norepinephrine Studies
The role of norepinephrine in the psychopathology of schizophrenia has been creating interest for a long time. The process by which this may occur, however, is not well understood. Norepinephrine is a catecholamine found in high concentrations throughout the nervous system, but it is primarily predominant in the hypothalamus, thalamus, limbic system, and the cerebellum. It is thought primarily to be involved in learning and memory, mood and affect, sleep-wake cycle regulation, anxiety, nocioperception, reinforcement and in the reward system (Kaplan & Sadock, 1995).
The question of norepinephrine involvement is interesting because of the apparent relationship between certain schizophrenic symptoms and raised norepinephrine levels. Heightening norepinephrine levels can induce one such symptom, anehedonia (Kaplan & Sadock, 1995). Anehedonia involves an impaired capacity for emotional gratification and decreased ability to experience pleasure (American Psychiatric Association, 1994). It was this observation that led to investigations of schizophrenias involvement in the norepinephrine reward system.
To comprehend these phenomena, understanding the norepinephrine reward system is necessary. The norepinephrine reward system is a series of positive and negative feedback circuits that aid in the modulation of both dopamine and norepinephrine production. The system begins at a series of norandrenergic receptors. Two primary subdivisions are the alpha-receptors and the beta-receptors. Beta-receptors, which are found in cortical projections and in the cerebellum, are primarily inhibitory in nature. Alpha-receptors, like beta-receptors, are found in cortical projections, but are primarily present in limbic system structures. Alpha-receptors are again divided into two sub groups, alpha1 and alpha2. Alpha2 receptors are pre-synaptic, while alpha1 are post-synaptic. All three receptors, two aplha's and a beta, are linked to cyclic adenosine monophasphate (cAMP) second messenger activation (Kaplan & Sadock, 1995).
They have also proposed that schizophrenia may be related to a defect in this noradrenergic reward system. Hyperactivity of the system would produce raised norepinephrine levels, which creates a state of heightened autonomic arousal. They have observed this state throughout all phases of the psychosis (Hemmings & Hemmings, 1978).
Selective neural degeneration within the norepinephrine reward system could account for many aforementioned effects. Such degeneration would likely occur on the beta-receptor, where the damage lessens or prevents inhibition of norepinephrine production (Kaplan & Sadock, 1995). This concept has been supported by a study that suggested that the beta-receptor agonist popranolol (Inderal) alleviates schizophrenic symptoms. A second, more recent, study somewhat confirms the popranolol experiment, while introducing a second receptor correlation to schizophrenia. This study showed a negative correlation between beta-adrenergic receptor activity on lymphocytes and the antipsychotic effects of popranolol. This suggests that when beta-receptor inhibitory activity is at very low levels, norepinephrine levels increase. These levels cause schizophrenia like symptoms. The addition of popranolol reactivates beta-receptors, eventually lowers the norepinephrine levels and alleviates the schizophrenia symptoms. The study also found an increase of alpha2 receptors, which cause a deficiency in cAMP production (John & Mahableshwarkar, 1995). Such a deficiency could be another form of neural circuit breakdown occurring in schizophrenia.
Other biochemical and pharmacological studies of norepinephrine involvement have been troublesome and inconsistent. Some more reliable studies have shown norepinephrine, and its metabolite 3-methoxyl-4-hydroxyphenylglycol (MHPG), at increased levels in plasma, urine and CSF. Post mortem studies have shown the same increases in the limbic system, mesencephalon, and nucleus accumbens (Kaplan & Sadock, 1995).
Research shows that antipsychotic drugs inhibit norepinephrine metabolism. However, recent studies show that elevated norepinephrine levels are present both before and after somatic treatment, in schizophrenic subjects (Kaplan & Sadock, 1995).
The pharmacological evidence of norepinephrine's involvement in schizophrenia is weak. Except for popranolol, norepinephrine agents have had mixed success. Two studies have shown mild success with one such agent, clonidine. Though it was effective in lowering norepinephrine and MHPG plasma levels, the relief of symptoms was only marginal when compared to antipsychotics. As an augmenting agent clonidine was largely unsuccessful (John & Mahableshwarkar, 1995)
The raised levels of norepinephrine in schizophrenia are no longer in doubt. What norepinephrine's role is, however, what part its reward system plays, and to what extent it modulates dopamine levels is still under question.
The Treatment of Schizophrenia
Modern treatment for schizophrenia relies primarily on somatic drug therapy. Pharmacological treatments for schizophrenia did not begin, however, until approximately a century ago. Before this, beliefs surrounding all mental illness's were grounded in religious dogma. The mentally ill were either hidden away, institutionalized or executed. It was not until the 19th century that they made any substantial advances. The first advance occurred when they discovered the mood altering effects of exogenous opiates. They still hold the hypothesized relationship between the opiate system and schizophrenia today. Other treatments included sedatives, electroconvulsive therapy (ECT), artificially induced comas and frontal lobotomies. Though each treatment did have benefits, the side effects and complications, associated with them, often outweighed any therapeutic results (Kaplan & Sadock, 1995).
In 1979 the discovery of Chlorpromazine (CPZ or Thorazine) revolutionized psychiatric treatment. Though originally designed as a sedative for cattle, they soon recognized its antipsychotic benefits in humans (Hemmings & Hemmings, 1978). CPZ, which is still used widely today, was experimented with for the next fourteen years despite there being little understanding of how or why it worked.
In 1963 Arvid Carleson and M. Lindquist noted the impact of antipsychotic medications on dopamine metabolism (Kaplan & Sadock, 1995). From then on pharmacological knowledge would build at increasing paces, resulting in today's lightning fast advances.
Currently two categories of antipsychotics are in common use. They term these typical and atypical antipsychotics.
Typical antipsychotics, or neuroleptics as they previously termed them, were the first antipsychotics to reach mainstream use. Neuroleptics primarily act on the brains dopaminergic pathways and show very little regional specificity. They are usually effective in controlling the positive symptoms of the illness but are associated with potentially lethal complications like neuroleptic malignant syndrome or extrapyramidal side effects(EPS) and the long term problem, tardive dyskinesia. Today they are still in common use, but over that last few years the have begun to lose their position as the primary assault against schizophrenia, as newer, atypical antipsychotic drugs were developed (F. Decaire, personal communication, April, 1997).
One of the most common, and most potent, typical antipsychotics in current use is haloperidol (Haldol). Haldol is thought to work by blocking dopaminergic neurotransmission in the mesolimbic tract (Kaplan & Sadock, 1995). In the mesolimbic tract dopaminergic pathways are thought to be involved in arousal, memory, stimulus processing, locomotor activity, and motivational behavior. Hyperactivity in this area causes over excitation of the different processes and is associated with the positive symptoms of schizophrenia (Ereshefsky & Lacombe, 1993).
Haloperidol, along with other typical antipsychotics is, unfortunately, not very selective in which dopaminergic pathways it antagonizes. This can lead to unwanted reactions in the mesocortical tract and the nigrostriatal pathway. The mesocortical tract projects into the prefrontal and frontal cortices. This system has been implicated in cognition, communication and social activity impairment (Ereshefsky & Lacombe, 1993). They have observed diminished dopamine activity in this area in numerous schizophrenia studies, and it is thought to be responsible for degradation in the mesocortical's activities (Kaplan & Sadock, 1995). As a result, they think reduced levels of dopamine are the primary cause of schizophrenia's negative symptoms. For these reasons, haloperidol, which reduces dopamine levels even further, is relatively ineffective in relieving negative symptoms. In fact, at high doses haloperidol can lead to exacerbation of these symptoms (Ereshefsky & Lacombe, 1993).
The nigrostriatal pathway is involved in neuroleptic therapy. It originates in the zona compacta, projecting through to the basal ganglia. Typical antipsychotics block dopamine receptors at these sites, leading to motor dysfunction and EPS side effects. Haldol in particular seems to have a particular affinity for causing EPS in young males, a group that makes up the bulk of newly diagnosed schizophrenics (F. Decaire, personal communication, April, 1997). Such side effects are the main reason that they discontinue a typical antipsychotic in individual cases (Ereshefsky & Lacombe, 1993).
The newest category of medication used in the treatment of schizophrenia is the atypical antipsychotic. They call these antipsychotics atypical because they differ dramatically in their actions on dopaminergic and serotoninergic receptors. These medications act on dopaminergic paths in only a minute way. Their primary roles are as antagonists to the serotoninergic system (Kaplan & Sadock, 1995). They are also associated with a lower incidence of unwanted side effects. Two atypical antipsychotics are currently in worldwide use. These are clozapine and resperidone. A third one, called olanzopine, has just recently been approved and is not yet in common use.
Clozapine (Clorazil, tetracyclic N-methyl-piperanzinyl-dibenzodiazepine HF-1854) is a heterotricyclic benzodiazepine derivative. It was one of the first antipsychotics to be found that had only a very limited ability to induce EPS (Baldessarini & Frankenburg, 1991). Clozapine's D1 and D2 receptor antagonism affinities are low. Unlike typical antipsychotics Clozapine has a regional specificity for mesolimbic dopamine tracts, with only weak affinities for striatal D2 receptors (Azpiroz, Brain, Garmendia, Sanchez, & Simon, 1991). The regional specificity allows clozapine, and the other atypical antipsychotics, to act upon the mesolimbic induced positive symptoms without creating major side effects. Clozapine does not block behaviors induced by amphetamine or apomorphine, further suggesting that any dopamine antagonism is secondary to other activities (Baldessarini & Frankenburg, 1991).
Clozapine's main receptor affinities are to HT2 and HT3 receptors. Other potent affinities include alpha1-adrenergic receptors, sigma-opoids, and muscarinic acetylcholine receptors. Clozapine may indirectly induce super-sensitivity to GABA and therefor secondarily inhibit dopamine (Baldessarini & Frankenburg, 1991).
Clozapine's serotonin antagonism action can be seen in drug augmentation studies. Fluoxetine, a selective serotonin uptake inhibitor, has been somewhat successful in the treatment of both positive and negative symptoms. When used to augment traditional antipsychotics fluoxetine showed marked improvement of negative symptoms. When used with clozapine, they observed no significant differences. This suggests that fluoxetine's therapeutic action, serotonin level reduction, was already occurring at an optimum rate (Ball, Breir, Bryant, Buchanan & Kirkpatrick, 1996).
The antipsychotic effects of clozapine seem to result in the lessening of both positive and negative symptoms, without the system degenerating side effects. Many studies, each with thousands of subjects, have stated that most patients showed symptom improvement on clozapine. Of neuroleptic resistant subjects 79% showed superior clinical results with clozapine (Baldessarini & Frankenburg, 1991).
Clozapine appears to have an acute, clearly dose dependent, effect on aggressive behavior associated with schizophrenia. Low doses suppressed aggressive behavior, while high doses abolished it completely (Azpiroz, et al.).
Even clozapine has unwanted side effects. These unwanted reactions have necessitated the discontinuation of clozapine therapy in 8% of patients. Minor, but relatively common, side effects include akathisia (restlessness), muscle stiffness, sedation, nausea, vomiting, excess salivation and weight gain (Baldessarini & Frankenburk, 1991). Some major, yet common, complications include hypotension (low arteriole blood pressure), blood dyscrasia (abnormal material in blood), and hyperprolactinemia (increased prolactin levels), tardive dyskinesia (involuntary movements), neuroleptic malignant syndrome (muscle rigidity, high temperature ) and liver abnormalities (Kaplan & Sadock, 1995). These side effects are seen in all antipsychotics, both typical and atypical, but they occur more often with neuroleptic therapy.
The most deadly side effect of clozapine is agranulocytosis. Abnormally low granulocyte or total white blood cell count characterizes agranulocytosis (Baldessarini & Frankenburg, 1991). This factor led to eight deaths in Finland and the eventual removal of clozapine from the North American market for more than ten years (Addington, et al., 1996). Upon its return, they implemented a new regime of tests to protect patients treated with clozapine. Weekly they follow hematological monitoring religiously and as a result only one death due to agranulocytosis has occurred (Baldessarini & Frankenburg, 1991). This strict regime is not common worldwide however. In China, where access to sophisticated technology is limited, doctors simply monitor clozapine patients for finger tremors. Finger tremors are usually the first visible indicators of a negative reaction to clozapine. This simple test is almost as effective as the more sophisticated and expensive testing system used here (F. Decaire, personal communication, April, 1997).
Although clozapine has proven extremely successful as an antipsychotic, in North America it cannot be employed to treat schizophrenia until trials of all other typical antipsychotics have failed to produce significant results. This fact is not directly due to the risk of agranulocytosis, but to the relatively high cost of the drug and both the complexity and expense of weekly hematological monitoring (F. Decaire, personal communication, April, 1997).
Risperidone (Resperidol) is the second atypical antipsychotic to come into common use. Unlike clozapine it can be used as a first line of assault against schizophrenia, and is in wide spread use throughout North America. Risperidone acts upon the same receptor sites as clozapine with a few extra affinities for histamine H1-receptors, benzodiazepine receptors, 5-HT1-receptors, alpha2-adrenergic, and beta-adrenergic receptors (Ereshefsky & Lacombe, 1993).
Risperidone's side effect profile is similar to clozapine, however, the risks of tardive dyskinesia appear lower and no case of agranulocytosis has ever been recorded (Ereshefsky & Lacombe, 1993). Risperidone appears to reduce both positive and negative symptoms with the same efficiency as clozapine (Arnott & Chovinard, 1993). Its more frequent prescription rate appears to be due to its lower cost and lessened risk of agranulocytosis.
Olanzopine (Zyprexia, 2-methyl-4[4-methyl-1-piperazinyl]-10H-thieno<2,3-b><1,5>benzodiazepine) is the newest approved atypical antipsychotic. Its efficiency seems to match clozapine and risperidone, while its side effect profile is identical to resperidone (Beasly, et al., 1996). Olanzopine has not provided us with amazing new results or lessened side effects. It does, however, add to our arsenal of effective medications antipsychotic that can be used, and hopefully aid, the large percentage of patients that continue to experience the debilitating effects of schizophrenia despite the use of typical antipsychotic medications.
Other new antipsychotic medications are on the horizon. Remoxipride is one example. It differs substantially from both typical and atypical antipsychotics. Remoxipride is a substitute benzamide, a selective D2 antagonist and potent sigma-receptor blocker (Meltzer, 1993). It is only a moderately potent dopamine antagonist, weaker then both haloperidol and chlorpromazine, and acts upon only striatum receptors. This limbic performance and remoxipride's virtually nonexistent D1 affinity may account for its antipsychotic ability with virtually none of the side effects usually associated with antipsychotic medications. Remoxipride's antipsychotic effects tend to match those of haloperidol, with side effects lower then any other currently used antipsychotic (Meltzer, 1993).
Though it may prove to be one of the weaker antipsychotics when it comes to eliminating schizophrenic symptoms, remoxipride's virtually nonexistent side effects may lead to the drugs usefulness in subjects with severe neuroleptic resistence and providing new directions in therapeutic drug development.
Benzodiazepines (BDZ's), such as Valium, can induce many neurobehavioural effects through its actions on GABAergic and other systems (Kaplan & Sadock, 1995). They are often used as an augmenting agent with typical antipsychotics, providing decreased hostility, tension, and excitement, as well as increased spontaneous social engagement. Diazepam and chlordiazapoxide are the most commonly used benzodiazepines (John & Mahableshwarkar, 1995). These two BDZ's are safer, longer lasting and have milder withdraw symptoms.
It seemed likely that some antipsychotic activity does occur with BDZ's because they are known to increase GABA activity and then, in theory, reduce dopamine activity (Kaplan & Sadock, 1995). This idea appears to have been confirmed with the introduction of bretazenil, an imidazobenzodiazepine that is highly selective and short acting BDZ-receptor agonist (Berdah-Tordjman & Delini-Stula, 1996). Bretazenil provided a 50% decrease in symptoms, 10% more then the DSM-IV requires for a drug to be considered clinically efficient (American Psychiatric Association, 1994). However benzodiazepine's must be used carefully due to their potential of abuse, seizure and social withdraw (John & Mahableshwarkar, 1995).
Like benzodiazepines, barbiturates also aid in increased GABA activity. Barbiturates compete directly with picrotoxin, a convulsent, and act in an opposite manner, as an anticonvulsent. At lower doses barbiturates can potentiate the effects of GABA, increasing the duration of ion channel opening, while at higher doses they may induce channel activity directly (Kaplan & Sadock, 1995).
A third antipsychotic augmenting agent that is commonly used is lithium carbonate. Lithium carbonate is a medication widely used in the treatment of bipolar affective disorder. Studies have shown that its addition to neuroleptic therapy improved outcomes for treatment resistant patients. Lithium, used alone as an antipsychotic, was ineffective. They documented improvements in psychotic symptoms, cooperation, social competence, neatness, irritability and excitement (John & Mahableshwarkar, 1995). Some researchers have found that, with the addition of lithium, they could reduce the dose of antipsychotics to a level that lessens the risk of side effects (Kaplan & Sadock, 1995).
Electroconvulsive therapy has proven be a successful antidepressant. It is particularly useful in treating extremely suicidal, severely depressed individuals. Tried as an antipsychotic, ECT treatment had only very limited success. In the short term, symptoms appear reduced but soon return. When used in conjunction with antipsychotic medications ECT has shown to have some long term benefits (Kaplan & Sadock, 1995).
Schizophrenia is an extensively investigated mental illness that is still widely misunderstood. Its origins and mechanisms of action are continually being investigated, providing mountains of research and almost as many theories. Schizophrenia is a complex disorder. The studies that have identified different underlying causes of the disease support the conclusion that schizophrenia is likely best used as a term to describe a group of disorders rather than a single disease. All studies, to date, have identified some neural circuit involvement in schizophrenia. Therefore, concentrating further investigation on a neurocircuit theory of schizophrenia might be useful. A study of genetically linked schizophrenics might reveal some similar neurocircuit abnormalities that will greatly increase our understanding of the disease.
Antipsychotics have aided significantly in the reduction of schizophrenic symptoms. Augmenting agents have shown promise in alleviating the system degrading side effects of such treatments. These drugs provide a window of opportunity for schizophrenia's victims. It is imperative to take timely advantage of this opportunity. Even the purveyors of these new, often dramatically successful, medications admit that such medications are not magic pills. They open a window of opportunity for the successful treatment of the victims of this disabling disease. Simple, unilateral use of medication to treat schizophrenia will likely end in a recurrence of psychosis. Just as a diabetic has to learn to adopt a new lifestyle as well as take their prescribe insulin dose, antipsychotic medication alone will not control the symptoms of schizophrenia. The most effective treatment of schizophrenia consists of following up the atypical medications with psychosocial rehabilitative training and support. Psychosocial rehabilitation enables patients to take advantage of their new found abilities and hopefully prevent relapse of this debilitating mental illness.
Hopefully, in the future, we will have learned to control, or even eradicate, this devastating illness that cripples so many of our friends and family members. Only experimentation and research will provide the answer.
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Written By Michael W. Decaire