Psychotic Behavior and Dementia-Roles of Specific Neurotransmitter Systems

Psychotic Behavior and Dementia-Roles of Specific Neurotransmitter Systems

Clinical studies of patients with different psychoses or different types of dementia have suggested that many of these conditions result from diminished function of neurons that secrete a specific neurotransmitter. Use of appropriate drugs to counteract loss of the respective neurotransmitter has been successful in treating some patients.

This disease results from loss of neurons in the substantia nigra whose nerve endings secrete dopamine in the caudate nucleus and putamen. We pointed out that in Huntington’s disease, loss of GABA-secreting neurons and acetylcholine-secreting neurons is associated with specific abnormal motor pat-terns plus dementia occurring in the same patient.

Depression and Manic-Depressive Psychoses—Decreased Activity of the Norepinephrine and Serotonin Neurotransmitter Systems

Much evidence has accumulated suggesting that mentaldepression psychosis, which occurs in about 8 millionpeople in the United States, might be caused by dimin-ished formation in the brain of norepinephrine or sero-tonin, or both. (New evidence has implicated still other neurotransmitters.) Depressed patients experience symptoms of grief, unhappiness, despair, and misery. In addition, they often lose their appetite and sex drive and have severe insomnia. Often associated with these is a state of psychomotor agitation despite the depression.

Moderate numbers of norepinephrine-secretingneurons are located in the brain stem, especially inthe locus ceruleus. These neurons send fibers upward to most parts of the brain limbic system, thalamus, and cerebral cortex. Also, many serotonin-producingneurons located in the midline raphe nuclei of the lowerpons and medulla send fibers to many areas of the limbic system and to some other areas of the brain.

A principal reason for believing that depres-sion might be caused by diminished activity of norepinephrine- and serotonin-secreting neurons is that drugs that block secretion of norepinephrine and sero-tonin, such as reserpine, frequently cause depression. Conversely, about 70 per cent of depressive patients can be treated effectively with drugs that increase the exci-tatory effects of norepinephrine and serotonin at the nerve endings—for instance, (1) monoamine oxidaseinhibitors, which block destruction of norepinephrineand serotonin once they are formed; and (2)tricyclicantidepressants, such as imipramine and amitriptyline,which block reuptake of norepinephrine and serotonin by nerve endings so that these transmitters remain active for longer periods after secretion.

Mental depression can be treated by electroconvul-sive therapy—commonly called “shock therapy.” In this therapy, electrical current is passed through the brain to cause a generalized seizure similar to that of an epilep-tic attack. This has been shown to enhance norepine-phrine activity.

Some patients with mental depression alternate between depression and mania, which is called either bipolar disorder or manic-depressive psychosis, and afew people exhibit only mania without the depressive episodes. Drugs that diminish the formation or action of norepinephrine and serotonin, such as lithium com-pounds, can be effective in treating the manic phase of the condition.

It is presumed that the norepinephrine and serotonin systems normally provide drive to the limbic areas of the brain to increase a person’s sense of well-being, to create happiness, contentment, good appetite, appropri-ate sex drive, and psychomotor balance—although too much of a good thing can cause mania. In support of this concept is the fact that pleasure and reward centers of the hypothalamus and surrounding areas receive large numbers of nerve endings from the norepinephrine and serotonin systems.

Schizophrenia—Possible Exaggerated Function of Part of the Dopamine System

Schizophrenia comes in many varieties. One of the most common types is seen in the person who hears voices and has delusions of grandeur, intense fear, or other types of feelings that are unreal. Many schizophrenics (1) are highly paranoid, with a sense of persecution from outside sources; (2) may develop incoherent speech, dis-sociation of ideas, and abnormal sequences of thought; and (3) are often withdrawn, sometimes with abnormal posture and even rigidity.

There are reasons to believe that schizophrenia results from one or more of three possibilities: (1) mul-tiple areas in the cerebral cortex prefrontal lobesin which neural signals have become blocked or where processing of the signals becomes dysfunctional because many synapses normally excited by the neurotransmit-ter glutamate lose their responsiveness to this transmit-ter; (2) excessive excitement of a group of neurons that secrete dopamine in the behavioral centers of the brain, including in the frontal lobes; and/or (3) abnormal func-tion of a crucial part of the brain’s limbic behavioralcontrol system centered around the hippocampus.

The reason for believing that the prefrontal lobes are involved in schizophrenia is that a schizophrenic-like pattern of mental activity can be induced in monkeys by making multiple minute lesions in widespread areas of the prefrontal lobes.

Dopamine has been implicated as a possible cause of schizophrenia because many patients with Parkinson’s disease develop schizophrenic-like symptoms when they are treated with the drug called L-dopa. This drug releases dopamine in the brain, which is advantageous for treating Parkinson’s disease, but at the same time it depresses various portions of the prefrontal lobes and other related areas.

It has been suggested that in schizophrenia excess dopamine is secreted by a group of dopamine-secreting neurons whose cell bodies lie in the ventral tegmentum of the mesencephalon, medial and superior to the sub-stantia nigra. These neurons give rise to the so-called mesolimbic dopaminergic system that projects nervefibers and dopamine secretion into the medial and ante-rior portions of the limbic system, especially into the hippocampus, amygdala, anterior caudate nucleus, and portions of the prefrontal lobes. All of these are pow-erful behavioral control centers.

An even more compelling reason for believing that schizophrenia might be caused by excess production of dopamine is that many drugs that are effective in treat-ing schizophrenia—such as chlorpromazine, haloperi-dol, and thiothixene—-all either decrease secretion of dopamine at dopaminergic nerve endings or decrease the effect of dopamine on subsequent neurons.

Finally, possible involvement of the hippocampus in schizophrenia was discovered recently when it was learned that in schizophrenia, the hippocampus is oftenreduced in size, especially in the dominant hemisphere.

Alzheimer’s Disease—Amyloid Plaques and Depressed Memory

Alzheimer’s disease is defined as premature aging of the brain, usually beginning in mid-adult life and progress-ing rapidly to extreme loss of mental powers—similar to that seen in very, very old age. The clinical features of Alzheimer’s disease include (1) an amnesic type of memory impairment, (2) deterioration of language, and (3) visuospatial deficits. Motor and sensory abnormali-ties, gait disturbances, and seizures are uncommon until the late phases of the disease. One consistent finding in Alzheimer’s disease is loss of neurons in that part of the limbic pathway that drives the memory process. Loss of this memory function is devastating.

Alzheimer’s disease is a progressive and fatal neu-rodegenerative disorder that results in impairment of the person’s ability to perform activities of daily living as well as a variety of neuropsychiatric symptoms and behavioral disturbances in the later stages of the disease. Patients with Alzheimer’s disease usually require continuous care within a few years after the disease begins.

Alzheimer’s disease is the most common form of dementia in the elderly and about 5 million people in the United States are estimated to be afflicted by this disorder. The percentage of persons with Alzheimer’s disease approximately doubles with every five years of age, with about 1 percent of 60-year-olds and about 30 percent of 85-year-olds having the disease.

Alzheimer’s Disease Is Associated with Accumulation of Brain Beta-Amyloid Peptide. Pathologically, one finds increasedamounts of beta-amyloid peptide in the brains of patients with Alzheimer’s disease. The peptide accumu-lates in amyloid plaques, which range in diameter from 10 micrometers to several hundred micrometers and are found in widespread areas of the brain, including in the cerebral cortex, hippocampus, basal ganglia, thalamus, and even the cerebellum. Thus, Alzheimer’s disease appears to be a metabolic degenerative disease.

A key role for excess accumulation of beta-amyloid peptide in the pathogenesis of Alzheimer’s disease is suggested by the following observations: (1) all cur-rently known mutations associated with Alzheimer’s disease increase the production of beta-amyloid peptide; (2) patients with trisomy 21 (Down syndrome) have three copies of the gene for amyloid precursor protein and develop neurological characteristics of Alzheimer’s disease by midlife; (3) patients who have abnormality of a gene that controls apolipoprotein E, a blood protein that transports cholesterol to the tissues, have accelerated deposition of amyloid and greatly increased risk for Alzheimer’s disease; (4) transgenic mice that overproduce the human amyloid precursor protein have learning and memory deficits in associa-tion with the accumulation of amyloid plaques; and (5) generation of anti-amyloid antibodies in humans with Alzheimer’s disease appears to attenuate the disease process.

Vascular Disorders May Contribute to Progression of Alzheimer’s Disease. There is also accumulating evidence thatcerebrovascular disease caused byhypertension and atherosclerosis may play a role in Alzheimer’s disease.Cerebrovascular disease is the second most common cause of acquired cognitive impairment and dementia and likely contributes to cognitive decline in Alzheimer’s disease. In fact, many of the common risk factors for cerebrovascular disease, such as hyperten-sion, diabetes, and hyperlipidemia, are also recognized to greatly increase the risk for developing Alzheimer’s disease.