The Disordered Mind

by Eric R. Kandel

  Paul Charpentier, a French chemist working for the pharmaceutical firm Rhône-Poulenc, had begun work on an antihistamine that he hoped would be effective against allergies but without producing the numerous side effects of existing antihistamines. The drug he developed in 1950 was called Thorazine (its generic name is chlorpromazine). As Thorazine went into clinical trials, everyone was amazed at its effect: it made people calmer, much more relaxed.

  Seeing Thorazine’s calming effects, Pierre Deniker and Jean Delay, two French psychiatrists, decided to give the drug to their psychotic patients. It was a magic bullet, particularly for their patients with schizophrenia. By 1954, when the U.S. Food and Drug Administration approved the drug, 2 million people in the United States alone had been treated with Thorazine. A great many of them were able to leave state mental hospitals.

  Thorazine was originally thought to act as a tranquilizer, calming patients without sedating them unduly. However, by 1964 it became clear that Thorazine and related drugs produce specific effects on the positive symptoms of schizophrenia: they mitigate or abolish delusions, hallucinations, and some types of disordered thinking. Moreover, if patients take them during periods of remission, these antipsychotic drugs tend to reduce the rate of relapse. Yet the drugs have significant side effects, including neurological symptoms characteristic of Parkinson’s disease. People taking the drugs develop a tremor of their hands, bend forward when they walk, and experience rigidity in their body.

  Scientists eventually developed new drugs with fewer and less severe neurological side effects. Those drugs include clozapine, risperidone, and olanzapine, and they all are effective at controlling positive symptoms of the disease. Only clozapine is considered to be more effective than the earlier antipsychotics in treating the negative symptoms and cognitive defects of schizophrenia, and then only marginally so. The newer drugs are referred to as “atypical” antipsychotics because they all produce fewer Parkinson’s-like side effects than the earlier, “typical” drugs.

  The first clue to how typical antipsychotics work came from analysis of their neurological side effects. Since these drugs produce the same effects on movement as Parkinson’s disease, which is caused by a deficiency in the modulatory neurotransmitter dopamine, scientists reasoned that the drugs might act by reducing dopamine in the brain. They also reasoned, by extension, that schizophrenia might result in part from excessive action of dopamine. In other words, reducing dopamine in the brain might account for both the drugs’ therapeutic effects and their adverse side effects.

  How would this work? How could a drug produce both undesirable and beneficial effects? It depends on where in the brain the drug acts.

  When neurons release dopamine into a synapse, the dopamine ordinarily binds to receptors on target neurons. If those receptors are blocked by antipsychotics, the action of dopamine is attenuated. As it turns out, many typical antipsychotics act by blocking dopamine receptors. This finding bolstered the idea that either excessive dopamine production or an excessive number of dopamine receptors is an important factor in causing schizophrenia. It also supported the idea emerging from studies of Parkinson’s disease that dopamine deficiency causes abnormal movement. Thus, understanding the role that dopamine plays in schizophrenia also taught us a bit more about the normal functioning of this neurotransmitter.

  Most dopamine-producing neurons are located in two clusters in the midbrain: the ventral tegmental area and the substantia nigra. The axons that extend outward from these two clusters of neurons form the neural circuits known as the dopaminergic pathways. Two of these dopaminergic pathways—the mesolimbic pathway and the nigrostriatal pathway—are the neural pathways primarily affected in schizophrenia and are therefore the most important ones to examine in looking for treatments (fig. 4.3).

  The mesolimbic pathway extends from the ventral tegmental area to parts of the prefrontal cortex, hippocampus, amygdala, and nucleus accumbens. These regions are important for thought, memory, emotion, and behavior—the mental functions that are adversely affected by schizophrenia. The nigrostriatal pathway begins in the substantia nigra and extends to the dorsal striatum, a region of the brain that is involved with spatial and motor functions. This is the pathway that degenerates in Parkinson’s disease. Antipsychotic drugs act on both pathways, which explains how they can produce both therapeutic effects and adverse side effects.

  To test the validity of the idea that typical antipsychotics block dopamine receptors, scientists had to identify the specific dopamine receptors on which the drugs exert their effect. There are five major known types of dopamine receptors, D1 to D5. Typical antipsychotic drugs were found to have a high affinity for the D2 receptor; atypical antipsychotics have a lower affinity for this receptor.

  Figure 4.3. The two dopaminergic pathways affected by antipsychotic drugs: the mesolimbic pathway and the nigrostriatal pathway. Dopamine-producing neurons are concentrated in the ventral tegmental area, which transmits dopamine along the mesolimbic pathway, and in the substantia nigra, which sends dopamine along the nigrostriatal pathway.

  D2 receptors are normally present in particularly large numbers in the striatum and to a lesser extent in the amygdala, the hippocampus, and parts of the cerebral cortex. Research suggests that wholesale blocking of D2 receptors in the nigrostriatal pathway results in too little dopamine in regions of the striatum that require adequate dopamine for normal movement. This explains the Parkinson’s-like effects of typical antipsychotics. Atypical antipsychotics also block the D2 receptors in the striatum, but because these drugs have a lower affinity for D2 receptors, they block fewer of them, thus leaving movement intact.

  Another way in which atypical antipsychotics differ from typical ones is that their affinities are more diverse. Atypical antipsychotics bind to D4 dopamine receptors and to receptors for other modulatory neurotransmitters as well, notably serotonin and histamine. This diversity of action raises the possibility that schizophrenia involves abnormalities in serotonergic and histaminergic pathways as well as in dopaminergic pathways.

  EARLY INTERVENTION

  One key to improved treatment of any medical disorder is early intervention. Scientists have successfully identified high-risk lifestyles for a heart attack and have developed interventions to prevent them. Why not do the same for schizophrenia?

  We know that genetic and environmental factors act on the developing brain before birth and in early childhood to increase the risk of schizophrenia, and we may eventually be able to pinpoint them and intervene before the disease manifests itself years later. One genetic variation that acts on the developing brain has already been identified, as we shall see later. In addition, computerized brain imaging can sometimes indicate areas of increased dopamine activity, which might serve as a biomarker of the disease before psychosis develops.

  As we have seen, the first psychotic episode of schizophrenia is usually triggered in late adolescence or early adulthood, when the stresses of daily life can prove too heavy a burden to bear. If treatment is begun immediately, young people can usually be stabilized. All too often, however, they don’t seek treatment until after they have been sick for several years. In addition, if a person with schizophrenia stops taking medication, the regulation of dopaminergic pathways and other neural circuits will be disrupted, and he or she will begin to experience symptoms again.

  The most promising preemptive treatment thus far is to provide cognitive psychotherapy to adolescents and young adults who exhibit early signs of schizophrenia, in what is known as the prodromal phase. These signs, which precede the first psychotic episode, are unfortunately a bit vague. A young person may be slightly depressed, not handling stress as well as usual, or feeling less inhibited than usual—often saying out loud what he or she is thinking. As we know, major psychiatric disorders are often characterized by exaggerations of everyday behavior, so initial, subtle changes can be difficult to recognize.

  Preemptive treatments are designed to help young people build up the cog
nitive capacity and executive functions of the prefrontal cortex that regulate their ability to control their behavior. This will improve their ability to manage day-to-day stress and organize their lives more effectively, thereby reducing the likelihood that they will have a psychotic episode.

  PREDISPOSING ANATOMICAL ABNORMALITIES

  During pregnancy, environmental factors, such as nutritional deficits, infections, or exposure to stress or toxins, may interact with genes to increase the risk that the fetus will develop abnormally functioning dopaminergic pathways. Malfunctioning pathways set the stage for developing schizophrenia years later, when the brain of the adolescent responds to the stresses of everyday life by generating excessive dopamine.

  The same adverse environmental events or situations during pregnancy may also affect the way certain circuits in the prefrontal cortex develop, circuits that mediate the thinking and executive functions of the brain. Abnormalities in these neural circuits result in the cognitive symptoms that people with schizophrenia experience, notably a disturbance of working memory.

  Think of working memory as the ability to remember, for a short period of time, the information you need to guide your thoughts or behavior. Right now, you are using your working memory to keep in mind the points you just read so that the next thing you read will follow logically. Impaired working memory would make this difficult, just as it would make it hard for you to plan your day or hold a job.

  Working memory develops from childhood through the late teens, getting progressively better over time. At age seven, children who will be diagnosed with schizophrenia ten or fifteen years later have normal working memory. But by age thirteen, their working memory has fallen well below where it should be at that stage of development. A key component of working memory is the pyramidal neurons of the prefrontal cortex, so called because the cell body of these neurons is shaped roughly like a triangle. In every other respect these cells are like other neurons, both structurally and functionally.

  As we have seen, neurons send information outward along the axon, which forms synaptic connections with a target cell’s dendrites. Most of a pyramidal neuron’s synapses are located on small protrusions from the dendrites called dendritic spines. The number of dendritic spines on a neuron is a rough measure of the amount and richness of the information it receives.

  Dendritic spines begin to form on pyramidal neurons during the third trimester of pregnancy. From then through the first few years of life, the number of dendritic spines, and the number of synapses on them, expands rapidly. In fact, a three-year-old’s brain contains twice as many synapses as an adult’s brain. Beginning at about puberty, synaptic pruning removes the dendritic spines that the brain isn’t using, including spines that aren’t actually helping working memory. Synaptic pruning becomes particularly active during adolescence and early adulthood.

  Figure 4.4. Pruning of a pyramidal neuron’s dendritic outgrowth—the dendritic spines in the normal brain and the brain of someone with schizophrenia

  In schizophrenia, synaptic pruning appears to go haywire during adolescence, snipping off far too many dendritic spines (fig. 4.4). Consequently, the pyramidal neurons are left with too few synaptic connections in the prefrontal cortex to form the robust neural circuits we need for an adequate working memory and other complex cognitive functions. This excessive-pruning hypothesis for schizophrenia, first proposed by Irwin Feinberg, now at the University of California, Davis,2 has been documented by David Lewis and Jill Glausier at the University of Pittsburgh.3 A similar defect is thought to affect pyramidal neurons located in the hippocampus of people with schizophrenia, which would adversely affect memory.

  Since synaptic pruning is designed to rid the brain of unused dendrites, Lewis reasoned that excessive pruning might be the result of not having enough dendrites in play—that is, something might be preventing the pyramidal neurons from receiving enough sensory signals to keep the dendritic spines busy and functional. The likely culprit in this case would be the thalamus, the part of the brain that is supposed to relay sensory signals to the prefrontal cortex. If the thalamus has fallen down on the job, it might be because the thalamus itself has lost cells. Indeed, some studies have found that the thalamus is smaller than normal in people with schizophrenia.

  Thus, schizophrenia presents quite a different problem than depression or bipolar disorder. As we saw in chapter 3, those disorders result from a functional defect, in which properly built neural circuits fail to work correctly. Such defects can often be reversed. Schizophrenia, like autism spectrum disorders, involves an anatomical defect, in which certain neural circuits fail to develop correctly. To remedy these anatomical defects in schizophrenia, scientists will have to think of some way to either intervene in synaptic pruning during development or create compounds that stimulate the growth of new spines later on.

  Schizophrenia is characterized by other anatomical abnormalities as well. These include a thinning of layers of gray matter in the temporal and parietal regions of the cortex and in the hippocampus, as well as dilation of the lateral ventricles, the hollow spaces that carry the cerebrospinal fluid. Enlargement of the lateral ventricles probably results secondarily from the loss of gray matter in the cortex. Like excessive synaptic pruning, these brain abnormalities appear early in life, which suggests that they contribute to the development of schizophrenia. The existence of anatomical abnormalities and their parallel to the emergence of cognitive symptoms have strengthened the longstanding belief that the cognitive symptoms of schizophrenia emerge from abnormal functioning of the gray matter of the cerebral cortex.

  THE GENETICS OF SCHIZOPHRENIA

  If you had an identical twin with schizophrenia, you would have about a 50-50 chance of developing the disease, regardless of whether the two of you were raised together or apart. That risk of developing schizophrenia is much higher than the 1 in 100 risk for the general population. The twin data tell us two things: first, schizophrenia has a strong genetic component, regardless of environment; and second, those genes can’t be acting alone, because the risk isn’t 100 percent. Genes and the environment must interact to cause the disease (fig. 4.5).

  In recent years, a collaboration involving many scientists and tens of thousands of schizophrenic patients and their families set out to understand that genetic risk. They wanted to know what genes contribute to the brain abnormalities of people with schizophrenia and what sorts of functions those genes mediate.4 They found that even though symptoms of the disease don’t appear until the late teens, many of the genes involved in schizophrenia act on the developing brain before birth. This finding is consistent with the fact that people are vulnerable to environmental risk factors early in life, even though they do not manifest signs of disease until much later.

  Scientists have recently come to appreciate that genetic variations that contribute to complex disorders such as autism, schizophrenia, or bipolar disorder may be either common or rare. A common variation is one that was introduced into the human genome many generations ago and is now present in more than 1 percent of the world’s population; such variations are called polymorphisms. Rare variations, or mutations, occur in less than 1 percent of the world’s population. Either type of variation can contribute to the likelihood of having a disease or developmental disorder. Each type of variation can predispose a person to schizophrenia.

  Figure 4.5. The genetic risk of developing schizophrenia. As this graph shows, the general population has a 1 in 100, or 1 percent, risk of developing schizophrenia, whereas relatives of someone with the disorder have a higher risk, reaching almost 50 percent in identical twins.

  The rare variant mechanism of disease illustrates that rare mutations in a person’s genome greatly increase that person’s risk of developing a relatively common disorder. As we saw in chapter 2, a rare change in the structure of a chromosome, known as a copy number variation, can markedly increase the risk of autism spectrum disorders. The same is true of schizophrenia—in fact, the same copy num
ber variation on chromosome 7 that increases the risk of autism spectrum disorders also increases the risk of schizophrenia. Moreover, as is the case with autism spectrum disorders, rare de novo mutations in DNA—mutations that occur spontaneously in the sperm of the father—increase the risk of schizophrenia and bipolar disorder. Because the sperm of older men continue to divide and the older sperm undergo more frequent mutations, older fathers are more likely than younger fathers to have children who develop schizophrenia.

  The common variant mechanism of disease illustrates that both schizophrenia and autism spectrum disorders result when many common polymorphisms of a number of different genes act together to increase risk. Unlike the rare mutation, which exerts an outsize effect on risk, each of these common variants exerts only a very small effect. The strongest evidence for the common variant mechanism comes from the collaborative study of schizophrenia. These scientists have studied associations between schizophrenia and millions of common variants in the genomes of tens of thousands of individuals. Approximately one hundred gene variants related to schizophrenia have already been found. In this respect, the genetics of schizophrenia closely mirrors that of other common medical conditions, such as diabetes, heart disease, stroke, and autoimmune disorders.

  For a while, the rare variant and common variant mechanisms of disease were thought to be mutually exclusive, but recent studies of autism, schizophrenia, and bipolar disorder suggest that each disorder has an underlying genetic risk, quite apart from any rare genetic variation caused by copy number variations or de novo mutations (chapter 1, table 1). The underlying risk for schizophrenia, for example, is 1 percent, or 1 in 100 people in the general population. The relative contribution of rare and common genetic variations to underlying risk is somewhat different for each disorder, but certain characteristics seem to be universal. Common variations, each of which carries a small risk, contribute to the disorder in relatively large numbers of people, whereas rare mutations, each of which carries a larger risk, typically contribute to the disorder in fewer than 1 in 100 affected individuals.