Milieu therapy and token economy programs helped improve the gloomy outlook for patients diagnosed with schizophrenia, but it was the discovery of antipsychotic drugs in the 1950s that truly revolutionized treatment for schizophrenia. These drugs eliminate many of its symptoms and today are almost always a part of treatment.

The discovery of antipsychotic medications dates back to the 1940s, when researchers developed the first antihistamine drugs to combat allergies. The French surgeon Henri Laborit soon discovered that one group of antihistamines, phenothiazines, could also be used to help calm patients about to undergo surgery. After experimenting with several phenothiazine antihistamines and becoming most impressed with one called chlorpromazine, Laborit reported, “It provokes not any loss of consciousness, not any change in the patient’s mentality but a slight tendency to sleep and above all ‘disinterest’ for all that goes on around him.”

Laborit suspected that chlorpromazine might also have a calming effect on people with severe psychological disorders. Psychiatrists Jean Delay and Pierre Deniker (1952) tested the drug on six patients with psychotic symptoms and did indeed observe a sharp reduction in their symptoms. In 1954, chlorpromazine was approved for sale in the United States as an antipsychotic drug under the trade name Thorazine (Adams et al., 2014).

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Since the discovery of the phenothiazines, other kinds of antipsychotic drugs have been developed. The ones developed throughout the 1960s, 1970s, and 1980s are now referred to as “conventional” antipsychotic drugs in order to distinguish them from the “second-generation” antipsychotics (also called “atypical” antipsychotic drugs) that have been developed in recent years. The conventional drugs are also known as neuroleptic drugs because they often produce undesired movement effects similar to the symptoms of neurological diseases. Among the best known conventional drugs are thioridazine (Mellaril), fluphenazine (Prolixin), trifluoperazine (Stelazine), and haloperidol (Haldol). As you saw in Chapter 14, antipsychotic drugs reduce psychotic symptoms at least in part by blocking excessive activity of the neurotransmitter dopamine, particularly at the brain’s dopamine D-2 receptors (Chun et al., 2014; During et al., 2014).

Research has shown that antipsychotic drugs reduce symptoms in at least 65 percent of patients diagnosed with schizophrenia (Advokat et al., 2014; Ellenbroek, 2011; Geddes et al., 2011). Moreover, in direct comparisons the drugs appear to be a more effective treatment for schizophrenia than any of the other approaches used alone, such as psychotherapy, milieu therapy, or electroconvulsive therapy.

For patients helped by the drugs, the medications bring about clear improvement within a period of weeks and maximum improvement within six months (Rabinowitz et al., 2014). However, symptoms may return if the patients stop taking the drugs too soon (Razali et al., 2014; Barnes & Marder, 2011). In one study, when the antipsychotic medications of people with chronic schizophrenia were changed to a placebo after 5 years, 75 percent of the patients relapsed within a year, compared with 33 percent of similar patients who continued to receive medication (Sampath et al., 1992).

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As you read in Chapter 14, antipsychotic drugs, particularly the conventional ones, reduce the positive symptoms of schizophrenia (such as hallucinations and delusions) more completely, or at least more quickly, than the negative symptoms (such as restricted affect, poverty of speech, and loss of volition) (Millan, et al., 2014; Stroup et al., 2012). Correspondingly, people whose symptoms are largely positive generally have better rates of recovery from schizophrenia than those with predominantly negative symptoms.

Although antipsychotic drugs are now widely accepted, patients often dislike the powerful effects of the drugs—both intended and unintended—and some refuse to take them (Liersch-Sumskis et al., 2014; Mohamed et al., 2014).

In addition to reducing psychotic symptoms, the conventional antipsychotic drugs sometimes produce disturbing movement problems (Advokat et al., 2014; Stroup et al., 2012). These effects are called extrapyramidal effects because they appear to be caused by the drugs’ impact on the extrapyramidal areas of the brain, areas that help control motor activity. These undesired effects include Parkinsonian and related symptoms, neuroleptic malignant syndrome, and tardive dyskinesia.

Parkinsonian and Related SymptomsThe most common extrapyramidal effects are Parkinsonian symptoms, reactions that closely resemble the features of the neurological disorder Parkinson’s disease. At least half of patients on conventional antipsychotic drugs have muscle tremors and muscle rigidity at some point in their treatment; they may shake, move slowly, shuffle their feet, and show little facial expression (Geddes et al., 2011; Haddad & Mattay, 2011). Some also have related symptoms such as movements of the face, neck, tongue, and back; and a number experience significant restlessness and discomfort in their limbs, which causes them to move their arms and legs continually in search of relief.

The Parkinsonian and related symptoms seem to be the result of medication-induced reductions of dopamine activity in the basal ganglia and the substantia nigra, parts of the brain that coordinate movement and posture (Advokat et al., 2014). In most cases, the symptoms can be reversed if the person takes an anti-Parkinsonian drug along with the antipsychotic drug. Alternatively, clinicians may have to reduce the dose of the antipsychotic drug or stop it altogether.

Neuroleptic Malignant SyndromeIn as many as 1 percent of patients, particularly those who are elderly, conventional antipsychotic drugs produce neuroleptic malignant syndrome, a severe, potentially fatal reaction consisting of muscle rigidity, fever, altered consciousness, and improper functioning of the autonomic nervous system (Haddad & Mattay, 2011). If a person is identified as having the syndrome, he or she is immediately taken off the drug and each neuroleptic symptom is treated medically. In addition, the patient may be given dopamine-enhancing drugs.

Tardive DyskinesiaWhereas most undesired drug effects appear within days or weeks, a reaction called tardive dyskinesia (meaning “late-appearing movement disorder”) does not usually unfold until after a person has taken conventional antipsychotic drugs for more than a year. Sometimes it does not even appear until after the medications are stopped (Advokat et al., 2014). This syndrome may include involuntary writhing or ticlike movements of the tongue, mouth, face, or whole body; involuntary chewing, sucking, and lip smacking; and jerky movements of the arms, legs, or entire body. It is sometimes accompanied by memory difficulties (Haddad & Mattay, 2011).

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Most cases of tardive dyskinesia are mild and involve a single symptom, such as tongue flicking; however, some are severe and include such features as continual rocking back and forth, irregular breathing, and grotesque twisting of the face and body. It is believed that more than 10 percent of the people who take conventional antipsychotic drugs for an extended time develop tardive dyskinesia to some degree, and the longer the drugs are taken, the higher the risk becomes (Achalia, 2014; Advokat et al., 2014). Patients over 50 years of age seem to be at greater risk.

Tardive dyskinesia can be difficult, sometimes impossible, to eliminate (Combs et al., 2008). If it is discovered early and the conventional drugs are stopped immediately, it eventually disappears in most cases. Early detection, however, is elusive because some of the symptoms are similar to psychotic symptoms. Clinicians may easily overlook them, continue to administer the drugs, and unintentionally create a more serious case of tardive dyskinesia. Researchers do not fully understand why conventional antipsychotic drugs cause tardive dyskinesia; however, they suspect that, once again, the problem is related to the drugs’ effect on dopamine receptors in the basal ganglia and substantia nigra (Advokat et al., 2014).

How Should Conventional Antipsychotic Drugs Be Prescribed?Today clinicians are more knowledgeable and more cautious about prescribing conventional antipsychotic drugs than they were in the past (see Table 15-1). Previously, when patients did not improve with such a drug, their clinician would keep increasing the dose; today a clinician will typically add an additional drug to achieve a synergistic effect (called polypharmacy), stop the drug and try an alternative one, or stop all medications (Li et al., 2014; Roh et al., 2014; Leucht, Correll, & Kane, 2011). Today’s clinicians also try to prescribe the lowest effective doses for each patient and to gradually reduce medications weeks or months after the patient begins functioning normally (Barnes & Marder, 2011). Research indicates that, for many such patients, reductions of this kind do not lead to a return of symptoms (Takeuchi et al., 2014). For others, however, only small reductions in dosage are possible, and treatment for these patients typically involves the long-term use of carefully monitored high dosages of antipsychotic drugs (Deutschenbaur et al., 2014).

Chapter 14 noted that second-generation (“atypical”) antipsychotic drugs have been developed. The most widely used of these newer drugs are clozapine (trade name Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify). As you have read, the drugs were called atypical initially because their biological operation differs from that of the conventional antipsychotic medications: the atypicals are received at fewer dopamine D-2 receptors and more D-1, D-4, and serotonin receptors than the others (Advokat et al., 2014; Nord & Farde, 2011).

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Second-generation antipsychotic drugs appear to be more effective than the conventional drugs (Advokat et al., 2014; Bianchini et al., 2014; Geddes et al., 2011). Clozapine is often the most effective such drug, but the other second-generation drugs also bring significant change for many people. Recall, for example, Cathy, the woman whom we met at the beginning of this chapter, and how well she responded to risperidone after years of doing poorly on conventional antipsychotic drugs. Unlike the conventional drugs, the new drugs reduce not only the positive symptoms of schizophrenia, but also the negative ones (Millan et al., 2014; Waddington et al., 2011). Another major benefit of the second-generation antipsychotic drugs is that they cause fewer extrapyramidal symptoms and seem less likely to produce tardive dyskinesia (Abouzaid et al., 2014; Geddes et al., 2011) (see Figure 15-1).

Given such advantages, more than half of all medicated patients with schizophrenia now take the second-generation drugs, which are considered the first line of treatment for the disorder (Barnes & Marder, 2011; Combs et al., 2008). Many patients with bipolar or other severe mental disorders also seem to be helped by several of these antipsychotic drugs. Studies indicate, for example, that olanzapine, prescribed alone or in combination with mood-stabilizing drugs, is very effective in cases of acute mania (Advokat et al., 2014). Clinicians use the same general prescription strategies for the second-generation antipsychotic drugs as they do for the conventional antipsychotic drugs.

Yet the second-generation antipsychotic drugs have serious problems as well (Barnes & Marder, 2011; Haddad & Mattay, 2011; Waddington et al., 2011). For example, people who use one of these drugs, clozapine, have around a 1 percent risk of developing agranulocytosis, a life-threatening drop in white blood cells (other atypical antipsychotic drugs do not produce this undesired effect). Patients who take clozapine must therefore have frequent blood tests so that agranulocytosis can be spotted early and the drug stopped. In addition, some of the second-generation antipsychotic drugs may cause weight gain, particularly among women; dizziness; metabolic problems; and significant elevations in blood sugar, as we also saw in the case of Cathy (Thibaut, 2014). Also, research indicates that although these medications do often reduce the symptoms of psychosis, they, like the conventional antipsychotics, typically produce only modest changes in overall life satisfaction among those who have chronic schizophrenia (Fervaha et al., 2014).

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