45-1 What are the drug therapies? How do double-blind studies help researchers evaluate a drug’s effectiveness?

Since the 1950s, discoveries in psychopharmacology (the study of drug effects on mind and behavior) have revolutionized the treatment of people with severe disorders. Thanks to drug therapy and support from community mental health programs, today’s resident population of U.S. state and county mental hospitals has dropped to a small fraction of what it was a half-century ago. For some who are unable to care for themselves, however, release from hospitals has meant homelessness.

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Many new treatments are greeted by an initial wave of enthusiasm as many people apparently improve. But that enthusiasm often diminishes after researchers subtract the rates of (1) normal recovery among untreated persons and (2) recovery due to the placebo effect, which arises from the positive expectations of patients and mental health workers alike. Even mere exposure to advertising about a drug’s supposed effectiveness can increase its effect (Kamenica et al., 2013). To control for these influences when testing a new drug, researchers give half the patients the drug, and the other half a similar-appearing placebo. Because neither the staff nor the patients know who gets which, this is called a double-blind procedure. The good news: In double-blind studies, several types of drugs lessen psychological disorders.

An accidental discovery launched a treatment revolution for people with psychosis. The discovery was that some drugs used for other medical purposes calmed the hallucinations or delusions that are part of these patients’ split from reality. First-generation antipsychotic drugs, such as chlorpromazine (sold as Thorazine), reduce patients’ overreactions to irrelevant stimuli. Thus, they provide the most help to people experiencing positive symptoms of schizophrenia, such as auditory hallucinations and paranoia (Lehman et al., 1998; Lenzenweger et al., 1989).

The molecules of most conventional antipsychotic drugs are similar enough to molecules of the neurotransmitter dopamine to occupy its receptor sites and block its activity. This finding reinforces the idea that an overactive dopamine system contributes to schizophrenia.

Antipsychotics also have powerful side effects. Some produce sluggishness, tremors, and twitches similar to those of Parkinson’s disease (Kaplan & Saddock, 1989). Long-term use of antipsychotics can produce tardive dyskinesia, with involuntary movements of the facial muscles (such as grimacing), tongue, and limbs. Although not more effective in controlling schizophrenia symptoms, many of the newer-generation antipsychotics, such as risperidone (Risperdal) and olanzapine (Zyprexa), work best for those with severe symptoms and have fewer side effects (Furukawa et al., 2015). These drugs may, however, increase the risk of obesity and diabetes (Buchanan et al., 2010; Tiihonen et al., 2009).

Despite their drawbacks, antipsychotics, combined with life-skills programs and family support, have given new hope to many people with schizophrenia (Guo, 2010). Hundreds of thousands of patients have left the wards of mental hospitals and returned to work and to near-normal lives (Leucht et al., 2003).

Like alcohol, antianxiety drugs, such as Xanax or Ativan, depress central nervous system activity (and so should not be used in combination with alcohol). Antianxiety drugs are often successfully used in combination with psychological therapy. Experiments indicate that a drug can enhance exposure therapy’s extinction of learned fears and help relieve the symptoms of posttraumatic stress disorder and obsessive-compulsive disorder (Davis, 2005; Kushner et al., 2007).

One criticism made of antianxiety drugs is that they may reduce symptoms without resolving underlying problems, especially if used as an ongoing treatment. “Popping a Xanax” at the first sign of tension can create a learned response; the immediate relief reinforces a person’s tendency to take drugs when anxious. Anxiety drugs can also be addictive. Regular users who stop taking antianxiety drugs may experience increased anxiety, insomnia, and other withdrawal symptoms.

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Over the dozen years at the end of the twentieth century, the rate of outpatient treatment for anxiety disorders, obsessive-compulsive disorder, and posttraumatic stress disorder nearly doubled. The proportion of psychiatric patients receiving medication during that time increased from 52 to 70 percent (Olfson et al., 2004). And the new standard drug treatment for anxiety disorders? Antidepressants.

The antidepressant drugs were named for their ability to lift people up from a state of depression. Until recently, this was their main use. These drugs are now increasingly used to treat anxiety disorders, obsessive-compulsive disorder, and posttraumatic stress disorder (Wetherell et al., 2013). Many of these drugs work by increasing the availability of neurotransmitters, such as norepinephrine or serotonin, which elevate arousal and mood and are scarce when a person experiences feelings of depression or anxiety.

The most commonly prescribed drugs in this group, including Prozac and its cousins Zoloft and Paxil, work by blocking the normal reuptake of excess serotonin from synapses (FIGURE 45.1). Given their use in treating disorders other than depression, from anxiety to strokes, these drugs are most often called SSRIs—selective serotonin reuptake inhibitors (rather than antidepressants) (Kramer, 2011).

Some of the older antidepressant drugs work by blocking the reabsorption or breakdown of both norepinephrine and serotonin. Though effective, these dual-action drugs have more potential side effects, such as dry mouth, weight gain, hypertension, or dizzy spells (Anderson, 2000; Mulrow, 1999). Administering them by means of a patch, which bypasses the intestines and liver, helps reduce such side effects (Bodkin & Amsterdam, 2002).

Be advised: Patients with depression who begin taking antidepressants do not wake up the next morning singing “It’s a beautiful day!” Although the drugs begin to influence neurotransmission within hours, their full psychological effect often requires four weeks (and may involve a side effect of diminished sexual desire). One possible reason for the delay is that increased serotonin promotes new synapses plus neurogenesis—the birth of new brain cells, reversing stress-induced neuron loss (Launay et al., 2011). Researchers are also exploring the possibility of quicker-acting antidepressants. One, ketamine, blocks hyperactive receptors for glutamate, a neurotransmitter, and causes a burst of new synapses—but with possible side effects such as hallucinations (Grimm & Scheidegger, 2013; McGirr et al., 2015; Naughton et al., 2014).

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Antidepressant drugs are not the only way to give the body a lift. Aerobic exercise, which calms people who feel anxious and energizes those who feel depressed, does about as much good as antidepressant drugs for most people with mild to moderate depression, and has additional positive side effects. Cognitive therapy, which helps people reverse their habits of thinking negatively, can boost the drug-aided relief from depression and reduce posttreatment relapses (Hollon et al., 2002; Keller et al., 2000; Vittengl et al., 2007). Antidepressant drugs work from the bottom up to affect the emotion-forming limbic system. Cognitive-behavioral therapy works from the top down to alter frontal lobe activity and change thought processes. Together, they can attack depression (and anxiety) from both directions (Cuijpers et al., 2010; Hollon et al., 2014; Kennard et al., 2014; Walkup et al., 2008).

Researchers generally agree that people with depression often improve after a month on antidepressant drugs. But after allowing for natural recovery and the placebo effect, how big is the drug effect? Not big, report some researchers (Kirsch et al., 1998, 2002, 2010, 2014). In double-blind clinical trials, placebos produced improvement comparable with about 75 percent of the active drug’s effect. In a follow-up review that included unpublished clinical trials, the antidepressant drug effect was again modest (Kirsch et al., 2008). The placebo effect was less for those with severe depression, which made the added benefit of the drug somewhat greater for them. “Given these results, there seems little reason to prescribe antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed,” Irving Kirsch concluded (BBC, 2008). A newer analysis confirms that the antidepressant benefit compared to placebos is “minimal or nonexistent, on average, in patients with mild or moderate symptoms.” For those folks, aerobic exercise or psychotherapy is often effective. But among patients with “very severe” depression, the medication advantage becomes “substantial” (Fournier et al., 2010).

In addition to antipsychotic, antianxiety, and antidepressant drugs, psychiatrists have mood-stabilizing drugs in their arsenal. One of them, Depakote, was originally used to treat epilepsy. It was also found effective in controlling the manic episodes associated with bipolar disorder. Another, the simple salt lithium, effectively levels the emotional highs and lows of this disorder. Kay Redfield Jamison (1995, pp. 88–89) described the effect: “Lithium prevents my seductive but disastrous highs, diminishes my depressions, clears out the wool and webbing from my disordered thinking, slows me down, gentles me out, keeps me from ruining my career and relationships, keeps me out of a hospital, alive, and makes psychotherapy possible.”

Australian physician John Cade discovered the benefits of lithium in the 1940s when he administered it to a patient with severe mania and the patient became well in less than a week (Snyder, 1986). About 7 in 10 people with bipolar disorder benefit from a long-term daily dose of this cheap salt (Solomon et al., 1995). Their risk of suicide is but one-sixth that of people with bipolar disorder who are not taking lithium (Oquendo et al., 2011). Naturally occurring lithium in drinking water has correlated with lower suicide rates (across 18 Japanese cities and towns) and lower crime rates (across 27 Texas counties) (Ohgami et al., 2009; Schrauzer & Shrestha, 1990, 2010; Terao et al., 2010). Although we do not fully understand why, lithium works.

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