In the United States, around half of those with unipolar depression receive treatment from a mental health professional each year. Access to such treatment differs among ethnic and racial groups. As you read in the previous chapter, only 34 percent of depressed Hispanic Americans and 40 percent of depressed African Americans receive treatment, compared with 54 percent of depressed white Americans (González et al., 2010).

In addition, many people in therapy experience depressed feelings as part of another disorder, such as an eating disorder, or in association with changes or general problems that they are encountering in life. Thus much of the therapy being done today includes a focus on unipolar depression.

A variety of treatment approaches are currently in widespread use for unipolar depression. In this chapter, we first look at the psychological approaches, focusing on the psychodynamic, behavioral, and cognitive therapies. We then explore the socio-cultural approaches, including a highly regarded intervention called interpersonal psychotherapy. Next, we look at effective biological approaches, including electroconvulsive therapy, antidepressant drugs, and new brain stimulation interventions. In the process, we can see that unipolar patterns of depression are indeed among the most successfully treated of all psychological disorders.

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The psychological treatments used most often to combat unipolar depression come from the psychodynamic, behavioral, and cognitive schools of thought. Psycho-dynamic therapy, the oldest of all modern psychotherapies, continues to be used widely for depression even though research has not offered strong evidence of its effectiveness. Behavioral therapy, effective primarily for mild or moderate depression, is practiced less often today than it was in past decades. Cognitive therapy and cognitive-behavioral therapies have performed so well in research that they have a large and growing following among clinicians (Young et al., 2014).

Psychodynamic TherapyBelieving that unipolar depression results from unconscious grief over real or imagined losses, compounded by excessive dependence on other people, psychodynamic therapists seek to help clients bring these underlying issues to consciousness and work them through. Using the arsenal of basic psychodynamic procedures, they encourage the depressed client to associate freely during therapy; suggest interpretations of the client’s associations, dreams, and displays of resistance and transference; and help the person review past events and feelings (Busch et al., 2004). Free association, for example, helped one man recall the early experiences of loss that, according to his therapist, had set the stage for his depression:

Psychodynamic therapists expect that in the course of treatment depressed clients will eventually gain awareness of the losses in their lives, become less dependent on others, cope with losses more effectively, and make corresponding changes in their functioning. The transition of a therapeutic insight into a real-life change is seen in the case of a middle-aged executive:

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Despite successful case reports such as this, researchers have found that long-term psychodynamic therapy is only occasionally helpful in cases of unipolar depression (Prochaska & Norcross, 2013). Two features of the approach may help limit its effectiveness. First, depressed clients may be too passive and feel too weary to join fully into the subtle therapy discussions. And second, they may become discouraged and end treatment too early when this long-term approach is unable to provide the quick relief that they desperately seek. Generally, psychodynamic therapy seems to help most in cases of depression that clearly involve a history of childhood loss or trauma, a long-standing sense of emptiness, feelings of perfectionism, and extreme self-criticism (Luyten & Blatt, 2011; Blatt, 1999, 1995). Short-term psychodynamic therapies have performed better than the traditional, longer-term approaches (Midgley et al., 2013; Lemma, Target, & Fonagy, 2011).

Behavioral TherapyBehaviorists, whose theories of depression tie mood to the rewards in a person’s life, have developed corresponding treatments for unipolar depression. Most such treatments are modeled after the intervention proposed by Peter Lewinsohn, the behavioral theorist whose theory of depression was described in Chapter 7 (see pages 229, 231). In a typical behavioral approach, therapists (1) reintroduce depressed clients to pleasurable events and activities, (2) appropriately reward nondepressive behaviors and withhold rewards for depressive behaviors, and (3) help clients improve their social skills (Dimidjian et al., 2014).

First, the therapist selects activities that the client considers pleasurable, such as going shopping or taking photos, and encourages the person to set up a weekly schedule for engaging in them. Studies have shown that adding positive activities to a person’s life—sometimes called behavioral activation—can indeed lead to a better mood (Dimidjian et al, 2014; Martell et al., 2010). In the following case description, a therapist describes this process, revealing how detailed the client–therapist planning sessions must be:

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While reintroducing pleasurable events into a client’s life, the therapist makes sure that the person’s various behaviors are reinforced correctly. Behaviorists argue that when people become depressed, their negative behaviors—crying, ruminating, complaining, or self-depreciation—keep others at a distance, reducing chances for rewarding experiences and interactions. To change this pattern, therapists guide clients to monitor their negative behaviors (see MindTech on page 260) and to try new, more positive ones (Dimidjian et al, 2014; Martell et al., 2010). In addition, the therapist may use a contingency management approach, systematically ignoring a client’s depressive behaviors while praising or otherwise rewarding constructive statements and behavior, such as going to work. Sometimes family members and friends are recruited to help with this feature of treatment.

Finally, behavioral therapists may train clients in effective social skills (Thase, 2012; Hersen et al., 1984). In group therapy programs, for example, members may work together to improve eye contact, facial expression, posture, and other behaviors that send social messages.

These behavioral techniques seem to be of only limited help when just one of them is applied. In one classic study, for example, depressed people who were instructed to increase their pleasant activities showed no more improvement than those in a control group who were told simply to keep track of their activities (Hammen & Glass, 1975). However, when two or more behavioral techniques are combined, behavioral treatment does appear to reduce depressive symptoms, particularly if the depression is mild (Dimidjian et al, 2014; Martell et al., 2010; Jacobson et al., 2001, 1996). It is worth noting that Lewinsohn himself has combined behavioral techniques with cognitive strategies in recent years, in an approach similar to the cognitive-behavioral treatments discussed in the next section.

Cognitive TherapyIn Chapter 7 you saw that Aaron Beck viewed unipolar depression as resulting from a pattern of negative thinking that may be triggered by current upsetting situations. Maladaptive attitudes lead people repeatedly to view themselves, their world, and their future in negative ways—the so-called cognitive triad. Such biased views combine with illogical thinking to produce automatic thoughts, unrelentingly negative thoughts that flood the mind and produce the symptoms of depression.

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To help clients overcome this negative thinking, Beck has developed a treatment approach that he calls cognitive therapy. He uses this label because the approach is designed primarily to help clients recognize and change their negative cognitive processes and thus to improve their mood (Beck & Weishaar, 2014; Young et al., 2014). However, as you will see, the approach also includes a number of behavioral techniques (Figure 8-2), particularly as therapists try to get clients moving again and encourage them to try out new behaviors. Thus, many theorists consider this approach a cognitive-behavioral therapy rather than the purely cognitive intervention implied by its name. Beck’s approach is similar to Albert Ellis’ rational-emotive therapy (discussed in Chapters 3 and 5), but it is tailored to the specific cognitive errors found in depression. The approach follows four phases and usually requires fewer than 20 sessions (see Table 8-1 below).

PHASE 1: INCREASING ACTIVITIES AND ELEVATING MOODUsing behavioral techniques to set the stage for cognitive treatment, therapists first encourage clients to become more active and confident. Clients spend time during each session preparing a detailed schedule of hourly activities for the coming week. As they become more active from week to week, their mood is expected to improve.

PHASE 2: CHALLENGING AUTOMATIC THOUGHTSOnce people are more active and feeling some emotional relief, cognitive therapists begin to educate them about their negative automatic thoughts. The individuals are instructed to recognize and record automatic thoughts as they occur and to bring their lists to each session. Therapist and client then test the reality behind the thoughts, often concluding that they are groundless. Beck offers the following exchange as an example of this sort of review:

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PHASE 3: IDENTIFYING NEGATIVE THINKING AND BIASESAs people begin to recognize the flaws in their automatic thoughts, cognitive therapists show them how illogical thinking processes are contributing to these thoughts. The depressed student, for example, was using dichotomous (all-or-nothing) thinking when she concluded that any grade lower than A was “terrible.” The therapists also assist clients in recognizing that almost all their interpretations of events have a negative bias and to change that style of interpretation.

PHASE 4: CHANGING PRIMARY ATTITUDESTherapists help clients change the maladaptive attitudes that set the stage for their depression in the first place. As part of the process, therapists often encourage clients to test their attitudes, as in the following therapy discussion:

Over the past several decades, hundreds of studies have shown that Beck’s therapy and similar cognitive and cognitive-behavioral approaches help with unipolar depression. Depressed adults who receive these therapies improve much more than those who receive placebos or no treatment at all (Young et al., 2014; Hollon & Cuijpers, 2013). Around 50 to 60 percent show a near-total elimination of their symptoms. In view of this strong research support, many depression therapists have adopted cognitive and cognitive-behavioral approaches, offering them in either individual therapy, group therapy, or cybertherapy formats, all with considerable success (Straub et al., 2014; Andersson et al, 2013; Petrocelli, 2002).

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It is worth noting that a growing number of today’s cognitive-behavioral therapists do not agree with Beck’s proposition that individuals must fully discard their negative cognitions in order to overcome depression. These therapists, the new-wave cognitive-behavioral therapists about whom you read in Chapters 3 and 5, including those who practice acceptance and commitment therapy (ACT), guide depressed clients to recognize and accept their negative cognitions simply as streams of thinking that flow through their minds, rather than as valuable guides for behavior and decisions. As clients increasingly accept their negative thoughts for what they are, they can better work around the thoughts as they navigate their way through life (Levin et al., 2014; Wells et al., 2012; Hayes et al., 2006).

As you read in Chapter 7, sociocultural theorists trace the causes of unipolar depression to the broader social structure in which people live and the roles they are required to play. Two groups of sociocultural treatments are now widely applied in cases of unipolar depression—multicultural approaches and family-social approaches.

Multicultural TreatmentsIn Chapter 3, you read that culture-sensitive therapies are designed to address the unique issues faced by members of cultural minority groups (Comas-Díaz, 2014). For such approaches, therapists typically have special cultural training and a heightened awareness of their clients’ cultural values and the culture-related stressors, prejudices, and stereotypes that their clients face. They make an effort to help clients develop a comfortable (for them) bicultural balance and to recognize the impact of their own culture and the dominant culture on their views of themselves and on their behaviors (Prochaska & Norcross, 2013).

In the treatment of unipolar depression, culture-sensitive approaches increasingly are being combined with traditional forms of psychotherapy to help minority clients overcome their disorders (Aguilera, Garza, & Muñoz, 2010; Stacciarini et al., 2007). A number of today’s therapists, for example, offer cognitive-behavioral therapy for depressed minority clients while also focusing on the clients’ economic pressures, minority identity, and related cultural issues. A range of studies indicate that Hispanic American, African American, American Indian, and Asian American clients are more likely to overcome their depressive disorders when a culture-sensitive focus is added to the form of psychotherapy that they are otherwise receiving (Comas-Díaz, 2014; Ward, 2007). Unfortunately, this kind of combination therapy for depression, while on the increase, is still unavailable to most minority clients (Dwight-Johnson & Lagomasino, 2007).

It also appears that the medication needs of many depressed minority clients, especially those who are poor, are inadequately addressed. As you will see later in this chapter, for example, minority clients are less likely than white American clients to receive the most helpful antidepressant medications.

Family-Social TreatmentsTherapists who use family and social approaches to treat depression help clients change how they deal with the close relationships in their lives. The most effective family-social approaches are interpersonal psychotherapy and couple therapy.

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INTERPERSONAL PSYCHOTHERAPYDeveloped by clinical researchers Gerald Klerman and Myrna Weissman, interpersonal psychotherapy (IPT) holds that any of four interpersonal problem areas may lead to depression and must be addressed: interpersonal loss, interpersonal role dispute, interpersonal role transition, and interpersonal deficits (Bleiberg & Markowitz, 2014; Verdeli, 2014). Over the course of around 16 sessions, IPT therapists address these areas.

First, depressed people may, as psychodynamic theorists suggest, be having a grief reaction over an important interpersonal loss, the loss of a loved one. In such cases, IPT therapists encourage clients to explore their relationship with the lost person and express any feelings of anger they may discover. Eventually clients develop new ways of remembering the lost person and also look for new relationships.

Second, depressed people may find themselves in the midst of an interpersonal role dispute. Role disputes occur when two people have different expectations of their relationship and of the role each should play. IPT therapists help clients examine whatever role disputes they may be involved in and then develop ways of resolving them.

Depressed people may also be going through an interpersonal role transition, brought about by major life changes such as divorce or the birth of a child. They may feel overwhelmed by the role changes that accompany the life change. In such cases, IPT therapists help them develop the social supports and skills the new roles require.

Finally, some depressed people display interpersonal deficits, such as extreme shyness or social awkwardness, that prevent them from having intimate relationships. IPT therapists may help such clients recognize their deficits and teach them social skills and assertiveness in order to improve their social effectiveness. In the following discussion, the therapist encourages a depressed man to recognize the effect his behavior has on others:

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Studies suggest that IPT and related interpersonal treatments for depression have a success rate similar to that of cognitive and cognitive-behavioral therapies (Bleiberg & Markowitz, 2014; Frank & Levenson, 2011). That is, symptoms almost totally disappear in 50 to 60 percent of clients who receive treatment. After IPT, not only are their depressive symptoms reduced, but clients also function more effectively in their social and family interactions. Not surprisingly, IPT is considered especially useful for depressed people who are struggling with social conflicts or undergoing changes in their careers or social roles (Ravitz, Watson, & Grigoriadis, 2013).

COUPLE THERAPYAs you have read, depression can result from marital discord, and recovery from depression is often slower for people who do not receive support from their spouse (Whisman & Beach, 2012; Whisman & Schonbrun, 2010). In fact, as many as half of all depressed clients may be in a dysfunctional relationship. Thus it is not surprising that many cases of depression have been treated by couple therapy, the approach in which a therapist works with two people who share a long-term relationship (Cohen et al., 2014).

Therapists who offer integrative behavioral couples therapy teach specific communication and problem-solving skills to couples and further guide them to be more accepting of each other (see Chapter 3). When the depressed person’s relationship is filled with conflict, this approach and similar ones may be as effective as individual cognitive therapy, interpersonal psychotherapy, or drug therapy in helping to reduce depression (Lebow et al., 2012, 2010; Franchi, 2004). In addition, depressed clients who receive couple therapy are more likely than those in individual therapy to be more satisfied with their marriage after treatment.

Like several of the psychological and sociocultural therapies, biological treatments can bring significant relief to people with unipolar depression. Usually biological treatment means antidepressant drugs or popular herbal supplements (see InfoCentral below), but for severely depressed people who do not respond to other forms of treatment, it sometimes means electroconvulsive therapy, an approach that has been around for more than 70 years, or brain stimulation, a relatively new group of approaches.

Electroconvulsive TherapyOne of the most controversial forms of treatment for depression is electroconvulsive therapy (ECT). Clinicians and patients alike vary greatly in their opinions of this procedure. Some consider it a safe biological approach with minimal risks; others believe it to be an extreme measure that can cause troublesome memory loss and even neurological damage. Despite the heat of this controversy, ECT is used frequently, largely because it is an effective and fast-acting intervention for unipolar depression (Pfeiffer et al., 2011; Loo, 2010).

THE TREATMENT PROCEDUREIn an ECT procedure, two electrodes are attached to the patient’s head, and 65 to 140 volts of electricity are passed through the brain for half a second or less. This results in a brain seizure that lasts from 25 seconds to a few minutes. After 6 to 12 such treatments, spaced over 2 to 4 weeks, most patients feel less depressed (Fink, 2014, 2007, 2001). In bilateral ECT, one electrode is applied to each side of the forehead, and a current passes through both sides of the brain. In unilateral ECT, the electrodes are placed so that the current passes through only one side.

THE ORIGINS OF ECTThe discovery that electric shock can be therapeutic was made by accident. In the 1930s, clinical researchers mistakenly came to believe that brain seizures, or the convulsions (severe body spasms) that accompany them, could cure schizophrenia and other psychotic disorders. They observed that people with psychosis rarely suffered from epilepsy (brain seizure disorder) and that people with epilepsy rarely were psychotic, and so concluded that brain seizures or convulsions somehow prevented psychosis. We now know that the observed correlation between seizures and lack of psychotic symptoms does not necessarily imply that one causes the other. Nevertheless, swayed by faulty logic, clinicians in the 1930s searched for ways to induce seizures as a treatment for patients with psychosis.

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A Hungarian physician named Joseph von Meduna gave the drug metrazol to patients suffering from psychosis, and a Viennese physician named Manfred Sakel gave them large doses of insulin (insulin coma therapy). These procedures produced the desired brain seizures, but each was quite dangerous and sometimes even caused death. Finally, an Italian psychiatrist named Ugo Cerletti discovered that he could produce seizures more safely by applying electric currents to a patient’s head, and he and his colleague Lucio Bini soon developed ECT as a treatment for psychosis (Cerletti & Bini, 1938). As you might expect, much uncertainty and confusion accompanied their first clinical application of ECT. Did experimenters have the right to impose such an untested treatment against a patient’s will?

ECT soon became popular and was tried out on a wide range of psychological problems, as new techniques so often are. Its effectiveness with severe depression in particular became apparent. Ironically, however, doubts were soon raised concerning its usefulness for psychosis, and many researchers have since judged it ineffective for psychotic disorders, except for cases that also include severe depressive symptoms (Freudenreich & Goff, 2011; Taube-Schiff & Lau, 2008).

CHANGES IN ECT PROCEDURESAlthough Cerletti gained international fame for his procedure, eventually he abandoned ECT and spent his later years seeking other treatments for mental disorders (Karon, 1985). The reason: he abhorred the broken bones and dislocations of the jaw or shoulders that sometimes resulted from ECT’s severe convulsions, as well as the memory loss, confusion, and brain damage that the seizures could cause. Other clinicians have stayed with the procedure, however, and have changed it over the years to reduce its undesirable consequences. Today’s practitioners give patients strong muscle relaxants to minimize convulsions, thus eliminating the danger of fractures or dislocations. They also use anesthetics (barbiturates) to put patients to sleep during the procedure, reducing their terror. With these precautions, ECT is medically more complex than it used to be, but also less dangerous and somewhat less disturbing (Lihua et al., 2014; Pfeiffer et al., 2011).

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Patients who receive ECT, particularly bilateral ECT, typically have difficulty remembering some events, most often events that took place immediately before and after their treatments (Merkl et al., 2011). In most cases, this memory loss clears up within a few months, but some patients are left with gaps in more distant memory, and this form of amnesia can be permanent (Hanna et al., 2009; Wang, 2007; Squire, 1977). Understandably, these patients may become embittered about the procedure.

EFFECTIVENESS OF ECTECT is clearly effective in treating unipolar depression. Studies find that between 60 and 80 percent of ECT patients improve (Perugi et al., 2011; Loo, 2010). The approach is particularly effective when patients follow up the initial cluster of sessions with continuation therapy—either ongoing antidepressant medications or periodic ECT sessions (Fink et al., 2014). The procedure seems to be particularly effective in severe cases of depression that include delusions (Rothschild, 2010). It has been difficult, however, to determine why ECT works so well (Baldinger et al., 2014; Cassidy et al., 2010). After all, this procedure delivers a broad insult to the brain that activates a number of brain areas, causes neurons all over the brain to fire, and leads to the release of all kinds of neurotransmitters, and it affects many other systems throughout the body as well.

Although ECT is effective and ECT techniques have improved, its use has generally declined since the 1950s. Two reasons for this decline are the memory loss caused by ECT and the frightening nature of the procedure (Fink, Kellner, & McCall, 2014). Another is the emergence of effective antidepressant drugs.

Antidepressant DrugsTwo kinds of drugs discovered in the 1950s reduce the symptoms of depression: monoamine oxidase (MAO) inhibitors and tricyclics. These drugs have now been joined by a third group, the so-called second-generation antidepressants (see Table 8-2).

MAO INHIBITORSThe effectiveness of MAO inhibitors as a treatment for unipolar depression was discovered accidentally. Physicians noted that iproniazid, a drug being tested on patients with tuberculosis, had an interesting effect: it seemed to make the patients happier (Sandler, 1990). It was found to have the same effect on depressed patients (Kline, 1958; Loomer, Saunders, & Kline, 1957). What this and several related drugs had in common biochemically was that they slowed the body’s production of the enzyme monoamine oxidase (MAO). Thus they were called MAO inhibitors.

Normally, brain supplies of the enzyme MAO break down, or degrade, the neurotransmitter norepinephrine. MAO inhibitors block MAO from carrying out this activity and thereby stop the destruction of norepinephrine. The result is a rise in norepinephrine activity and, in turn, a reduction of depressive symptoms. Approximately half of depressed patients who take MAO inhibitors are helped by them (Ciraulo, Shader, & Greenblatt, 2011; Thase, Trivedi, & Rush, 1995). There is, however, a potential danger with regard to these drugs. When people who take MAO inhibitors eat foods containing the chemical tyramine—including such common foods as cheeses, bananas, and certain wines—their blood pressure rises dangerously. Thus people on these drugs must stick to a rigid diet. In recent years, a new MAO inhibitor has become available in the form of a skin patch that allows for slow, continuous absorption of the drug into the client’s body (Advokat et al., 2014; VanDenBerg, 2012). Because the doses absorbed across the skin are low, dangerous food interactions do not appear to be as common with this kind of MAO inhibitor.

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TRICYCLICSThe discovery of tricyclics in the 1950s was also accidental. Researchers who were looking for a new drug to combat schizophrenia ran some tests on a drug called imipramine (Kuhn, 1958). They discovered that imipramine was of no help in cases of schizophrenia, but it did relieve unipolar depression in many people. The new drug (trade name Tofranil) and related ones became known as tricyclic antidepressants because they all share a three-ring molecular structure.

In hundreds of studies, depressed patients taking tricyclics have improved much more than similar patients taking placebos, although the drugs must be taken for at least 10 days before such improvements take hold (Advokat et al., 2014). About 65 percent of patients who take tricyclics are helped by them (FDA, 2014).

If depressed people stop taking tricyclics immediately after obtaining relief, they run a high risk of relapsing within a year. If, however, they continue taking the drugs for five months or more after being free of depressive symptoms—“continuation therapy”—their chances of relapse decrease considerably (FDA, 2013; Kim et al., 2011; Ballas, Benton, & Evans, 2010). Certain studies further suggest that patients who take these antidepressant drugs for three or more years after initial improvement—a practice called “maintenance therapy”—may reduce the risk of relapse even more. As a result, clinicians often keep patients on the antidepressant drugs indefinitely.

Most researchers have concluded that tricyclics reduce depression by acting on neurotransmitter “reuptake” mechanisms (Ciraulo et al., 2011). Remember from Chapter 3 that messages are carried from the “sending” neuron across the synaptic space to a receiving neuron by a neurotransmitter, a chemical released from the axon ending of the sending neuron. However, there is a complication in this process. While the sending neuron releases the neurotransmitter, a pumplike mechanism in the neuron’s ending immediately starts to reabsorb it in a process called reuptake. The purpose of this reuptake process is to control how long the neurotransmitter remains in the synaptic space and to prevent it from overstimulating the receiving neuron. Unfortunately, reuptake does not always progress properly. The reuptake mechanism may be too efficient in some people—cutting off norepinephrine or serotonin activity too soon, preventing messages from reaching the receiving neurons, and producing clinical depression. Tricyclics block this reuptake process, allowing neurotransmitters to remain in the synapse longer, and thus increasing their stimulation of the receiving neurons (see Figure 8-3 below).

If tricyclics act immediately to increase norepinephrine and serotonin activity, why do the symptoms of depression continue for 10 or more days after drug therapy begins? Growing evidence suggests that when tricyclics are ingested, they initially slow down the activity of the neurons that use norepinephrine and serotonin (Ciraulo et al., 2011; Lambert & Kinsley, 2010). Granted, the reuptake mechanisms of these cells are immediately corrected, thus allowing more efficient transmission of the neurotransmitters, but the neurons themselves respond to the change by releasing smaller amounts of the neurotransmitters. After a week or two, the neurons finally adapt to the tricyclic drugs and go back to releasing normal amounts of the neurotransmitters. Now the corrections in the reuptake mechanisms begin to have the desired effect: the neurotransmitters reach the receiving neurons in greater numbers, hence triggering more neural firing and producing a decrease in depression.

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Soon after tricyclics were discovered, they started being prescribed more often than MAO inhibitors. Tricyclics did not require dietary restrictions as MAO inhibitors did, and people taking them typically showed higher rates of improvement than those taking MAO inhibitors. On the other hand, some people respond better to MAO inhibitors than to either tricyclics or the new antidepressants described next, and such people continue to be given MAO inhibitors (Advokat et al., 2014; Thase, 2006).

SECOND-GENERATION ANTIDEPRESSANTSA third group of effective antidepressant drugs, structurally different from the MAO inhibitors and tricyclics, has been developed during the past few decades. Most of these second-generation antidepressants are called selective serotonin reuptake inhibitors (SSRIs) because they increase serotonin activity specifically, without affecting norepinephrine or other neurotransmitters. The SSRIs include fluoxetine (trade name Prozac), sertraline (Zoloft), and escitalopram (Lexapro). More recently developed selective norepinephrine reuptake inhibitors, such as atomoxetine (Strattera), which increase norepinephrine activity only, and serotonin-norepinephrine reuptake inhibitors, such as venlafaxine (Effexor), which increase both serotonin and norepinephrine activity, are also now available (Advokat et al., 2014; Stahl, 2014; Ciraulo et al., 2011).

In effectiveness and speed of action, the second-generation antidepressant drugs are about on a par with the tricyclics, yet their sales have skyrocketed. Clinicians often prefer the new antidepressants because it is harder to overdose on them than on the other antidepressants. In addition, they do not pose the dietary problems of the MAO inhibitors or produce some of the unpleasant effects of the tricyclics, such as dry mouth and constipation. At the same time, the new antidepressants can produce undesirable side effects of their own. Some people gain weight or have a reduced sex drive, for example (Advokat et al., 2014; Stahl, 2014; Taube-Schiff & Lau, 2008). Decisions about which kinds of antidepressants are prescribed for patients can also be influenced by other factors, such as insurance coverage or financial means (see PsychWatch).

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People who have been helped by the antidepressants readily sing their praises. Consider, for example, the following comments, offered in a recent survey of antidepressant users:

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As popular as the antidepressants are, it is important to recognize that they do not work for everyone. In fact, as you have read, even the most successful of them fails to help at least 35 percent of clients with depression. In fact, some recent reviews have raised the possibility that the failure rate is higher still, especially for people with mild or modest levels of depression (Hegerl et al., 2012; Isacsson & Alder, 2012). How are clients who do not respond to antidepressant drugs treated currently? Researchers have noted that, all too often, their psychiatrists or family physicians simply prescribe alternative antidepressants or antidepressant mixtures—one after another—without directing the clients to psychotherapy or counseling of some kind. Melissa, a depressed woman for whom psychotropic drug treatment has failed to work over many years, reflects on this issue:

Brain StimulationIn recent years, three additional biological approaches have been developed for the treatment of depressive disorders—vagus nerve stimulation, transcranial magnetic stimulation, and deep brain stimulation.

VAGUS NERVE STIMULATIONThe vagus nerve, the longest nerve in the human body, runs from the brain stem through the neck down the chest and on to the abdomen, serving as a primary channel of communication between the brain and major organs such as the heart, lungs, and intestines.

A number of years ago, a group of depression researchers surmised that they might be able to stimulate the brain by electrically stimulating the vagus nerve. They were hoping to mimic the positive effects of ECT without producing the undesired effects or trauma associated with ECT. Their efforts gave birth to a new treatment for depression—vagus nerve stimulation.

In this procedure, a surgeon implants a small device called a pulse generator under the skin of the chest. The surgeon then guides a wire, which extends from the pulse generator, up to the neck and attaches it to the vagus nerve (see Figure 8-4). Electrical signals travel from the pulse generator through the wire to the vagus nerve. The stimulated vagus nerve then delivers electrical signals to the brain. The pulse generator, which runs on battery power, is typically programmed to stimulate the vagus nerve (and, in turn, the brain) every five minutes for a period of 30 seconds.

In 2005, the U.S. Food and Drug Administration (FDA) approved vagus nerve stimulation for long-term, recurrent, and/or severe depression and for cases of depression that have not improved even after the use of at least four other treatments. The reason for this approval? Ever since vagus nerve stimulation was first tried on depressed human beings in 1998, research has found that the procedure brings significant relief. Indeed, in studies of severely depressed people who have not responded to any other form of treatment, as many as 40 percent improve significantly when treated with vagus nerve stimulation (Berry et al., 2013; Christmas et al., 2013; Howland et al., 2011).

As with ECT, researchers do not yet know precisely why vagus nerve stimulation reduces depression. After all, like ECT, the procedure activates neurotransmitters and areas all over the brain. This includes, but is not limited to, serotonin and norepinephrine and the brain areas that have been implicated in depression (Kosel et al., 2011).

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TRANSCRANIAL MAGNETIC STIMULATIONTranscranial magnetic stimulation (TMS) is another technique that is being used to try to stimulate the brain without subjecting depressed patients to the undesired effects or trauma of ECT. In this procedure, first developed in 1985, the clinician places an electromagnetic coil on or above the patient’s head. The coil sends a current into the prefrontal cortex. As you’ll remember from the previous chapter, at least some parts of the prefrontal cortex of depressed people are underactive; TMS appears to increase neuron activity in those regions.

TMS has been tested by researchers on a range of disorders, including depression. A number of studies have found that the procedure reduces depression when it is administered daily for two to four weeks (Fitzgerald & Daskalakis, 2012; Fox et al., 2012; Rosenberg et al., 2011). Moreover, according to a few investigations, TMS may be just as helpful as ECT when it is administered to severely depressed people who have been unresponsive to other forms of treatment (Mantovani et al., 2012; Rasmussen, 2011). In 2008, TMS was approved by the FDA as a treatment for major depressive disorder.

DEEP BRAIN STIMULATIONAs you read in the previous chapter, researchers have recently linked depression to high activity in Brodmann Area 25, a brain area located just below the cingulate cortex, and some suspect that this area may be a kind of “depression switch.” This finding led neurologist Helen Mayberg and her colleagues (2005) to administer an experimental treatment called deep brain stimulation (DBS) to six severely depressed patients who had previously been unresponsive to all other forms of treatment, including electroconvulsive therapy.

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Mayberg’s approach was modeled after deep brain stimulation techniques that had been used successfully in cases of brain seizure disorder and Parkinson’s disease, both of which are related to overly active brain areas. For depression, the Mayberg team drilled two tiny holes into the patient’s skull and implanted electrodes in Area 25. The electrodes were connected to a battery, or “pacemaker,” that was implanted in the patient’s chest (for men) or stomach (for women). The pacemaker powered the electrodes, sending a steady stream of low-voltage electricity to Area 25. Mayberg’s expectation was that this repeated stimulation would reduce Area 25 activity to a normal level and “recalibrate” and regulate the depression brain circuit.

In the initial study of DBS, four of the six severely depressed patients became almost depression-free within a matter of months (Mayberg et al., 2005). Subsequent research with other severely depressed individuals has also yielded promising findings (Berlim et al., 2014; Taghva, Malone, & Rezai, 2013; Hamani et al., 2011). In addition to significant mood improvements, patients undergoing the procedure have reported improvements in their short-term memory and quality of life.

Understandably, all of this has produced considerable enthusiasm in the clinical field. Nevertheless, it is important to recognize that research on DBS is in its earliest stages. Investigators have yet to run properly controlled studies of the procedure using larger numbers of research participants, to determine its long-term safety, or to fully clarify its undesired effects. We must remember that in the past, certain promising brain interventions for psychological disorders, such as the lobotomy, later proved problematic or even dangerous upon closer inspection.

For most kinds of psychological disorders, no more than one or two treatments or combinations of treatments, if any, emerge as highly successful. Unipolar depression seems to be an exception. One of the most treatable of all abnormal patterns, it may respond to any of several approaches. During the past 20 years, researchers have conducted a number of treatment outcome studies, which have revealed some important trends:

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