The Modern Advent of Biomedical Treatments

Early attempts to understand mental illness included supernatural theories and related forms of treatment that often included intense physical and emotional interventions such as exorcisms and trephination, as well as some forms of somatogenic theories and treatments. As time passed, still lacking a scientific explanation for mental disorders and their symptoms, society created asylums to isolate individuals suffering from mental disorders, adding to stigma against the mentally ill and creating painful and stressful living conditions, despite the efforts of reformers such as Dorothea Dix. However, near the end of the 19th century, new ideas and theories began to emerge, such as those of Sigmund Freud and his peers, that emphasized more psychogenic explanations for symptoms. The emergence of the fields of psychiatry and psychology began to approach these issues from a more scientific perspective, although they were still mostly unidimensional in approach. The discovery of the syphilis bacteria as a biological agent that could generate symptoms mimicking those of mental disorders as well as early studies and efforts to understand the brain also began to strengthen the appeal of somatogenic (body or biological) treatments as a way to reduce symptoms, which is a strong emphasis that continues today. One of the earliest modern forms of somatogenic or biomedical treatments was the use of lobotomy.

Lobotomy is a form of psychosurgery in which parts of the frontal lobe of the brain are destroyed or their connections to other parts of the brain severed. The goal of lobotomy was usually to calm symptoms in people with serious psychological disorders, such as schizophrenia. Lobotomy was widely used during the twentieth century; indeed, it was so mainstream that António Moniz, a Portuguese neurosurgeon, won a Nobel Prize in physiology or medicine in 1949 for his work on a specific lobotomy procedure. However, lobotomy was always highly controversial, partly because the results were irreversible, and widely criticized as a tool for behavioral control of people who were engaged in behaviors that were not actually clinical symptoms (see NPR’s report on Howard Dully). In addition, lobotomy did not actually eliminate the disorder being “treated,” and while it did reduce emotional expressions and made patients more “manageable,” side effects could include death; seizures; brain damage; and severe impacts on a patient’s personality, cognition, and social responsiveness, often referred to as “mental dullness.” Women were also given more lobotomies than men, raising significant ethical concerns regarding discrimination. By the 1960s and 1970s, lobotomy fell out of favor in the United States.

Another reason that lobotomy fell out of favor was the development in the 1950s and 1960s of new medications for the treatment of mental disorders; these have now become the most widely used forms of biological treatment. While these medications are often used in combination with psychotherapy, they also are taken by individuals not in therapy. This is known as biomedical therapy or treatment. Medications used to treat mental disorders are called psychotropic or psychoactive medications and are prescribed by medical doctors, including psychiatrists. In Louisiana and New Mexico as well as in the military, specially trained psychologists are able to prescribe some types of these medications as well (American Psychological Association, 2014). Specially trained nurse practitioners are also able to prescribe psychotropic drugs under the supervision of a physician.

Neurotransmitters and Psychotropic Drugs

There are several different types of neurotransmitters released by different neurons, and we can speak in broad terms about the kinds of functions associated with different neurotransmitters (Table 1). Much of what psychologists know about the functions of neurotransmitters comes from research on the effects of drugs in psychological disorders. Psychotropic or psychoactive drugs are any type of drug or chemical that alters the way a person thinks, feels, or behaves; most people have experience with at least some of these compounds, caffeine being the most common example. Some psychoactive drugs are illegal, mostly due to their potential for addiction (e.g., cocaine, heroin, and methamphetamine), but we will focus here on psychoactive drugs used in treatment. Research on the effects of different neurotransmitters, their interactions, and their role in mental disorders is ongoing, and we continue to learn.

Psychotropic drugs can act as agonists or antagonists for a given neurotransmitter system. Agonists are chemicals that mimic a neurotransmitter at the receptor site and thus strengthen its effects. An antagonist (like an opponent), on the other hand, blocks or impedes the normal activity of a neurotransmitter at the postsynaptic receptor. We know from the biopsychosocial model and epigenetics that there are complex interactions between neurotransmitter systems and also with the environment. For example, there is evidence that obsessive-compulsive disorder (OCD) involves interactions between serotonin systems and dopamine systems, and some studies have shown similar increased levels of serotonin in patients who responded to treatment, whether that treatment involved the use of medications or only psychotherapy with no drug treatment. Although mental disorder symptoms are not caused solely by dysfunctions in a neurotransmitter system, drug treatments have been developed to target specific symptoms and improve functioning.

For example, Parkinson’s disease, a progressive nervous system disorder, is associated with low levels of dopamine due to the death of neurons that produce dopamine. Therefore, a common treatment strategy for Parkinson’s disease involves using dopamine agonists, which mimic the effects of dopamine by binding to dopamine receptors. In contrast, some symptoms of schizophrenia are associated with overactive dopamine neurotransmission. The antipsychotics used to treat these symptoms are antagonists for dopamine—they block dopamine’s effects by binding its receptors without activating them. Thus, they prevent dopamine released by one neuron from signaling information to adjacent neurons. Remember that these issues are complex. For instance, there have been at least five different dopamine receptor types in the brain and two more are being investigated; these are further divided into two “families” of dopamine receptors. The effects of dopamine binding to these different postsynaptic receptors may vary depending on which receptor is activated by the neurotransmitter.

In contrast to agonists and antagonists, which both operate by binding to receptor sites, reuptake inhibitors prevent unused neurotransmitters from being transported back to the neuron. This allows neurotransmitters to remain active in the synaptic cleft for longer durations, increasing their effectiveness. Depression, which has been consistently linked with reduced serotonin levels, is commonly treated with selective serotonin reuptake inhibitors (SSRIs). By preventing reuptake, SSRIs strengthen the effect of serotonin, giving it more time to interact with serotonin receptors on the postsynaptic dendrites. Common SSRIs on the market today include Prozac, Paxil, and Zoloft. The drug LSD is structurally very similar to serotonin, and it affects the same neurons and receptors as serotonin.

Psychotropic drugs are not instant solutions for people suffering from psychological disorders. Often, an individual must take a drug for several weeks before seeing improvement, and many psychoactive drugs have significant negative side effects. Furthermore, individuals vary dramatically in how they respond to the drugs, sometimes leading patients to feel that they are being “experimented on.” In a way, this perception is true—the doctor is testing which drug and dosages produce the best effect for a given individual. At this moment, we do not have any type of blood test or other way to reveal which dose or which drug would work best for a given patient. Doctors often base initial doses on national recommendations and types of drugs based on family history. For example, if a patient’s older sister was diagnosed with depression and tried several drugs, but she found that Celexa worked better than Paxil, then the psychiatrist might begin the patient’s treatment with Celexa. This may work, but it may not. In addition, some people just do not improve with antidepressants at all (Ioannidis, 2008). As we better understand why individuals differ, the easier and more rapidly we will be able to help people in distress.

One area that has received interest recently has to do with an individualized treatment approach. We now know that there are genetic differences in some of the cytochrome P450 enzymes found in our cells and their ability to break down drugs. The general population falls into the following four categories: 1) ultra-extensive metabolizers break down certain drugs (like some of the current antidepressants) very, very quickly; 2) extensive metabolizers are also able to break down drugs fairly quickly; 3) intermediate metabolizers break down drugs more slowly than either of the two above groups; and finally 4) poor metabolizers break down drugs much more slowly than all the other groups.

Now consider someone receiving a prescription for an antidepressant—what would the consequences be if they were either an ultra-extensive metabolizer or a poor metabolizer? The ultra-extensive metabolizer would be given antidepressants and told it will probably take four to six weeks to begin working (this is true), but they metabolize the medication so quickly that it will never be effective for them. In contrast, the poor metabolizer given the same daily dose of the same antidepressant may build up such high levels in their blood (because they are not breaking the drug down) that they will have a wide range of side effects and feel really badly—also not a positive outcome. What if instead, prior to prescribing an antidepressant, the doctor could take a blood sample and determine which type of metabolizer a patient actually was? They could then make a much more informed decision about the best dose to prescribe. There are new genetic tests now available to better individualize treatment in just this way. A blood sample can determine (at least for some drugs) which category an individual fits into, but we need data to determine if this test actually is effective for treating depression or other mental illnesses (Zhou, 2009). Currently, this genetic test is expensive and not many health insurance plans cover this screen, but this test may be an important component in the future of psychopharmacology.

Another approach to improve chances for success is for people receiving pharmacotherapy to undergo psychological and/or behavioral therapies as well. Some research suggests that combining drug therapy with other forms of therapy tends to be more effective than any one treatment alone (for one such example, see March et al., 2007).

Brain Stimulation Treatments

Figure 1. The Bergonic Chair was a device used in the World War I era to deliver an early form of ECT.

Brain stimulation therapies can play a role in treating certain mental disorders. These therapies involve activating or inhibiting neuron systems directly using electricity. The electricity can be given directly by electrodes surgically implanted in the brain, or non-invasively through electrodes placed on the scalp. The electricity can also be induced by using magnetic fields applied to the head that penetrate into the brain. While these types of therapies are less frequently used than medication and psychotherapies, they can be helpful for treating certain mental disorders that have not responded to previous treatments with medications and/or psychotherapy or in cases where a rapid response is required such as patients with high suicide risk or catatonia, a form of psychosis in which the patient is unable to move or respond to the outside world and in cases where patients may not be eating or drinking. In other words, they are often considered to be “second line” treatments. In order to reduce the possibility of relapse, many of these treatments may involve follow-up treatment with medications and/or therapy.

Figure 2. ECT is often portrayed in the media as scary, but ECT today is administered in a safe and controlled environment and known to be effective in treating severe depression.

Electroconvulsive therapy (ECT; depicted in Figure 1 and previously called “electroshock therapy,” a term that is no longer used) is the best-studied brain stimulation therapy and has the longest history of use. ECT is most often used to treat severe, treatment-resistant depression, but it may also be sometimes useful in other mental disorders, such as bipolar disorder or schizophrenia, especially when used in combination with medications.^[1] Two major advantages of ECT over medications are that ECT usually begins to work more quickly, often starting within the first week, and older individuals respond especially quickly. Before ECT is administered, a person is sedated with general anesthesia and given a medication called a muscle relaxant to prevent movement during the procedure, reducing the risk of physical injury. An anesthesiologist monitors breathing, heart rate, and blood pressure during the entire procedure, which is conducted by a trained medical team, including physicians and nurses. At the start of the procedure, electrodes are placed at precise locations on the head. Through the electrodes, an electric current passes through the brain, causing a seizure that lasts generally less than one minute. Because the patient is under anesthesia and has taken a muscle relaxant, it is not painful and the patient cannot feel the electrical impulses. Five to ten minutes after the procedure ends, the patient awakens. They may feel groggy at first as the anesthesia wears off. But after about an hour, the patient usually is alert and can resume normal activities.

A typical course of ECT is administered about three times a week until the patient’s depression improves (usually within six to 12 treatments). After that, maintenance ECT treatment is sometimes needed to reduce the chances that symptoms will return. ECT maintenance treatment varies depending on the needs of the individual, and may range from one session per week to one session every few months. As noted above, follow-up treatment may include medications and/or psychotherapy. The most common side effects associated with ECT include headache, upset stomach, muscle aches, and memory loss. Some people may experience more significant memory problems, especially of memories around the time of the treatment. Less commonly, these memory problems may be more severe, but usually, they improve over the days and weeks following the end of an ECT course. Research has found that memory problems seem to be more associated with the traditional type of ECT called bilateral ECT, in which the electrodes are placed on both sides of the head. In unilateral ECT, the electrodes are placed on just one side of the head—typically the right side because it is opposite the brain’s learning and memory areas. Unilateral ECT has been found to be less likely to cause memory problems and therefore is preferred by many doctors, patients, and families.

Figure 2. A woman undergoing transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) uses a magnet to activate neurons in the brain. First developed in 1985, repetitive transcranial magnetic stimulation (rTMS) has been studied as a treatment for depression, psychosis, anxiety, and other disorders. Unlike ECT, in which electrical stimulation is more generalized, repetitive transcranial magnetic stimulation (rTMS) can be targeted to a specific site in the brain. Scientists believe that focusing on a specific site in the brain reduces the chance for the types of side effects associated with ECT. But experts have not yet reached a conclusion as to what site is best. In 2008, rTMS was approved for use by the FDA as a treatment for major depression for patients who do not respond to at least one antidepressant medication in the current episode. It is also used in other countries as a treatment for depression in patients who have not responded to medications and who might otherwise be considered for ECT. The evidence supporting rTMS for depression was mixed until the first large clinical trial, funded by NIMH, was published in 2010. The trial found that 14% achieved remission with rTMS compared to 5% with an inactive (placebo) treatment that mimics real rTMS. After the trial ended, patients could enter a second phase in which everyone, including those who previously received the placebo treatment, was given rTMS. Remission rates during the second phase climbed to nearly 30%.

A typical rTMS session lasts 30 to 60 minutes and does not require anesthesia. During the procedure, an electromagnetic coil is held against the forehead near an area of the brain that is thought to be involved in mood regulation. Then, short electromagnetic pulses are administered through the coil. The magnetic pulses easily pass through the skull and cause small electrical currents that stimulate nerve cells in the targeted brain region. Because this type of pulse generally does not reach further than two inches into the brain, scientists can select which parts of the brain will be affected and which will not be. The magnetic field is about the same strength as that of a magnetic resonance imaging (MRI) scan. Generally, the person feels a slight knocking or tapping on the head as the pulses are administered. There are still disagreements among scientists on the best way to position the magnet on the patient’s head or administer the electromagnetic pulses. At this time, it is also unclear if rTMS works best when given as a single treatment or combined with medication and/or psychotherapy. More research is underway to determine the safest and most effective uses of rTMS. Sometimes a person may have discomfort at the site on the head where the magnet is placed. The muscles of the scalp, jaw, or face may contract or tingle during the procedure. Mild headaches or brief light-headedness may result. It is also possible that the procedure could cause a seizure, although documented incidences of this are uncommon. Two large-scale studies on the safety of rTMS found that most side effects, such as headaches or scalp discomfort, were mild or moderate, and no seizures occurred. Because the treatment is relatively new, however, long-term side effects are unknown.

Magnetic seizure therapy (MST) borrows certain aspects from both ECT and rTMS. Like rTMS, magnetic seizure therapy (MST) uses magnetic pulses instead of electricity to stimulate a precise target in the brain. However, unlike rTMS, magnetic seizure therapy (MST) aims to induce a seizure similar to ECT. The pulses are given at a higher frequency than that used in rTMS, and the patient must be anesthetized and given a muscle relaxant to prevent movement. The goal of MST is to retain the effectiveness of ECT while reducing its cognitive side effects. MST is in the early stages of testing for mental disorders, but initial results are promising. A recent review article that examined the evidence from eight clinical studies found that MST triggered remission from major depression or bipolar disorder in 30–40% of individuals. MST carries the risk of side effects that can be caused by anesthesia exposure and the induction of a seizure. Studies in both animals and humans have found that MST produces fewer memory side effects, shorter seizures, and a shorter recovery time than ECT.

Vagus nerve stimulation (VNS) works through a device, called a pulse generator, implanted under the skin that sends electrical pulses through the left vagus nerve, half of a prominent pair of nerves that run from the brainstem through the neck and down to each side of the chest and abdomen. The vagus nerves carry messages from the brain to the body’s major organs (e.g. heart, lungs and intestines) and to areas of the brain that control mood, sleep, and other functions. Vagus nerve stimulation (VNS) was originally developed as a treatment for epilepsy. However, scientists noticed that it also had favorable effects on mood, especially depressive symptoms. Using brain scans, scientists found that the device affected areas of the brain that are involved in mood regulation. The pulses appeared to alter the levels of serotonin, norepinephrine, GABA, and glutamate. In 2005, the U.S. Food and Drug Administration (FDA) approved vagus nerve stimulation (VNS) for use in treating treatment-resistant depression in specific circumstances: the patient is an adult (over 18 years of age), the disorder has persisted over two years or more and is severe or recurrent, and there has been no significant relief after attempting four prior treatments. According to the FDA, it is not intended to be a first-line treatment, even for patients with severe depression. Despite FDA approval, VNS is not frequently used because results of early studies testing its effectiveness for major depression were mixed. But a newer study, which pooled together findings from only controlled clinical trials, found that 32% of depressed people responded to VSN and 14% had a full remission of symptoms after being treated for nearly two years. It is important to note that it may be several months before the patient notices any benefits and not all patients will respond to VNS. Patients undergoing VNS are expected to continue use of other treatments even with the pulse generator in place.

Additionally, there may be complications from VNS such as infection from the implant surgery, or the device may come loose, move around or malfunction, which may require additional surgery to correct. Some patients have no improvement in symptoms and some actually get worse. Other wide effects may include voice changes or hoarseness, cough or sore throat, neck pain, discomfort or tingling where the pulse generator is implanted, breathing problems during exercise (the generator can be temporarily turned off for exercise), and difficulty swallowing. Long-term side effects are unknown at this time.

Deep brain stimulation (DBS) was first developed as a treatment for Parkinson’s disease to reduce tremor, stiffness, walking problems, and uncontrollable movements. In deep brain stimulation (DBS), a pair of electrodes is implanted in the brain and controlled by a generator that is implanted in the chest. Stimulation is continuous and its frequency and level are customized to the individual. Deep brain stimulation (DBS) has been studied as a treatment for obsessive-compulsive disorder (OCD) and depression, although its use in treating depression is still considered experimental. A review of all 22 published studies testing DBS for depression found that only three of them were of high quality because they included both a treatment group and a control group. The review found that across the studies, 40–50% of patients showed greater than 50% improvement in symptoms.

Unlike VNS, DBS requires brain surgery, guided by MRI scans of the brain. Once inside the skull, the surgeon threads a slender tube down into the brain to place electrodes on each side of a specific area of the brain. For OCD, the electrodes are placed in an area of the brain (the ventral capsule/ventral striatum) believed to be associated with the disorder. In the case of depression, the first area of the brain targeted by DBS is called Area 25, or the subgenual cingulate cortex. This area has been found to be overactive in depression and other mood disorders. But later research targeted several other areas of the brain affected by depression. The electrodes in the brain are then attached to wires that run from the head down to the chest, where a pair of battery-operated generators are implanted. From here, electrical pulses are continuously delivered over the wires to the electrodes in the brain. Although it is unclear exactly how the device works to reduce OCD or depression, scientists believe that the pulses help to “reset” the area of the brain that is malfunctioning so that it works normally again. Because DBS involves surgery, there is a list of potential side-effects including bleeding in the brain or stroke, infection, disorientation or confusion, mood changes, movement disorders, lightheadedness, and trouble sleeping. Because the procedure is still being studied, other side effects not yet identified may be possible. Long-term benefits and side effects are unknown.