Future Directions for Treating Depression
Introduction
Unipolar depression is one of the fastest growing and most widespread disorders recognized today. Particularly distressing is the fact that depression now strikes young people at an unprecedented rate. Approximately one-sixth of all high school students will be affected before graduation, and one-quarter of all college students may have symptoms of depression (1). Treatment of unipolar depression is a pressing issue in the field of abnormal psychology, yet our knowledge of depression remains incomplete. The etiology is still uncertain – in fact, most of the available treatments for depression were not the result of directed research, but rather were the result of accidental discoveries over 50 years old (2). It is obvious that research into new and alternative treatments for depression to supplement the current treatments must be a priority. Fortunately, several promising approaches are already emerging.
Deep Brain Stimulation
Current evidence suggests that depression is a disorder that is the result of multiple issues. Genetic predisposition, brain damage, and stress are all contributors to the development of depression, and may involve multiple brain pathways and neurotransmitters. Neuroimaging has shown that multiple areas of the brain may be involved in depression, including the subgenual cingulated region (Cg25). Cg25 has been shown to be involved in acute sadness, and has shown reduced activation in response to common antidepressant treatments, including specific serotonin reuptake inhibitors and electroconvulsive therapy. Areas linked to Cg25 are also involved in controlling many of the behaviors that are affected by severe depression (3). As a result, Cg25 theoretically presents a prime target area for applying deep brain stimulation (DBS) to unipolar depression. Delivering electrical pulses to Cg25 in order to compensate for reduced activation may alleviate particularly difficult cases of depression.
Deep brain stimulation involves the use of electric current to stimulate a target brain area. Four electrodes are implanted into the targeted brain area under local anesthesia. The electrodes are tested and connected to a pulse generator which is implanted in the body under general anesthesia. The pulse generator allows patients to continue a normal life by continuously delivering electrical current pulses to the target brain area even after the patient leaves the hospital (3).
The use of deep brain stimulation can effectively treat tremors caused by Parkinson’s disease. Use of DBS for Parkinson’s patients has demonstrated that repeated stimulation of overactive brain regions may be beneficial (3, 4). Additionally, DBS has shown the ability to modulate brain activity in obsessive-compulsive disorder (4). As a result, researchers in Canada attempted to use DBS to modulate Cg25 activation in order to treat severe, treatment-refractory depression (TRD) (3).
TRD patients have shown a distinctive lack of response to even aggressive treatment plans. The effective use of DBS to treat TRD patients would be a significant step forward in the treatment of depression. Although DBS targeting Cg25 was effective as described by the Canadian researchers Mayberg et al., the sample size used was very small (n=6), and DBS was completely ineffective for one patient and effective only in the short-term for another (3).
The patient population was selected to meet standardized DSM IV-TR descriptions for major depressive disorder, with a major depressive episode of one year or longer. Each of the selected patients also met the criteria for TRD, as all failed to improve after treatment with antidepressants, psychotherapy and electroconvulsive therapy (3).
During the course of the initial implantation of DBS electrodes, the electrodes were sequentially tested with varying voltages. The patients were blind to testing, but all reported beneficial effects, including “sudden calmness,” “disappearance of the void,” “heightened awareness,” “sudden brightening of the room,” “sharpening of visual details,” and “intensification of colors” (3). The effects were associated with stimulation through the electrodes, and none were associated with “sham” stimuli. Additional improvements were noted in motor speed and volume (3).
Magnetic Resonance Imaging confirmed DBS electrode placement in Cg25. Placebo effects were controlled by blinding patients to the electrode settings and to whether the electrodes were active. This testing confirmed that placebo effects were not responsible for the improvements. Testing six months later confirmed that, ultimately, the depression of three patients had gone into remission. At peak response two months after implantation, five of the patients showed improvement. However, by the time the study ended at the 6 month time point, two patients had failed to show sustained improvement. Many effects were observed, including normalization of sleep, increased energy, increased psychomotor speed, decreased anhedonia, and improvement in ability to perform tasks, improvement in intellectual function, and improved mood and emotional states (3).
Since the sample size was very small, conclusions are difficult to draw. However, the research performed by Mayberg et al. seems to show promising results for the use of DBS to treat TRD. Four of six patients responded, a conspicuously high response rate for a patient population that is notoriously difficult to treat. Neuroimaging established that in patients with a lasting positive response to the DBS targeting, Cg25 normalized brain activation where many abnormalities were observed before treatment (3).
If further research into DBS for depression shows promise, it will be an important advancement in treatment for this disorder. DBS offers multiple advantages, including reversibility and the ability to tailor the treatment parameters to the individual patient (4). DBS in the mode used by Mayberg et al. also offers compactness and portability because the circuitry and the pulse generated are all implanted within the body (3).
However, there are many special considerations to take into account with TRD patients and this mode of treatment. DBS requires delicate surgery to implant electrodes, and there is always the possibility that even TRD patients may eventually respond to less risky conventional treatment (4). Care should be taken to ensure that if DBS is adopted as a common treatment for depression, treatment be limited to appropriate patients. There is the dangerous possibility that patients may see DBS as a panacea for their troubles.
Reward Circuit
Another future target for the treatment of depression involves the reward system of the brain, including the nucleus accumbens (4). The nucleus accumbens (NAc) receives dopamine inputs from an area known as the ventral tegmental area (VTA), and together these areas form the mesolimbic dopamine system – the brain’s reward circuit for food, sex, and narcotics. The NAc is an interesting target of action for treatment of depression primarily because of the depressive symptoms of anhedonia, lack of motivation, and low energy. Additionally, studies performed with dopamine receptor antagonists indicated the involvement of the reward pathway in controlling depression symptom behaviors (2).
Depression appears in more females than males, with a mean ratio of 2:1. This ratio is perplexing, but hypotheses range from sex differences in coping with depressive events to genetic theories regarding a “depressive gene” (1). One of these hypotheses notes that males may turn to alcoholism or other narcotics abuse to cope, and that these cases may lower the apparent rate of depression in men (1). If this proves to be true, treatments targeting NAc may have strong beneficial effects. Dopamine and the NAc are involved in the reward effects of many abused drugs. Opiates, for instance, activate dopamine transmission and receptors in the NAc (2). Treatment targeting the NAc may therefore show promise in treating disorders similar to, but separate from depression.
The NAc may also be able to mediate the abnormal sleep patterns of severely depressed individuals. Studies of circadian rhythm genes have shown that narcotic reward mechanisms at the reward pathway are influenced heavily by these genes (2). Therefore, it is also possible that depression’s symptoms may be rooted in these same circadian genes, influencing sleep pattern disruption as well as errors at the NAc and the reward pathway (2).
Based on the role of the NAc and the reward circuit in motivation, treatment targeting the NAc may also be helpful for mood disorders other than depression. In depression, it seems logical that an impairment of NAc and the reward circuit may be responsible for many of the symptoms of the disease. The development of treatments targeting NAc is lagging behind even the development of a procedure like DBS, which is still being researched for depression. DBS at least has concrete evidence of effectiveness in similar situations; treatments targeting NAc are still theoretical. However, these treatments are well worth researching. Treatments targeting NAc could supplement DBS or supplant it in cases where DBS is undesirable for its surgical aspects or for other reasons.
Conclusion
Finding future targets for treatment of depression may be difficult due to the limited current knowledge of the etiology and mechanisms of depression and its symptoms. Still, promising research has emerged in the form of deep brain stimulation targeting the subgenual cingulate in Brodmann’s Area 25. The effectiveness of this approach is still uncertain, given the limited nature of the research (3). Furthermore, studies have shown that there are important mechanistic differences across the different types of depression. These differences are likely relevant to the treatment of the types of depression (3). Deep brain stimulation’s successes in treating TRD cannot show effectiveness across the several types of depression. However, if it is possible to use DBS to treat TRD, it will offer a treatment for a type of depression that currently has few if any other treatments.
Furthermore, it is possible that other types of depression may be localized to other brain regions that would be potential targets for DBS.
It is also important to look further ahead for alternative targets. Molecular targets are an intriguing choice because, once developed, this type of treatment is much simpler and less risky – many molecular targets are treated with chemical pills like selective serotonin reuptake inhibitors. One promising location in which to hunt for molecular targets includes the nucleus accumbens. Targeting the reward pathway through the NAc seems like a promising and logical method of at least alleviating many symptoms of depression, including anhedonia, low energy, and lack of motivation. The NAc also offers the possibility of treating other disorders, including narcotic additions, alcoholism, and possibly sleep disorders (2).
Research into these future directions for treatment of depressive disorders is an important priority in the field of abnormal psychology. The apparent increase in rate of depression and the apparent decrease in age of onset are disturbing, but the outlook is hopeful. With many possible avenues for new research moving forward, and with promising treatments already gaining increased attention, there is hope that depression can be alleviated and that its effects may be reduced.
References
1.M.E.P. Seligman, E.F. Walker, and D.L. Rosenhan, Abnormal Psychology, 4th Edition (W.W. Norton and Company, New York City, 2001).
2.E.J. Nestler and W.A. Carlezon, Jr., Biological Psychiatry 59, 1151 (2006).
3.H.S. Mayberg et. al, Neuron 45, 651 (2005).
4.T.E. Schlaepfer and K. Lieb, The Lancet 366, 1420 (2005).