- An estimated six percent of Americans ages 65 and older in a given year (approximately 2 million of the 34 million adults in this age group in 1998), have a diagnosable depressive illness (major depressive disorder, bipolar disorder, or dysthymic disorder). (Narrow 1998)
- As a result of depression, older Americans are disproportionately likely to commit suicide. Although they comprise only 13 percent of the U.S. population, individuals ages 65 and older accounted for 19 percent of all suicide deaths in 1997. (Hoyert, 1999)
- New effective treatments, with fewer undesirable side-effects, are available for depression.
Major depression is a leading cause of disability in the United States and worldwide. (Murray 1996) In contrast to the normal emotional experiences of sadness, grief, loss, or passing mood states, depressive disorders can be extreme and persistent and can significantly interfere with an individual’s ability to function, robbing one of the joy of living. Depression often co-occurs with other illnesses such as cardiovascular disease, stroke, diabetes, and cancer, which have a significant incidence in seniors. (AHRQ, formerly AHCPR 1993) When depression co-occurs with medical conditions, it can interfere with the patient’s ability to follow the necessary treatment regimen or to participate in a rehabilitation program. It may also increase impairment from the medical disorder and impede its improvement.
Treatment of depression
Antidepressant medications are widely used effective treatments for depression. (Mulrow 1998) Existing antidepressant drugs are known to influence the functioning of certain neurotransmitters in the brain, primarily serotonin and norepinephrine. Older medications—tricyclic antidepressants and monoamine oxidase inhibitors—affect the activity of both of these neurotransmitters simultaneously. The disadvantage of these older medications is that they can be difficult to tolerate due to side effects or dietary and/or medication restrictions. Newer medications, such as the selective serotonin reuptake inhibitors (SSRIs), have significantly fewer side effects than older drugs, making it easier for patients, including older adults, to adhere to treatment. The anti-depressant effect of SSRIs is presumed to be linked to their inhibition of CNS neuronal uptake of serotonin. SSRIs include fluoxetine, paroxetine, citalopram, and sertraline.
Other recently introduced anti-depressants include the serotonin and noradrenaline reuptake inhibitors (SNRIs), venlafaxine and milnacipran. These drugs have a mechanism of action that is similar to the tricyclic antidepressants. Another new drug is reboxetine, a selective noradrenaline reuptake inhibitor. All these newer antidepressants may be better tolerated by patients suffering from depression.
Available in the United States since the 1980s, the first SSRI treatment was not available in Japan until 1999. Perhaps related to the relative unavailability of depression medication, Japan has the highest number of psychiatric inpatient beds in the world, in both absolute and relative terms. (Tajima 2001)
Drugs in the pipeline for depression
- Nicotinic-receptor stimulators to enhance cognitive function are being tested for the treatment of depression. (NIH 2002)
- New inhibitors of neurotransmitter uptake are being studied. (NIH 2002)
- Two compounds that act as antagonists for the glucocorticoid receptor (GR) are currently being studied in patients with severe major depression. (NIH 2002)
- Antagonists of substance P and corticotropin-releasing factor receptors are in clinical trials for the treatment of depression. (NIH 2002, Pacher 2001)
- Agonists and antagonists of different serotonin (5-HT) receptor subtypes are being investigated as potential antidepressants. (NIH 2002, Pacher 2001)
According to the Pharmaceutical Research and Manufacturers of America (PhRMA), 26 drugs for depression were in clinical trials in 2002. As medical science progresses, more effective and better tolerated treatments for depression will become available. Two principal strategies guide medication development efforts for depression. First, there are efforts to refine and reformulate existing medications known to work on “classic” neurotransmitter systems as a means of bringing more effective treatments to an expanded and more diverse population of persons with depression. Second, researchers are attempting to develop fundamentally new compounds that target novel brain mechanisms suggested by cutting edge research on the causes of depression.
Newer approaches to pharmaceutical treatment of depression target neuropeptide receptors and intracellular messenger systems. (Pacher 2001) Medications for depression currently under development include: corticotrophin releasing factor (CRF) receptor antagonists, substance P (neurokinin) receptor antagonists, and drugs that modulate glutamatergic transmission. (NIH 2002) Patients may tolerate these agents better than current drugs and, therefore, be more compliant with treatment regimens.
Abundant evidence suggests that increased production and/or release of CRF within the central nervous system occurs in patients with post-traumatic stress disorder and major depression. Preclinical studies show that CRF antagonists have anti-anxiety and antidepressant properties. Although CRF receptor antagonists appear promising as a novel class of antidepressants and anxiolytics, further study is needed into their clinical efficacy and safety.
Based on preclinical evidence suggesting anti-anxiety properties of inhibitors of the Substance P, selective compounds have been tested and found superior to placebo and equal to other antidepressants in treating depression. More evaluation of these agents is needed.
The neurotransmitter, glutamate, has been linked to anxiety and depression. Compounds that interfere with its action in the brain are among the candidate medications under development as potential antidepressants. (NIH 2002)
In addition to the approaches discussed, that have already led to the developing and testing of new types of antidepressants, rapid advances in neuroscience suggest medication development strategies that have yet to be undertaken. These include drugs that interact with second messenger systems, response elements and transcription factors, agents that enhance neuroprotective and neurogenic factors, and compounds that manipulate cytokine receptor activity.