Overview of Antidepressant Treatments
Despite the relative lack of knowledge of the etiology and pathophysiology of depression, there are very good treatments for it, with most patients showing significant improvement with optimal treatment. Mild depression responds to different forms of psychotherapy (Box 2: Currently Available Antidepressant Treatments). Mild and more severe forms of depression respond to a host of antidepressant medications, with a combination of medication and psychotherapy providing optimal treatment. Electroconvulsive therapy (ECT or shock treatment) is one of most effective treatments for depression, but is usually reserved for the more severely ill due to the availability of numerous pharmacotherapies. The utility of other so-called "somatic" therapies is still under investigation (Box 2: Currently Available Antidepressant Treatments).
Virtually all available medication treatments for depression are based on serendipitous discoveries made over a half century ago. Most of today's medications are based on the tricyclic antidepressants, which are believed to act by inhibiting the plasma membrane transporters for serotonin and/or norepinephrine. These older medications provided a template for the development of newer classes of antidepressants, including the SSRIs (serotonin-selective reuptake inhibitors), NRIs (norepinephrine reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors). Example of these medications are given in Box 2. However, as these newer medications have the same mechanism of action as the older tricyclics, their intrinsic efficacy and range of patients treated remain the same. Older monoamine oxidase inhibitors, which reduce the enzymatic breakdown of serotonin and norepinephrine, are also still used today with great success.
Knowledge of the acute mechanisms of action of these drugs led to the general belief that all effective antidepressant medications act by increasing the activity of the brain's serotonergic or noradrenergic system. Yet, all of these medications must be given for several weeks at least in order for their antidepressant actions to become manifest. Despite several decades of research, and many interesting and promising leads, the changes that the drugs induce in brain that underlie their therapeutic actions remain unclear.
While today's treatments for depression are generally safe and effective, they are far from ideal. In addition to the need to administer the drugs for weeks or months to see clinical benefit, side effects are still a major problem even with the newer medications. For example, the SSRI's, which lack the dry mouth, weight gain, and constipation often seen with the tricyclic drugs, cause sexual side effects (loss of libido, difficulty in achieving orgasm) in over a third of patients. And, most importantly, less than half of all patients with depression show full remission with optimized treatment, including trials on numerous medications with and without concurrent psychotherapy. Thus, there is still a great need for faster acting, safer, and more effective treatments for depression.
Based largely on the acute pharmacological mechanisms of action of the older tricyclic and monoamine oxidase inhibitor medications, and the newer more selective serotonin and norepinephrine transporter inhibitors, the vast majority of antidepressant drug discovery efforts over the past several generations have focused on finding more selective serotonin or norepinephrine receptor agonists or antagonists, which might produce actions like the other drugs, but more quickly and safely. Such efforts are still underway with some promising leads. However, despite billions of dollars of research in academia and industry, this approach has not yet succeeded in bringing any fundamentally new medications to market. There are a handful of newer, so-called "atypical antidepressants," with ascribed monoamine-based mechanisms, but the evidence is quite weak that their purported mechanisms actually account for the drugs' clinical efficacy (Box 2: Currently Available Antidepressant Treatments).
At the same time, there has been an impressive accumulation of knowledge about non-monoamine systems that might contribute to the pathophysiology of depression in animal models, with some human evidence available as well. For example, ketamine, a non-competitive antagonist of NMDA glutamate receptors, exerts rapid antidepressant responses in roughly half or two-thirds of patients with severe, treatment-resistant depression. Likewise, deep brain stimulation, which involves the neurosurgical placement of electrodes into specific areas of the brain, offers promise to severely depressed individuals. There is thus increasing excitement in the field that fundamentally new treatments, with different mechanisms of action, will be approved over the next 5-10 years. This excitement is based on the notion that drugs and related treatments with new mechanisms of action will be able to treat many of the patients not adequately treated with available (monoamine-acting) agents.