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<\/span><\/div>Stephen Rush, MD Treatment Resistant Depression (Part Two of Two)<\/p>\n See Treatment Resistant Depression Part One<\/a><\/p>\n In the last article, we discussed what depression is and what treatments are typically used to treat depression.\u00a0 We also discussed Treatment Resistant Depression (TRD) and the challenges and burdens this illness presents for patients, clinicians, and communities.\u00a0 Depression that is treatment resistant, defined by the failure to respond to at least 2 trials of antidepressant medications, occurs in up to 30% of people.\u00a0 However, many patients classified as \u201ctreatment resistant\u201d have had trials of multiple antidepressants and other medications, with limited positive effect on mood.<\/p>\n HOPE FOR RECOVERY:<\/p>\n There are several approaches to treatment of TRD when 2 or more antidepressant medications have not resulted in sufficient improvement.<\/p>\n One approach is the addition of a second medication that has been shown to increase response to an antidepressant, known as augmentation. FDA approved medications which can augment an antidepressant include Seroquel, Abilify, Vraylar and Rexulti, which are classified as \u201cantipsychotic\u201d medications though not used for that purpose here 1,2,3,4,<\/sup>.<\/p>\n In recent years there have been advances in treatments for depression including neuromodulation techniques such as Transcranial Magnetic Stimulation (TMS) as well as new medications such as esketamine. Another form of neuromodulation, electroconvulsive therapy, has been available for more than 50 years and has been demonstrated to be the most effective at treating depression, but is often avoided because of a history of pop-culture references that induce fear. The movie \u201cOne Flew Over the Cuckoo\u2019s Nest\u201d is the most famous of these5<\/sup>.<\/p>\n Transcranial Magnetic Stimulation is a noninvasive treatment that uses magnetic fields to induce an electric current, targeted at specific brain regions thought to be underactive in depression.\u00a0 To achieve this, an electric pulse generator is connected to a magnetic coil placed over the brain region known as the dorsolateral prefrontal cortex.\u00a0 When electromagnetic pulses are applied to this area at a high frequency (10 times per second), the activity in the DLPFC increases and, subsequently, results in increased activity in other brain regions thought to be involved in depression.\u00a0 Treatment is done 5 days per week, Monday through Friday, for 30-36 total treatments (6-7 weeks) with each treatment lasting from 4 to 45 minutes.\u00a0 The effects of TMS on depression are typically not seen until sometime after 20 treatments are completed, at week 4.\u00a0 The antidepressant effect of TMS is associated with increased brain activity, increased dopamine and serotonin transmission, and increased production of Brain Derived Neurotrophic Factor (BDNF) which is a protein vital for maintaining the health of neurons and neural pathways6<\/sup>.\u00a0 Recently, there has been an increased focus on the role of BDNF in depression.\u00a0 Studies show an association between low BDNF levels and higher severity of depression and, in response to TMS, increased BDNF levels and neuroplasticity (the ability of the brain to form and reorganize neural connection)7,8<\/sup>.\u00a0 TMS is not appropriate for people who have implanted or metallic devices such as aneurysm clips or coils and pacemakers.\u00a0 There are limited side effects that result from TMS treatment, including discomfort at the stimulation site and headaches.\u00a0 There is a known risk of seizures, though it is estimated that this side effect occurs in less than 1% of patients9<\/sup>.<\/p>\n Ketamine has long been used as an anesthetic agent that also has rapid-acting antidepressant effects.\u00a0 Ketamine can be administered through an IV, as an intramuscular injection and as an aerosolized nasal spray.\u00a0 Spravato, or esketamine, is a modified molecule derived from ketamine that was FDA approved for the treatment of treatment refractory depression and Major Depressive Disorder with acute suicidal ideation in 2019.\u00a0 This drug is self-administered by patients, under physician supervision, as a nasal spray.\u00a0 Both ketamine and Spravato are thought to have effects on at least 2 pathways in the brain: decreasing glutamate transmission at n-methyl-d-aspartate (NMDA) receptors and activating opioid receptors10<\/sup>.\u00a0 Dosing of this medication varies by patient and the antidepressant effect is usually seen within the first month, though may be dependent on continued dosing to sustain this response, done at frequencies that vary from weekly to monthly11<\/sup>.\u00a0 This treatment is generally well tolerated and side effects, including dissociation, alterations in heart rate and blood pressure, nausea, and sedation, typically resolve within 2 hours after administration12<\/sup>.<\/p>\n Electroconvulsive Therapy, or ECT, is a treatment where electricity is applied to the scalp with the intention of inducing a generalized seizure in the underlying brain regions.\u00a0 Patients receiving ECT are first sedated with general anesthesia and a muscle relaxant, the latter inhibiting convulsions so that seizure activity is only occurring in the brain while the body remains relaxed.\u00a0 Seizures last from 1 to 6 seconds and repeat treatments are typically done three times weekly for 6-12 treatments total over 2 to 4 weeks.\u00a0 For many patients, the effects of ECT are not sustained without maintenance treatment, which can be a single treatment done every 2-4 weeks after the initial 6-12 treatments.\u00a0 While the changes in the brain after ECT are not well understood, it is believed that seizure activity increases activity at serotonin receptors and increases the amounts of dopamine and norepinephrine available. ECT is more invasive than ketamine treatment or TMS, because of the risks associated with general anesthesia and cognitive impairments (memory, executive function, attention) which usually persist up to 6 months following the completion of treatment.<\/p>\n WHAT HAPPENS IN YOUR BRAIN<\/p>\n We are still trying to understand what is happening in the brain of those with treatment resistant depression. Studies suggest that patients with TRD are unique, in that they have markers of increased inflammation and immune dysregulation compared with patients without TRD. Like antidepressants in non-TRD, TRD treatments appear to increase neuroplasticity in ways that repair connectivity between neurons in brain regions important in the regulation of mood. Antidepressant medications are thought to work through modulation of monoamines, neurotransmitters derived from amino acids, including dopamine, serotonin, and norepinephrine, that regulate brain processes such as emotion, motivation, arousal, and cognition.\u00a0 While the treatments for TRD likely have some effect on monoamines, their primary mechanisms of action rely on interaction with pathways that are not affected by antidepressants.<\/p>\n GETTING BACK YOUR LIFE<\/p>\n Unfortunately, depression is often insufficiently treated until this brain disorder has resulted in significant and negative impacts on a person\u2019s sense of self, ability to function and overall sense of wellness.<\/p>\n However, there is hope. As scientists and doctors better understand depressive disorders, including treatment resistant depression, a patient\u2019s illness will be diagnosed as early as possible for the best possible outcome. From psychotherapy to medication to brain stimulation, many patients with TRD are getting their lives back and moving on with the things that they love. Today, there has never been as much hope as there is now for TRD.<\/p>\n
\nAssociate Professor of Clinical Psychiatry, University of Cincinnati<\/strong><\/p>\n<\/div><\/div><\/div>\n