Treatment-Resistant Depression (TRD) is diagnosed when an individual’s mood and daily functioning disturbances do not show improvement after two courses of different antidepressants, each taken for at least six weeks, or they may improve but sporadically return.  These are the hallmarks of Treatment-Resistant Depression (TRD).  Neuroscientists have found that depression can cause shrinkage of the hippocampus, which is the brain structure in control of memory and acquiring new information.  Both Ketamine (administered intraveneously) and Esketamine (administered as a nasal spray) are given in a doctor’s office and are typically used with an antidepressant regimen.

Ketamine and Esketamine work differently from selective serotonin reuptake inhibitors (SSRIs), which are the most commonly prescribed antidepressants.  While SSRI’s block the reabsorption (or reuptake) of serotonin, both Ketamine and Esketamine have been found to create more connections (synapses) between brain cells, thus rapidly improving one’s moods. This process has been observed as more effective in reducing depressive symptoms over a shorter period of time than with antidepressants, particularly because they also increase levels of glutamate, the most abundant chemical messenger in the brain.

Ketamine delivered in low doses can provide rapid relief of Treatment-Resistant Depression (TRD), lasting for days to weeks.  It is then delivered in decreasing frequency over several weeks, starting with two doses a week for 2 to 3 weeks, then once weekly, then once monthly, and then tapering off. Response rates as high as 70% have been observed in clinical trials involving regular infusions.  The only other approved drug therapy for Treatment-Resistant Depression (TRD) is a combination of Olanzapine (an antipsychotic drug) and Fluoxetine (a conventional antidepressant).  However, this treatment has significant long-term effects, such as substantial weight gain, metabolic changes, diabetes, and high blood pressure.  Research has shown that Esketamine can significantly reduce depression symptoms and that these effects can last for weeks after treatment ends, due to its potency and few reported side effects.  The intranasal version has been approved by the FDA, and many insurance companies will now cover this treatment.  Treatment for the Esketamine nasal spray is done on an outpatient basis. 


     In the prescribed dosages, Ketamine therapy can allow depressed individuals to open their subconscious in a less threatening manner.  This open state of awareness allows the individual to replace traumatic and other distressing memories with conscious and healthier cognitions and coping behaviors.  How does Ketamine produce this open state of awareness?  Based on neuroscience studies, the triggering of glutamate is the “superpower” of Ketamine therapy, because glutamate is involved in more than 90% of all excitatory functions in the human brain and allows nerve cells in the memory and learning centers of the brain to form new associations.  Ketamine can help the depressed brain to form new memories, based on the new information which can be developed through certain psychotherapeutic strategies.  Glutamate is also responsible for the production of the brain’s main calming neurotransmitter, gamma-aminobutyric acid (GABA).  This calming effect can greatly help depressed individuals to explore the sources of their symptoms.  For these reasons, at-home Ketamine therapy is often complemented with psychotherapeutic strategies aimed at the improvement of recognizing and managing depression triggers and also for controlling PTSD symptoms.       

     Dialectical Behavior Therapy (DBT) has also been a very successful approach for Treatment-Resistant Depression (TRD) by using four main strategies.  First, Mindfulness Training techniques help depressed individuals to devote undistracted time toward becoming more fully aware of their thoughts, emotions, and sensory reactions during depressive episodes.  Secondly, Distress Tolerance Training aims at teaching individuals to accept the reality of situations which cannot be changed and to create conscious self-talk which gives a sense of control over one’s emotions and actions.  Third, Emotion Regulation Training helps in recognizing situations and related emotions, so that effective behavioral coping skills can replace the “stuckness” of depression.  Finally, Interpersonal Effectiveness Training can be practiced during therapy sessions and implemented in daily life.  These four strategies can be effectively used for individuals who are literally changing their brain pathways during Ketamine therapy.

     A more recent psychotherapeutic approach, Eye Movement Integration (EMI), is being successfully utilized with Treatment-Resistant Depression individuals who are undergoing at-home Ketamine therapy.  EMI helps individuals, through guided eye movements, in accessing, processing, and resolving traumatic and other distressing memories.  The goal is to help the mind heal itself by using its own inner resources.  Ketamine therapy provides the perfect foundation for tapping into one’s higher self, through the increase of glutamate activity, and EMI can provide the necessary path for full effectiveness in Ketamine treatment.  Because all human experiences have a structure, the elements of past experiences can be recalled and examined in the present moment through EMI techniques.  Ketamine increases the brain’s ability to form new neuronal connections, and EMI works to help depressed individuals examine their stored painful and self-defeating beliefs and then to “reorganize” these beliefs to be more present-focused and self-empowering.  Because habitual patterns of thoughts and behaviors are organized and systematic, they also tend to be enduring attributes which fuel depressive episodes.  However, if interrupted, these habitual patterns will reorganize.  Treatment-Resistant Depression often causes individuals to lack awareness of the entrenched beliefs which are creating a large part of their distress. 

     In sum, emotional pain is an inevitable aspect of the natural order of life, but Treatment-Resistant Depression causes a perpetual state of being overwhelmed and “frozen” in all stressful situations.  Ketamine therapy can be a pathway for the brain to decrease depressive symptoms and to also develop new connections which are resilient to future depressive episodes.

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