Generalized Anxiety Disorder or GAD is characterized by excessive worrying which is difficult to control and causes significant and excessive burden to the individual and their quality of life. Anxiety disorders on a whole including generalized anxiety disorder, panic disorder, social anxiety disorder, and phobias are some of the most common illnesses in the United States, affecting 19% of the population, or approximately 40 million adults annually. The lifetime incidence specifically for generalized anxiety disorder in the United States is 5%, affecting females twice more often than males.
Generalized anxiety disorder is often closely associated with other comorbid disorders, with major depressive disorder being the most common. Major depressive disorder is reported to be present in 62% of individuals with generalized anxiety disorder. Additionally, generalized anxiety disorder has been found to be associated with higher incidences of substances abuse, PTSD, and obsessive-compulsive disorder. Approximately half of patients treated for generalized anxiety disorder will fail to respond to initial treatment. Treatment-resistant generalized anxiety disorder is defined as failure to respond to at least 1 trial of antidepressant therapy at adequate dose and duration. New options for treatment are sought after, with ketamine recently gaining interest among the public as a novel, safe, and effective treatment option for patients with anxiety disorders.
A number of biological factors are involved in the pathogenesis of anxiety including genetics, neurotransmitter disturbances, and brain metabolism. Data supports the fact that some individuals have genes that make them more susceptible to generalized anxiety disorder. One such gene increases the expression of serotonin transporters causing increased reuptake of serotonin into the cell, rendering it unavailable for neurotransmission. Serotonin plays important roles in mood, emotions, and motor skill and is a chemical that impacts nearly every part of the body including the gut, brain, and everything in between.
Individuals with generalized anxiety disorder have been found to have changes in brain metabolism (i.e. glucose) and structure. Decreased volumes of white matter have been seen in magnetic resonance imaging (MRI) studies comparing individuals with generalized anxiety disorder to healthy controls.
Psychological and developmental factors may be important reasons why some individuals are more prone to anxiety disorders than others. Individuals with generalized anxiety disorder often process emotional information more strongly, perceiving external stimuli in a hypervigilant and threatening manner. Major life stress and increase number of traumatic events in childhood and development increases the likelihood of the cultivation of depressive and anxiety disorders in adulthood.
The two main options for treatment of anxiety include medications with anxiolytic effects and cognitive-behavioral therapy (CBT). Individuals may choose the use of CBT alone, medications alone, or in combination with the hope of having synergistic effects. Pharmacotherapy may be the preferred initial treatment option for individuals with severe anxiety or comorbid conditions such as major depressive disorder, as these individuals are often found to be too symptomatic to fully engage and participate in CBT.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the preferred initial class of medications used for treatment of generalized anxiety disorder. Serotonin reuptake inhibitors have a delayed onset, several drug-drug interactions, and often poor overall tolerance. Side effects such as weight gain and sexual disfunction are often major concerns which may lead to poor compliance and long-term use.
While a number of other pharmacologic options are available for the treatment of anxiety disorders, our discussion would not be complete without mention of a specific class of medications called benzodiazepines. Benzodiazepines such as alprazolam, diazepam, and lorazepam are some of the more commonly used medications for generalized anxiety disorder. Albeit effective in the acute setting, benzodiazepines are considered second-line therapy given their short duration, potential for dependence, withdrawal with discontinuation, and other serious side effects including respiratory depression. Benzodiazepines are to not be considered a long-term solution for anxiety, but rather an option in an acute and short-term setting, with the recommended maximal duration of use between 2-8 weeks. To make matters worse, the long-term effectiveness of benzodiazepines is poor at best. A systematic review concluded that there was no significant differences in changes in Hamilton Anxiety Rating Scale (HAM-A), all-cause discontinuation, number of panic attacks, and side effects between benzodiazepines and antidepressants after 8 weeks of acute treatment.
Ketamine’s main antidepressant effects are mediated by its interaction with the NMDA receptor found on the cells of the brain. Normally an amino acid, called glutamate, binds to this receptor rendering it active, opening an ion channel on the cell which causes downstream effects. Ketamine acts as a non-competitive antagonist at this receptor, which means that rather than competing for glutamate binding site on the NMDA receptor, ketamine inhibits receptor function by blocking the ion channel itself, preventing influx of ions and thus activation/intracellular signaling.
Patients with anxiety have been found to have glutamate receptor damage within parts of the brain such as the hippocampus and prefrontal cortex. Receptor dysfunction results in mood disturbances and cognitive deficits. NMDA receptor inhibitors such as ketamine have been shown to restore brain function in stressed individuals by reducing NMDA receptor activity. Another mechanism of action is via ketamine’s indirect mechanism to increase level of brain derived neurotrophic factor (BDNF), a protein that plays an important role in neurogenesis, causing regrowth and strengthening of broken connections in stressed brains. Altered BDNF signaling has been linked to brain diseases, including mental disorders such as depression, neurodegenerative diseases such as Alzheimer’s disease, and even in brain tumors (i.e., glioblastoma). Furthermore, BDNF appears to serve a strong role in neuroprotection, thus rendering brain cells resilient to degeneration.
It is well established that low-dose ketamine has strong positive effects on patients with depression and treatment-resistant depression. As we previously mentioned, individuals with generalized anxiety disorder most often have comorbid depression, thus treatment with ketamine can be helpful for both conditions. In one study of patients with anxiety spectrum disorders, just one single infusion of ketamine showed positive effects with reduced irritability and panic at 24 hours post infusion. Another study using a single dose of ketamine showed treatment response within 3 hours post-ketamine infusion that persisted for 2 weeks. Other studies using ascending repeating (six) doses of IV ketamine (standard practice) in patients with anxious treatment-resistant depression show significant reduction in anxiety levels on Hamilton Anxiety Rating Scale (HAM-A). Additionally, depressive symptoms drastically improved on the Montgomery-Asberg Depression Rating Scale (MADRS). An 83% response rate was reported at a dose of 0.5mg-1mg/kg.
Neurocognition also showed several improvements, including faster speed of processing (SOP) in the anxious TRD group, and better verbal learning and memory (VLM). Moreover, faster baseline SOP was correlated with better improvements in anxiety in the anxious TRD group, while better baseline VLM was linked to greater improvements in depression in the non-anxious TRD group.
Low doses of ketamine effectively treat other types of anxiety, including refractory social anxiety, with only minor adverse effects, including mild raises in blood pressure, nausea, dizziness and blurred vision. These studies demonstrate the safe and effective use of ketamine administration, especially for those with treatment‐resistant anxiety and depression.
Studies suggest that patients with treatment-resistant generalized anxiety disorder often report reduction of symptoms within a week after dosing. Results from one study showed that of the 20 patients, 18 reported improved social functioning and/or work functioning, with Fear Questionnaire ratings and Hamilton Anxiety ratings decreased by approximately 50%, one hour after dosing. Our protocol at Innerbloom Ketamine Therapy includes one to two infusion a week for a total of six infusions, with a starting dose of 0.5mg/kg/hr, followed by a maintenance phase of as needed infusions (boosters).
Generalized anxiety disorder is very common among individuals in United States and is often associated with depression. There are various mechanisms linked to the cause of anxiety such as genetics, physiological, and psychological factors. Ketamine is an effective and safe treatment option for patients with anxiety, although it is important to note that results may be less favorable than in individuals with depression and or it may require more frequent ketamine therapy.
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