Depression is one of the most prevalent psychiatric disorders and a leading cause of disability worldwide, affecting an estimated 300 million people globally. Approximately one third of patients with major depressive disorder are diagnosed with treatment-resistant depression.
Symptoms vary, but generally, clinical depression is characterized by persistent sadness; fatigue; disturbed sleep; increased or decreased appetite; feelings of guilt; and low self-worth.
Beyond the subjective symptoms, depression is associated with disruptions in metabolic, hormonal, immune and inflammatory processes and is commonly understood to stem from a combination of psychological, physiological, and environmental factors and, in some cases, as the result of conditions like Parkinson’s or hypothyroidism.
Genetic predisposition is responsible for approximately one half of the overall risk of developing depression.
- Data from over 800,000 patients identified 269 genes associated with depression, many of which influence formation of synapses, neurotransmitter production, and metabolic function.
- Importantly, genetics are intimately linked to circadian rhythms, the autonomic regulatory processes that regulate sleep-wake cycles, and which are responsible for up to 40% of gene expression in the brain, liver and muscles. Disruption of circadian rhythms strongly influences the development of depression.
While helpful in the case of minor infections and injuries, chronic inflammation is associated with depression.
- In depressed individuals, consistently elevated levels of inflammatory biomarkers repeatedly trigger inflammation, leading to structural changes in the brain and disruptions in neuroendocrine functioning.
Rates of neurogenesis, the creation of new neurons, are another important factor in depression-related pathology.
- Ongoing neurogenesis is critical for establishing synaptic connections that improve neurological functioning throughout a person’s life. It is unsurprising then, that disturbed neurogenesis has been implicated in depression, and may also impede responsiveness to current frontline therapeutics.
Other potential causes and risk factors for depression include:
- side effects from pharmaceuticals, particularly beta-blockers, calcium channel blockers, and angiotensin II inhibitors;
- dietary habits that lead to deficiencies in nutrients that modulate inflammation, neurogenesis, and metabolism, as in the case of vitamins B6 and B12, and omega-3 fatty acids; and
- a lack of microbial diversity in the gut, which contributes to changes in immune function,
- decreased mood, and further
- disturbances in dietary preferences,
leading to a continual cycle of inflammation and depression.
Unfortunately, the prognosis for depression is not favorable. For the more than 340 million depression suffers, currently available front line treatments – typically selective serotonin reuptake inhibitors (SSRIs) coupled with cognitive behavioral therapy:
- have moderate response rates of 40-50%, with remission rates as low as 30%.
- come with a bevy of potential side effects, ranging from fatigue and hair loss to hypertensive crisis and mania and
- 80% will continue to suffer from the condition six years later.
Behavior-based treatment pathways do exist (with varying levels of efficacy).
- exercise mitigates depressive symptoms and assists with recovery, particularly in the case of moderate- to vigorous-intensity aerobic exercise;
- dietary modification has also been shown to be effective: one 12-week randomized controlled trial showed that changes promoting healthy nutritional choices were more effective than social support in ameliorating depressive symptoms;
- meditation has also been found to be a viable option, with one meta-analysis covering more than 3500 patients finding that mindfulness mediation was moderately effective at alleviating anxiety and depression;
- psychedelic drugs
- psilocybin – the active ingredient in magic mushrooms – ameliorated symptoms of depression and anxiety in patients with life-threatening cancer, with effects persisting for up to six-months after treatment.
- ketamine has shown efficacy at six hours that is equal to the effects of other antidepressant medications at six weeks, with responses in more than 80% of patients. However, despite positive early signals, additional research is necessary to establish the safety and efficacy of such interventions.
Depression is a complex condition. While current treatments are effective for some, only a minority of people with depression achieve remission and only a few have been shown to be effective to any significant degree but, nevertheless, research into novel therapeutics like psilocybin, ketamine and others, is critical if we are to provide relief to the estimated 100 million people living with treatment resistant depression. Source
Anxiety is considered a common aspect of life, however anxiety disorders develop when feelings of apprehension and unease persist over an extended period and potentially worsen over time.
- Anxiety disorders affect approximately 40 million adults, or 18% of the population making it the most common mental illness in the United States, and
- generalized anxiety disorder alone, affects almost 7 million adults.
Anxiety disorders are believed to stem from a set of risk factors including genetics, neurochemistry, life experiences and personality, can have a range of symptoms and lead to an impact on personal health as well as social and professional interactions.
It is common for those suffering with an anxiety disorder to also have a co-occurring disorder or physical illness, which can compound symptoms and complicate recovery. For example, it is estimated that half of patients diagnosed with depression also suffer from an anxiety disorder.
There are several types of anxiety disorders, including generalized anxiety disorder, social anxiety disorder and panic disorder, which are distinct but share common symptoms.
Generalized anxiety disorder:
- is characterized as excessive, prolonged and difficult to control anxiety and stress that can impact normal life activities;
- symptoms can vary, but may include behavioral traits such as unwarranted or disproportional anxiety, difficulty handling uncertainty and indecisiveness, in addition to physical signs such as fatigue, irritability and trembling;
- is diagnosed when an individual finds it challenging to control anxiety on more days than not for at least a six month period and has three or more symptoms; and
- can emerge gradually and most frequently manifests between childhood and middle age.
Anxiety disorders are generally treated with medication, psychotherapy or both. However, despite availability of a range of treatments, only approximately one third of those suffering an anxiety disorder receive treatment. First line therapy often involves use of antidepressants including:
- SSRIs, such as paroxetine, sertraline and citalopram that work by increasing levels of serotonin in the brain. Unfortunately, however, they typically have a slow onset of action, with treatment required for four to six weeks before significant therapeutic benefits are observed, with maximal benefits requiring up to twelve weeks of treatment. SSRIs also have a number of side effects, such as sexual dysfunction, drowsiness and weight gain.
- Benzodiazepines that can offer rapid reduction of symptoms with relief as soon as thirty minutes after administration. Unfortunately, however, their long-term use is associated with the development of tolerance, respiratory depression, particularly reduction of living compounds, and drug dependence. Some patients experience sedative side effects resulting in drowsiness or lethargy, decreased mental sharpness, slurring of speech and some decrease in coordination or unsteadiness of gait, less occupational efficiency or productivity and, occasionally, headache. Source
Schizophrenia is a chronic, psychiatric disorder characterized by a heterogeneous combination of symptoms, including psychosis, social withdrawal, flat emotional affect, cognitive impairment, ability to distinguish facial expressions, voice tone or pitch, and difficulty with tasks related to learning, memory and mental processing. People living with schizophrenia often experience a reduced quality of life and are more likely to be homeless, unemployed or living in poverty compared with the general population.
- is one of the most debilitating mental illnesses known and often requires patients to be under medical care for their entire lives;
- affects over 21 million people globally and approximately 2.4 million people in the United States;
- is diagnosed in approximately 300,000 new cases each year in the United States; and
- people with schizophrenia are two to three times more likely to die early than the general population, with suicide being the main contributor in the early course of the disease and cardiovascular disease being the main contributor in later years.
While antipsychotics are most commonly used to treat psychotic symptoms of schizophrenia, these medications fail to address the cognitive and negative symptoms and are often associated with severe dose-limiting effects.
To date, there are no pharmacological treatments approved for Cognitive impairment associated with schizophrenia. Source
Substance Use Disorders
Substance Use Disorders (SUDs) are highly prevalent disorders – over 20 million people live with a SUD in the U.S. that are characterized by an inability to control the use of a legal or illegal drug, medication, or other psychoactive compound.
- SUDs typically occur following prolonged, repeated use of a substance at high doses and/or high frequencies and can lead to significant health and social consequences.
- SUDs and related disorders are a significant source of morbidity and mortality and pose a substantial cost to society.
Opioid Use Disorder (OUD) is a form of SUD characterized by uncontrolled and persistent self-administration of opioids, resulting in significant impairment, distress, and mortality.
- 3 million people in the U.S. have had, or currently live with, an OUD;
- in 2020, about ¾ of overdose deaths involved opioids.
For many patients, pain relief, and addiction are fundamentally linked, since the use of opioids to manage acute pain can lead to drug dependence with 8% to 12% of individuals prescribed opioids for chronic pain ultimately developing OUD.
- While opioids are indeed effective for most forms of acute pain, they are associated with a variety of adverse effects, including risk of addiction, constipation, and respiratory depression, the latter being the main cause of death among opioid users.
- Of individuals prescribed at least one day of opioids, 6% are still taking them one year later.
There are limited pharmacological agents available to treat OUD, with the current options divided into two classes: synthetic opioid receptor agonists, such as buprenorphine and methadone, that are used as maintenance therapy with the primary goal of preventing relapse and opioid antagonists, such as naltrexone and naloxone that are used as rescue therapy for opioid overdose.
These therapies suffer from a number of limitations, including:
- high relapse rates,
- inconvenient treatment regimens, and access, partly due to treatments being controlled substances, which limit treatment availability and
- adherence, and an inability to maintain abstinence after medically assisted withdrawal.
Current treatment options are not highly effective; approximately 75% of patients undergoing OUD therapy experience relapse within one year of treatment.
- For abuse of other substances, such as cocaine or methamphetamine, no pharmacological agents have been approved.
Despite the limitations of current treatment options, the worldwide market for OUD therapies totaled $2.5 billion in 2020 expanding at a compounded annual growth rate (CAGR) of 8.7% per year due to the significant increase in opioid use and the heightened response to the opioid crisis. Source
Traumatic Brain Injury
In the United States, an estimated 1.7 million people sustain a traumatic brain injury (TBI) annually which occurs when a sudden force impacts the head or body and such injuries range in severity from mild, characterized by a brief change in mental status or consciousness, to severe, involving an extended period of unconsciousness or amnesia.
- Mild TBI (mTBI) accounts for 70 to 80% of all reported TBIs, but the prevalence may be even higher, as many cases often do not receive medical attention.
- Symptoms of mTBI may include headaches, fatigue, depression, irritability and impaired cognitive function and may persist for many years, negatively affecting quality of life.
- In addition, mTBI can lead to increased risk of affective mood disorders such as MDD, post-traumatic stress disorder and other psychiatric and nonpsychiatric disorders.
To date, there are no pharmacological treatments approved for mTBI, and there are limited assets in development and a lack of treatment may lead to an increased risk of affective disorders and long-term cognitive impairment, underscoring the need for new effective treatments.