From our understanding to our treatments, much work remains to be done
“Make no mistake about people who leap from burning windows... the fear of falling remains a constant. The variable here is the other terror, the fire’s flames: when the flames get close enough, falling to death becomes the slightly less terrible of two terrors. It’s not desiring the fall; it’s terror of the flames. And yet nobody down on the sidewalk, looking up and yelling ‘Don’t!’ and ‘Hang on!’, can understand the jump. Not really. You’d have to have personally been trapped and felt flames to really understand a terror way beyond falling.” (1)
[1] In this excerpt from his magnum opus, Infinite Jest, the American writer David Foster Wallace gives a glimpse into the world of depression. A depressive who kills himself, Wallace writes, does so to escape the “invisible agony” of his disease just as a person would jump from a burning skyscraper to avoid the flames. Since college, Wallace himself suffered from and battled depression, which he described as “a level of psychic pain wholly incompatible with human life as we know it... a nausea of the cells and soul.” He was medicated for 20 years but the drugs caused severe side effects and Wallace stopped taking them at his doctor’s suggestion. But the depression returned and remained, as even more extreme treatments failed to find traction. David Foster Wallace’s long struggle with depression ended in 2008 at age 46, in suicide (2).
[2] David Foster Wallace’s story is tragic and not uncommon. Though not all cases of depression meet the same unfortunate end, the statistics remain stark – approximately one in six Americans will be diagnosed with major depressive disorder in their lifetimes. The World Health Organization predicts that by the year 2020, depression will become the second most common cause of disability, following only ischemic heart disease (3). The myriad of symptoms that can accompany the illness speaks for itself: depressed mood, diminished pleasure (anhedonia), sleep disturbances, weight and eating disturbances, inescapable guilt, and recurrent thoughts of death or suicide (4). As Stanford neuroscience professor Robert Sapolsky puts it, in the realm of “human medical misery there is nothing out there like depression... Depression is like the worst disease you can get.” (5) Even other debilitating illnesses offer silver linings. Cancer patients often report that, in some ways, their diagnosis gave them greater appreciation for life and for their loved ones; the realness of the possibility of death opened them to the possibilities and beauties of life. Human resilience in the face of these challenges is remarkable. But depression has the capacity to destroy that, sapping hope and pleasure out of life. It is difficult to find silver linings when that’s the very ability that is taken.
[3] Given the pervasiveness of depression and the detriment it has on society, there is great interest in treating the disorder. The manufacturing of antidepressant drugs is a multibillion dollar industry (6). However, despite the great need, interest, effort, and money invested, the treatments available today are not adequate. Many patients, like David Foster Wallace, find the side effects of treatment to be as unbearable as what’s being treated. Indeed, some antidepressant side effects mirror the symptoms of depression itself with patients potentially experiencing sleep disturbances, weight changes, decreased sex drive, or even increased suicidal thoughts. Worse still, taking antidepressants and facing the risks of serious side effects does not guarantee a cure for depression. Far from it: only about 40% of patients will undergo full remission following drug treatment of their depression, even after trying many different options (3)(7).
[4] The difficulty in treating depression is twofold. The first reason is more readily apparent: depression is complicated and it manifests differently from person to person. Using the current diagnostic criteria, it is possible for two patients to be diagnosed as clinically depressed while experiencing drastically different symptoms. For example, one patient can have depressed mood, weight loss, insomnia, slowed movement, fatigue, and difficulty making decisions while another experiences diminished pleasure, weight gain, oversleeping, and feelings of worthlessness (4). Despite the vast differences in their suffering, both patients can walk away from their psychiatrist’s office diagnosed as having the same disease and slated to undergo similar treatments. As it stands, depression is defined based on a highly variable set of symptoms and not an objective test reflective of the biological underpinnings of the disorder. In fact, the Director of the National Institute of Mental Health (NIMH), Dr. Thomas Insel, recently criticized this symptom-based diagnosis used in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), which is often dubbed the “Bible” of psychiatry for its near ubiquitous use in defining mental disease and subsequent treatment in patients. In a blog post written for the NIHM, Dr. Insel argues that “[t]he weakness is its lack of validity... Indeed, symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment. Patients with mental disorders deserve better.” (8) To begin building a connection between the biology and diagnosis for mental illness, Dr. Insel announced an initiative to incorporate emerging research data – genetic, physiological, cognitive, brain imaging – into the foundation for a new psychiatric disease classification system. Currently, however, the biology of the depressed brain is remarkably and woefully not well understood. The second major reason is that we do not understand how many of the drugs we prescribe work. The mechanisms underlying even the most effective drugs are subject to debate and ongoing research decades after they first got signed off on the psychiatrist’s script pad. There remain vast gaps in understanding of the basic biology of depression and the final treatments that patients are told will help them. It is imperative to vastly expand our understanding of the biology of depression and seek out better ways to target the causes of depression in our treatments.
[5] Sheer serendipity has been the driving force for the discovery of many of the drugs used to treat psychiatric illness. In 1949, Australian psychiatrist John Cade had been injecting guinea pigs with the urine of people suffering from bipolar disorder in order to test his (incorrect) theory that an excess of uric acid (found in urine) was the underlying cause for the disorder. Cade found that the uric acid taken from bipolar patients were more toxic than the uric acid found in patients with other disorders and killed the guinea pigs at lower dosages. In order to make the uric acid more readily dissolve in water for injection, Cade began adding lithium and found that the guinea pigs fared better and had reduced uric acid toxicity. When only lithium was injected, the guinea pigs became sedated, an effect that held true when he tested lithium first on himself and then his patients. In 1970, lithium treatment for bipolar disorder was made standard and it remains a common treatment for patients to this day (9)(10). Despite its use in treating bipolar disorder for over 40 years, the mechanisms underlying lithium’s effectiveness remain a mystery. Other major psychiatric drugs were similarly discovered through luck or while following false leads. In an effort to develop a new treatment for schizophrenia, Swiss researchers sought to test a drug similar in function to one previously found to be effective. The trial ended with the treated schizophrenic patients becoming even more agitated and one patient riding to a nearby village while singing in his nightshirt. Undeterred by the embarrassment for the hospital overseeing the study, the researchers reasoned that if the drug could elevate the normal mood of schizophrenic patients, then it might be able to improve depressed mood as well. This drug, imipramine, went on to become the first antidepressant to be widely prescribed (10).
[6] More pharmaceutical breakthroughs followed closely on imipramine’s heels and, a decade after John Cade began injecting guinea pigs with urine and lithium, most of the major psychiatric drug classes had been discovered, including those used to treat depression. However, though many new antidepressants have been developed in the decades since, there has been little improvement in treatment efficacy since the first drug, imipramine. Important advances have been made in reducing toxicity and adverse side effects, but these newer drugs still produced the same remission and relapse rates as older ones (7).
[7] Unfortunately, much of what we thought we knew about depression comes from these pharmacological treatments. Around the same time as the initial psychiatric drug breakthroughs, it was also discovered that neurons communicate with one another using chemical messengers called neurotransmitters. Thus, drug makers and doctors reasoned, an imbalance of these chemicals could be causing depression and treating these imbalances may cure the disease. In 1965, nearly a decade after antidepressants were first created, Joseph Schildkraut of the National Institute of Mental Health came up with an explanation for why the drugs worked: they were affecting the neurotransmitters dopamine and norepinephrine. It later turned out that many of the antidepressants used were more greatly affecting another neurotransmitter, serotonin. Soon, new drugs were developed to target serotonin transmission. These selective serotonin reuptake inhibitors (SSRIs) would slow down the rate serotonin was removed after it is released by neurons thereby supposedly fixing imbalances of the chemical in the brain. SSRIs like Prozac, Paxil, and Zoloft soon became widely-prescribed and well-marketed(10)(11).
[8] This hypothesis that depression is the result of imbalances in serotonin, dopamine, and norepinephrine may not be accurate. If the mechanism of action of the drugs was merely increasing the concentration of these neurotransmitters in the brain, then the therapeutic effect should be observed almost immediately after the drug is taken when neurotransmitter levels are elevated in the brain. Instead, it is well-known that weeks to months must pass before the drugs begin to produce an observable effect (11). While the antidepressants may alter the neurotransmitter concentrations in the brain, this is probably not the direct reason why they are effective. Furthermore, there remains the issue of the ineffectiveness of the drugs for many patients – if less than half of patients taking these treatments remain symptom free, there are probably other mechanisms of depression that are not being treated by these drugs. Unfortunately, many of the treatments developed in the past half century still target the same neurotransmitters and the same mechanisms of action. This “me-too” approach to drug design has unsurprisingly failed to produce new cures (10).
[9] That the brain has been a difficult thing to target is not a surprise. It is a complicated system comprised of an estimated 80 billion neurons with each neuron potentially wired to and communicating with thousands of other neurons. These connections are ever-shifting, shaped by neural activity and a person’s experience making the brain very difficult to study. As MIT neuroscientist Sebastian Seung puts it: “Neural activity is constantly changing. It's like the water of the stream; it never sits still. The connections of the brain's neural network determines the pathways along which neural activity flows. And so the connectome is like bed of the stream; but the metaphor is richer than that, because it's true that the stream bed guides the flow of the water, but over long timescales, the water also reshapes the bed of the stream.” (16) It is possible that mood disorders like depression could be caused in part by abnormal wiring of neurons. Severe depression is associated with a reduction in the size of the hippocampus, which is important for learning and memory, as well as in the prefrontal cortex. Conversely, some antidepressant drugs increase the production of molecules that are associated with neuronal plasticity, the general modification of neural connections, which in turn might lead to adjustments in the neural connections to better adapt to changes in the environment (17). In addition, antidepressants affect neurotransmitter signaling but these neurotransmitters activate different receptors in varying manners. Different receptors for the same neurotransmitter are in turn differentially distributed in the brain. Taken together, there are potentially many biological mechanisms to investigate that might be specific to different areas of the brain, which is itself constantly changing. Using the brain to understand and fix parts of itself is a challenging endeavor.
[10] Furthermore, just examining human neurons would still be ignoring much of the brain. Neurons are not the only cells found in the brain, and they aren’t the only components of the brain affected by depression. Glial cells (from the Greek word for “glue”) are non-neuronal cells that were previously thought to provide only supporting roles in brain functioning and have only recently been recognized to have a much more active role. One type of glia, called oligodendrocytes, ensheaths neurons with a fatty insulation that speeds up the conductance of the neurons’ electrical signals. Another class of glia, called astrocytes (so named for their star-like projections), plays important roles in metabolic regulation for neurons, neurotransmitter release and removal, among other functions. Astrocytes may be the most numerous of cells in the mammalian brain, though there is still controversy on its ratio to the number of neurons (15). Previous studies have found that astrocytes may be involved in depression. However, there is one other glial cell type that could be worth investigating: microglia.
[11] Microglia are special: they technically are not glia cells like astrocytes and act instead as the immune cells-in-residence of the brain. In their resting state, microglial cells rapidly move around the brain. They are activated in response to neuronal damage and undergo a series of transformations in their shape and production of molecules involved in immune response. Importantly, these activated microglia mediates an inflammatory response (13). Coincidentally, depressed patients often have increased levels of proteins that generate signals that promote inflammation and exhibit overactive immune responses in general. And though microglia make up about 10% of all brain cells, little is known about how they are impacted by depression. A new study from Dr. Raz Yirmiya’s research group at The Hebrew University of Jerusalem seeks to address this very question, and investigates whether microglia can be targets for drug interventions in the treatment of depression (12).
[12] The researchers first characterized how chronic stress, a potential trigger for depression, affects microglial cells in mice. A group of mice were subject to five weeks of chronic unpredictable stress (CUS), an experimental procedure well established in producing depressive-like symptoms in rodents. Every day, the mice experienced two of a wide number of possible stressors: their cages could be shaken, reduced to a more claustrophobia-inducing size, or be inundated with noise or flashing lights; the cages could be wet or cold; or the light could be left on during the night or turned off during the day. While each of these stressors was acute, they were presented in a random order such that the mice remained uncertain in what they would have to endure the following day. Mice exposed to CUS had a significant decrease in sugar preference and social exploration, much like depression patients that exhibited a diminished ability to experience pleasure. In addition, there was a noticeable decrease in microglia found in the hippocampus of these stressed-out mice. This was an intriguing find because previous depression studies have found that this structure, well-known for its involvement in learning and memory, is decreased in volume in the brains of depressed humans(14). This decrease in microglia was not found in the cortex of the brain, so the effect may be relatively specific to the hippocampus.
[13] The finding that microglial cells were being suppressed by stress was surprising because previous studies showed the exact opposite effect: stress activates microglia. However, this difference might be due to the shorter stress exposure times in previous experiments. Indeed, when the researchers only subjected the mice to the same unpredictable stress for only two days, microglia proliferated substantially. But after three days of stress, the cells began to increase the expression of a protein known to activate microglia but also play a role in initiating the tightly regulated process of programmed cell death called apoptosis. Apoptosis is a natural, often advantageous, process that allows for the removal of damaged or defective cells before surrounding healthy cells are harmed. Because of the increase in apoptosis-promoting protein, four days after the stress exposure, mice had more microglial cells that died in the hippocampus. Thus, when mice are exposed to unpredictable stress, there is an initial increase in the number of microglia in the hippocampus, followed by a decrease as the stress becomes chronic.
[14] The initial microglial activation in response to stress may be what causes the subsequent microglia death and the development of depressive-like symptoms. To test this possibility, the researchers stopped the initial activation of microglial cells with minocycline, an antibiotic that selectively inhibits microglia, and completely reversed the acute increase in microglia in the hippocampus while reducing the amount of cell death after 3-4 days of unpredictable stress. When minocycline was administered throughout the 5-week CUS exposure period, there was no longer a decline in hippocampal microglia or a reduction in sucrose preference. There was a similar effect when the researchers used a genetic manipulation to block a microglia-stimulating protein: there were no longer decreases in microglia number in the hippocampus or a reduction in sucrose preference and social exploration. Interestingly, the first major antidepressant imipramine was initially known as an antihistamine when it was first tested in 1956 and was previously shown to produce anti-inflammatory effects. Accordingly, chronically administering imipramine to the mice unpredictably stressed for a 5-week period also blocked the decrease in hippocampal microglia and prevented the reductions in sucrose preference and social exploration. Thus, it seems likely that the decrease in microglia in the hippocampus may be involved in the depressive-like symptoms following CUS exposure.
[15] Microglial cells were stimulated by acutely administering microglia activators to mice that were chronically exposed to CUS and exhibited a decrease in sucrose preference and social exploration. Lipopolysaccahrides (LPS), large molecules found on the surface of certain bacteria, are known to induce strong immune responses and microglial activation in animals. When applied acutely, LPS was found to reverse depressive-like symptoms in the forced swim test. In the forced swim test, the mice are placed in a cylinder of water for a short period and assessed for the time they spend immobile before they are removed. This immobility is interpreted as a “despair-like” behavior in response to unavoidable stress and was reduced following LPS treatment compared to mice that were stressed but did not receive treatment. Another microglia activator called macrophage-colony-stimulating factor (M-CSF) was injected for a few days following the onset of depressive-like symptoms and also reduced time spent immobile in the forced swim test. Sucrose preference and social exploration were also restored in addition to an increase of microglia cells in the hippocampus following M-CSF treatment. Taken together, the results of this paper suggests that chronic stress cause dramatic changes to microglial states with an initial proliferation and activation stage followed by cell death and decline. This eventual decline in microglia can induce depressive-like behavior and be the target of antidepressant treatment.
[16] To counter the decline in microglia, it is possible to give two treatments in different stages following stress: one by using microglial inhibitors to reduce the initial activation of microglia after the initial stress and another to apply microglial stimulators to block the eventual, long-term decline of microglia. This treatment strategy holds promise, but is by no means perfect given the compounds tested in this study. First off, it is difficult to know when to block the initial stress-induced microglial activation: what kind of stress would eventually result in microglial death and how often can microglial response be suppressed without negative effects? A blockade of all microglial activation in the brain is unlikely to be without side-effects since microglia play an important role in combatting cellular damage in the brain. The strategy of stimulating microglia to compensate for stress-induced decline is fraught with challenges as well. The two stimulators tested had different effects on the depressive-like behavior measures. LPS did not reverse the decline in sucrose preference nor the reduction of social exploration when applied to stressed mice. Furthermore, its application actually induced depressive effects in non-stressed mice, suggesting that there needs to be a way to measure microglial levels in patients before treatment is applied or the treatment will induce exactly the symptoms it was trying to prevent. M-CSF showed more promise since it prevented the decline in sucrose preference and social exploration, and also did not induce depressive symptoms in non-stressed mice. However, it was not as effective as LPS in reducing the despair-like floating behavior in the forced swim test. It would also be crucial to examine what effects more long-term application of these microglial stimulators would have. Nonetheless, it is promising that even short-term treatment of microglial stimulators can induce such dramatic reversals of depressive-like behaviors. Yirmiya’s research group certainly thinks so: his university’s technology transfer company recently filed for a patent for treating depression with microglia-stimulating drugs (12).
[17] The news of a novel potential mechanism of depression to target arrives at a time when pharmaceutical giants – Merck, Pfizer, GlaxoSmithKline, Novartis – have cut back or closed down their neuroscience research branches. Developing drugs that target ailments of mind has been and remains exceedingly difficult (9). From 1993 to 2004, only 8% of drugs that target the central nervous system and were tested clinically in humans made it through the regulatory approval process. Many failed drugs were found to be highly toxic and were pulled from human trials. Others were rejected for the lack of any effect at all (6). The new drug pipeline for psychiatric medicines is running dry. While there has been some progress in finding new mechanisms of depression to target – recent trials with the application of ketamine have been promising in targeting a receptor for a different neurotransmitter, glutamate – it is a sign of the difficulties in psychiatric drug-making when these companies abandon a line research in a market that shows ever increasing need for new and better treatments.
[18] This is disheartening news, but there may be a silver lining. Acknowledging that our current understanding of depression and of our treatments is inadequate allows researchers and drug developers to be more open to exploring new possibilities in both new treatments and biological mechanisms of the disease. Research into areas previously overlooked, such as microglia, can potentially spur more innovative treatment options than have previously been available. In addition, new medical knowledge and technologies are still being developed. For example, the differences in the genetic backgrounds of psychiatric patients may soon be used to tailor drug or even therapy-based treatments for their particular set of genes. This “personalized medicine” approach acknowledges that treatments don’t work universally well or in the same manner for different patients. So while numerous challenges still remain, our understanding and ability to heal can only get better with time.
References:
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