Berkeley Pharma Tech Journal of Medicine Correspondence: suhina.sharma@berkeley.edu Keywords: Major Depressive Disorder (MDD) Antidepressants Ketamine Psilocybin Psychedelics Glutamate Serotonin Submitted: August 12, 2022 Accepted: October 31, 2022 Published: December 28, 2022 Full Open Access Creative Commons Attribution License 4.0 Abstract Depression is a complex neurological disorder that has many potential causes and treatment approaches. Though there are many conventional antidepressants available in the market, it is becoming increasingly difficult to rely on them as many patients may experience a lack of effectiveness or tolerance to these antidepressants. While current antidepressants increase serotonin and norepinephrine concentrations through reuptake inhibition, novel forms of antidepressants rely on the direct manipulation of receptors, thereby also improving neuroplasticity, which has emerged as a promising approach to treating depressive symptoms. In this literature review, various forms of novel antidepressants are analyzed. The mechanisms studied are Psilocybin’s long-term success, Ketamine’s rapid action, hormonal treatments’ direct targeted approach, and natural products’ reduction of neurotoxic side effects. Understanding how these powerful mechanisms work may allow for the research and creation of more effective antidepressants in the future. Novel Therapeutic Strategies for Depression By: Suhina Sharma, Matt Gostkowski, Jay Patel and Christina Yang Berkeley Pharma Tech Journal of Medicine | 21 1. Introduction Within the last few years, Major Depressive Disorder (MDD) has become one of the world’s leading health problems. Within the last year, there were over 45,000 deaths, about one death every 11 minutes, by suicide, making it one of the leading causes of death in the United States1. Since MDD causes significant impairment in daily life, effective antidepressant treatments are necessary. Many current antidepressants focus on increasing serotonin, norepinephrine, or dopamine in patients with moderate to severe depressive symptoms through reuptake inhibition2. However, these conventional forms of antidepressant therapies are often ineffective in patients because there are many types of depression, including stress-induced, anxious depression, and treatment-resistant depression3. This complexity makes it difficult to find therapies that work for each patient. Furthermore, there is a lot of uncertainty regarding the long-term effects of conventional antidepressants and the potentially toxic side effects. There have been recent attempts at implementing novel therapeutic strategies for depression that are more effective than conventional treatments. In this literature review, we will analyze Ketamine as a short- term therapeutic option4, Psilocybin as a long-term therapeutic option5, other psychedelic-related drugs6, natural depression remedies7, as well as hormonal treatments for depression8. All these novel strategies target depression differently through inhibition and modulation of specific receptors, neurotransmitters, and other biomarkers to significantly reduce suicide ideation and depressive symptoms. These novel antidepressants are researched because of their promising clinical tests and diverse mechanisms. Because these antidepressants have different mechanisms of treating depression, it is important to analyze which mechanisms are the most powerful in contributing to the most successful antidepressant, as it can be the baseline for the research and creation of more effective antidepressants in the future. The success of these novel antidepressants is measured based on their ability to prolong the therapeutic effect, increase neuroplasticity, and reduce neural toxicity. Berkeley Pharma Tech Journal of Medicine | 22 2. Pathophysiology of Depression Currently, many neurobiological theories exist for the pathophysiology of MDD. However, it has been difficult to choose one unified theory due to the clinical and etiological heterogeneity of the disorder9. For example, depressive pathophysiology can change significantly over the course of the illness, and all theories of depression are only relevant to some depressed patients in the population. As each patient is likely unique, it is critical to tailor treatment approaches specifically. This review will discuss a few of the current theories with the strongest empirical foundation, as each can be useful in developing novel therapies. The monoamine deficiency theory posits that the underlying pathophysiological basis of depression is a depletion of the neurotransmitters—serotonin, norepinephrine, or dopamine—in the central nervous system9. Depletion of these neurotransmitters happens when presynaptic cells take the neurotransmitters back up before it reaches the receptor or when too little of a specific neurotransmitter is produced. These neurotransmitters are part of the monoaminergic systems, which are involved in important brain functions such as mood regulation, reward processing, circadian rhythm, and attention. In clinical trials, almost every compound that inhibits monoamine reuptake has been an effective antidepressant. This observation is what led to the development of the monoamine deficiency theory. Although antidepressants that target the monoamine systems can be initially effective, full, and partial resistance to these drugs and delayed onset of action occurs. These limitations suggest that dysfunctions of monoaminergic neurotransmitter systems in MDD represent effects of other abnormalities9. The monoamine deficiency theory remains the clinically most relevant theory, and new findings on dopamine have shown further potential in producing novel therapeutic strategies for depression. The GABAergic hypothesis of MDD suggests that alterations in GABAergic transmission represent fundamentally important aspects of the etiological sequelae of MDD that are reversed by monoaminergic antidepressant drug action10. GABA is a neurotransmitter predominantly responsible for mediating neural inhibition in the brain. Magnetic resonance imaging Berkeley Pharma Tech Journal of Medicine | 23 studies have shown that in acute depression, there are consistent reductions in total GABA concentrations in the prefrontal and occipital cortex. This observation may be due to acute stress effects or reduction in the density and size of GABAergic interneurons. However, there is also contradictory evidence of the GABA hypothesis9. Circadian abnormalities have been hypothesized to be etiologically associated with MDD. The circadian rhythm is part of the body clock that helps regulate body fatigue through day and night11. Disruptions to sleep and daytime fatigue is a criterion for depression, which suggests a subgroup of depression patients may have impaired circadian rhythms. In clinical studies, adjustments to the circadian cycle have been shown to have specific effects on subsequent mood and can even have antidepressant effects. Based on these findings, this hypothesis suggests that shortened REM latency, the association between phase advance of the sleep-wake cycle and phase advances in nocturnal cortisol secretion, and the effect of antidepressants on circadian rhythms are etiologically associated with MDD9. However, more research is required into the molecular explanation. 3. Important Receptors Involved in Depressive Symptoms The serotonin hypothesis has dominated the field of depression research for decades. There are multiple receptors that have been implicated, but serotonin-1A (5-HT1A) and serotonin-1B (5-HT1B) are among the most important receptors as deemed by recent and ongoing research projects12. The 5-HT serotonin receptor group has been broadly linked to both anxiety and depression disorders13. The 5-HT receptor is found throughout the central and peripheral nervous systems in the form of either a G protein- coupled receptor or a ligand-gated ion channel. It is acted upon by the chemical serotonin and then proceeds to promote either excitatory or inhibitory neurotransmission. After binding to serotonin presynaptically, the receptor modulates the release of neurotransmitters such as glutamate, GABA, and dopamine and hormones such as oxytocin, prolactin, and cortisol, leading to physiological changes affecting emotion and cognition14. Furthermore, a growing and diverse body of evidence support the Berkeley Pharma Tech Journal of Medicine | 24 involvement of 5-HT1A, the main inhibitory serotonergic receptor, in both mental disorders. This important role of the serotonin receptor was initially discovered through studies of tryptophan depletion, as tryptophan is the molecular precursor to the 5-HT receptors15. Recent studies have focused on the direct role of 5-HT receptors. Studies have implicated dysregulation of 5-HT neurotransmission as a primary defect in mood and anxiety disorders13,15. Complementary research findings suggested that 5-HT may play a role in recovery from mood disorders via selective serotonin reuptake inhibitors (SSRIs) and other serotonergic agents16. The role of 5-HT receptors in depression has additionally been shown through human studies, 5-HT1A polymorphism research, preclinical pharmacological studies, and preclinical genetic approaches. Beyond the 5-HT receptor, other receptors affecting brain chemistry have been indicated to improve outcomes for patients with MDD. NMDA antagonists, such as ketamine, have been associated with antidepressant effects in patients suffering from MDD17. The NMDA receptor is typically activated by glutamate, which causes an influx of calcium ions and subsequent membrane depolarization for an action potential18. However, antagonists have been proposed to antagonize NMDA receptors on GABAergic interneurons and broadly increase levels of glutamate, the major excitatory neurotransmitter in the nervous system. AMPA receptor activation functions in a similar manner, except calcium ions, are substituted for sodium ions which allows for faster action potentials. In recent studies, compounds that augment signaling through AMPA receptors have been found to promote antidepressant-like behavioral effects in animal models19. 4. Molecular Mechanisms of Antidepressants Most current antidepressant medications fall under the category of reuptake inhibitors, namely selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs)20. These medications function by preventing neurotransmitters (serotonin and norepinephrine) from being reabsorbed back into neurons in the brain after they are released. The mechanism of these drugs is based on the monoamine hypothesis, which states that depression is caused by a lack of available monoamines. By blocking reuptake and increasing the extracellular Berkeley Pharma Tech Journal of Medicine | 25 concentration of monoamines, these drugs are thought to enhance and restore connections between neurons, ultimately resulting in an improved mood in patients21. Current research in antidepressants, however, is not based on the monoamine hypothesis and reuptake inhibition mechanism, largely due to the inconsistent results and efficacy of the current antidepressant medications. Reuptake inhibitors do not directly target the glutamatergic system, which plays a significant role in the brain and is thought to be a vital system regarding depressive symptoms20,21. Glutamate is an important neurotransmitter of the glutamatergic system and is released in response to increased 5-HT2A receptor activation22. While SSRIs and SNRIs indirectly interact with the 5-HT2A receptor by increasing neurotransmitter concentrations, they do not impact receptor activation or functionality22. Reuptake inhibitors have instead been found to cause postsynaptic receptor downregulation, which explains the delayed effects that patients often experience with current antidepressants23. SSRIs have also been shown to disrupt K+ channels that are necessary for glutamate reuptake by astrocytes, which are glutamate transporters. Blunted glutamate reuptake has recently been found to be associated with MDD23,24. Berkeley Pharma Tech Journal of Medicine | 26 Figure 1: Mechanism of Selective Serotonin Reuptake Inhibitors (SSRIs). When serotonin is released from a presynaptic cell into the synapse it can then bind to 5-HT receptors on the postsynaptic cell. This pathway, as mentioned before, is involved with important brain functions such as mood regulation, sleep, reward processing, and cardiac rhythm. Synaptic serotonin can also be reabsorbed by the presynaptic cell through 5-HT transporters, causing a decrease of serotonin available to bind to the postsynaptic 5-HT receptors. As seen in the figure above, SSRIs block the 5-HT transporter from reabsorbing serotonin, therefore increasing the concentration of serotonin in the synapse that can bind to postsynaptic 5-HT receptors. Novel antidepressant therapies currently being researched, such as ketamine and psilocybin, largely function as receptor agonists and antagonists. Receptor agonists activate a receptor to produce a response, which results in increased receptor functionality/activation. Psilocybin is an example of a receptor agonist, specifically activating 5-HT2A receptors. Receptor antagonists are molecules that block receptors to prevent a response, which in turn can increase neurotransmitter concentrations in the synapses and increase the activity of different receptor-mediated pathways, as seen with ketamine and the NMDA receptor25,26. While treatments of this nature show promise in effectively treating depression both short- and long-term, much is still unknown regarding the long-term adverse effects and the overall efficacy of repeated exposure to these drugs. The specific concerns and research required for these drugs are discussed below. Berkeley Pharma Tech Journal of Medicine | 27 Figure 2: Ketamine as a Receptor Antagonist. Ketamine functions as an NMDA receptor antagonist, blocking molecules, such as glutamate, from activating the receptor. When the NMDA receptor is activated on inhibitory GABA interneurons (left figure), it blocks the release of glutamate from nearby neurons and from activating AMPA receptors in postsynaptic neurons. Glutamate and the AMPA receptor are important components of the glutamatergic system, which is heavily linked with processes of mood regulation. When ketamine is present (right figure) it functions by blocking the NMDA receptor, therefore preventing the inhibitory effect of the GABA interneuron. This increases the amount of glutamate that is released into the synapse and preferentially activates the AMPA receptors, which causes a more rapid cascade reaction and antidepressant effect. Berkeley Pharma Tech Journal of Medicine | 28 Figure 3: Basic Mechanism of Receptor Agonists. Receptor agonists are molecules that can function like neurotransmitters and activate certain receptors, causing a cascade of reactions that ultimately lead to activation of other receptors or expression of specific genes and proteins. Psilocybin is an example of a receptor agonist, which is displayed as the red diamond in the figure above. 5. Treatments of Interest and their Efficacy in Treating the Different Forms of Treatment- Resistant Depression 5.1. Ketamine as a Short-Term Therapeutic Option There has been a lot of recent research utilizing ketamine as a short- term therapeutic option. Ketamine gained popularity with its efficacy for treatment-resistant depression. Due to its rapid onset and short duration of action, ketamine has a strong antidepressant effect. As mentioned earlier, ketamine is an NMDA receptor antagonist, therefore keeping glutamate levels higher. Ketamine affects glutamate levels, essentially targeting a neurotransmitter different from most common neurotransmitters targeted with conventional antidepressants27. Increased glutamate levels result in Berkeley Pharma Tech Journal of Medicine | 29 lessened depressive effects as scientific research confirms the involvement of the glutamatergic system in the processes of mood regulation. In addition, the glutamatergic system is involved in neuroplasticity processes28, such as the formation of synapses and the regulation of memory. However, other NMDA receptor antagonists do not have the same fast-acting effects, which suggests something else makes ketamine successful– ketamine metabolites29, depending on its structure and chemistry. Ketamine also acts on the mTOR pathway30, AMPA receptors and even the opioid receptors in the brain. The mTOR pathway is involved in cell proliferation, mortality, survival, and protein synthesis, resulting in the growth of new neural connections, and increasing neuroplasticity. Clinical trials have been done that show ketamine’s rapid antidepressant effects. In one study, twenty-five males were given one dose of ketamine and its changing effects were measured over time, starting baseline at 1 h and 2 weeks after the last dose of ketamine, and 1 month after the last dose31. The table between the three pairs are shown below. Berkeley Pharma Tech Journal of Medicine | 30 Hamilton Rating Depression Scale Mean ± SD Pair 1: Depression Baseline 23.40 ± 5.38 After 1 hr. of ketamine dose 21.20 ± 6.34 Pair 2: Depression Baseline 23.40 ± 5.38 After 2 weeks of ketamine dose 10.25 ± 6.40 Pair 3: Depression Baseline 23.40 ± 5.38 After 1 month of ketamine dose 10.45 +8.47 Table 1: Effect of ketamine treatment over time: Changes in the Hamilton Rating Scale for depression scores. The Hamilton Depression Rating Scale is the most used administered depression scale, with a higher rating indicating higher depressive levels in a patient31. From the table, it is clear that the mean reduction of depression scores decreased, with the most notable change being at the two-week mark31. However, after one month of ketamine doses, the numbers do not drop– they stay roughly the same. This data indicates that ketamine’s effects, though powerful and promising, are relatively short-term31. 5.2. Psilocybin as a long-term treatment option Psilocybin is a naturally occurring hallucinogen that has recently been identified as a potential long-term therapeutic option for depression. Psilocybin acts as a 5-HT2A receptor agonist, activating the receptor that is involved with mood, emotions, thoughts, perceptions, etc. 32. By stimulating 5-HT2A receptors on large glutamatergic pyramidal cells, psilocybin also increases the synaptic concentration of glutamate in the prefrontal cortex (PFC) 33. Rather than blocking the reuptake of Berkeley Pharma Tech Journal of Medicine | 31 neurotransmitters to increase synaptic concentrations like current antidepressant medications, psilocybin directly interacts and activates the 5- HT2A receptor to induce changes in mood and thoughts32. In December 2016, a randomized, double-blind clinical trial involving psilocybin administration to patients with life-threatening cancer found that treatment with a high dose of psilocybin administered under supportive conditions reduced depressive symptoms in patients as quickly as 1 week, with effects lasting up to 3 months in 12 patients. There was also a decrease in depressed mood in some patients at a 6 month follow-up34. Numerous adverse effects were observed, but none were deemed life-threatening. No adverse effects were displayed in patients after the study was concluded34. The table below shows the results of this study, with numerous different outcome measures used to evaluate symptoms of depression, anxiety, and overall mood. Each of the outcome measures used is briefly explained in the table. This was a 9- month study performed with 56 participants randomly assigned to two groups either receiving high doses or low doses of psilocybin; while the results of this study are promising, there is a need for a larger and more diverse patient population to fully examine the effects of psilocybin as an antidepressant. Berkeley Pharma Tech Journal of Medicine | 32 Measure Group Baseline Post-session 1 Post-session 2 6 months GRID-HAMD-17 (Depression)a Low-Dose 1st 22.32 14.80 6.50 6.95 High-Dose 1st 22.84 6.64 6.52 6.23 Beck Depression Inventory (BDI)b Low-Dose 1st 18.40 12.92 8.17 8.00 High-Dose 1st 17.77 7.00 5.80 6.17 HADS Depressionc Low-Dose 1st 9.48 6.04 4.57 4.64 High-Dose 1st 9.81 3.92 4.28 3.46 HAM-A (Anxiety)d Low-Dose 1st 25.68 16.64 8.92 7.95 High-Dose 1st 25.73 8.48 7.52 7.04 STAI-Trait Anxietye Low-Dose 1st 47.46 40.48 35.48 36.83 High-Dose 1st 47.73 34.64 34.28 35.32 POMS Total Low-Dose 1st 51.72 42.48 21.09 23.50 Mood Disturbancef High-Dose 1st 56.93 18.96 17.14 12.52 Brief Symptom Inventory (BSI)g Low-Dose 1st 41.76 33.74 26.08 23.50 High-Dose 1st 40.19 18.08 16.48 14.35 MQOL (Overall Quality of Life)h Low-Dose 1st 5.69 6.17 6.90 6.88 High-Dose 1st 5.32 7.14 7.46 7.65 MQOL (Meaningful Existence)i Low-Dose 1st 6.03 6.10 7.30 7.29 High-Dose 1st 5.43 7.23 7.30 7.62 LOT-R Optimismj Low-Dose 1st 13.56 13.60 15.96 16.68 High-Dose 1st 14.15 17.23 17.16 17.43 Table 2: Effects of Psilocybin. Changes in 10 different outcome measures/scales after session 1, 2, and at a 6- month follow-up in two groups receiving different dosages of psilocybin. __________________ a The GRID-HAMD-17 is a clinician-rated measure of depression, with lower scores correlating to fewer symptoms of depression34. Berkeley Pharma Tech Journal of Medicine | 33 b,c The BDI and HADS tests are self-rated measures of depression, with lower scores indicating fewer depressive symptoms34. d The HAM-A is a clinician-rated measure of anxiety, with lower scores signifying less anxiety in patients34. e The STAI test is a self-rated measure of anxiety, with lower scores signifying less anxiety34. f The POMS test is a self-rated mood measure, with lower scores indicating an overall better mood34. g The BSI score is a self-rated measure of psychiatric symptoms, with lower scores indicating fewer feelings of distress34. h, i The MQOL test is a self-rated measure of the overall quality of life, with higher scores indicating a better quality of life34. j The LOT-R test is a self-rated optimism measure, with higher scores correlating to more feelings of optimism34. Psilocybin also differs from current antidepressants in that limited exposure or administration of the drug has the potential for longer-lasting effects. Recent studies also show signs of high transient neuroplasticity after a single dose of psilocybin, which is a possible source of the longer-lasting effects associated with psilocybin33,34. Psilocybin targets inflammatory and oxidative stress pathways that lead to an increase in brain plasticity and cognitive flexibility, both of which are important gauges of neuroplasticity33. A study published in November 2021 also found that psilocybin increases the expression of genes related to neuroplasticity (c-Fos, Junb, Dusp1)33,34. This study refers to a clinical trial involving mice in which it finds that mice treated with psilocybin experienced increased density and strength of neural connections by 10 percent33. The same study published in 2021 also finds that suicidal behaviors are associated with neuroplastic dysfunction and that those that die from suicide have low levels of brain-derived neurotrophic factor (BDNF) in certain regions of the brain33. Psilocybin’s ability to increase neuroplasticity in patients suggests that it could be used to treat patients at high risk of suicidal behaviors. However, more research is needed to fully evaluate its efficacy for these conditions. While psilocybin has shown promise as a novel therapeutic option to treat depressive symptoms due to its prolonged effects on neuroplasticity, there is still much unknown. Many studies and trials performed involved small sample sizes, so their findings cannot be applied to a larger population33. There is a need for a trial involving administration in a clinical setting, which is not as ideal and accessible. Berkeley Pharma Tech Journal of Medicine | 34 5.3. Psychedelic-related drugs We have already seen an example of a popular, effective psychedelic-related drug– Psilocybin. Other drugs of similar properties will be discussed in this section. Ayahuasca is a psychoactive drink shown to have medicinal potential in treating psychological disorders. In recent clinical trials, the drug has been proven to decrease activity in the precuneus and medial prefrontal cortex35. These regions have also been implicated in the default mode network - a brain pathway most active during periods of introspection. Unsurprisingly, overstimulation of the default mode network has been associated with higher rates of depression and anxiety36. Ayahuasca combats stress-induced depression and anxiety through its composition of DMT and B-carboline37. DMT activates the Sig-1R receptor, which blocks neurodegeneration and regulates the production of protective antioxidants. B-carboline, meanwhile, has been shown to increase BDNF38. The drug ultimately leads to anti-inflammatory, neuroprotective, and potentially memory-boosting effects because of its focus on promoting nerve cell survival. Ayahuasca has added utility compared to traditional antidepressants due to its multifaceted approach to mental disorders: the drug has been shown to combat depression, anxiety, PTSD, and drug dependence39,40. Additionally, the psychedelic is faster-acting and lasts longer than other antidepressants that also target serotonin receptors 37. A recent clinical trial focused on ayahuasca’s effects on treatment-resistant depression35. Twenty-nine patients with persistent, moderate-to-severe depressive symptoms received either a single dose of a placebo or ayahuasca. The results of the study indicated that when compared to the placebo, ayahuasca generated significant antidepressant effects. Statistical analyses proved that the effects were rapid, and the positive outcomes persisted for at least seven days. Although ayahuasca is especially promising as an antidepressant medicine due to its rapid effect in combating depressive symptoms, some other key features contribute to its potential. The drug has a rare capability of improving depression in patients resistant to traditional antidepressant therapies35. Additionally, ayahuasca’s focus on the default mode network provides a direct focus on reducing the source of depressive Berkeley Pharma Tech Journal of Medicine | 35 thoughts and instead increases blood flow to areas that regulate emotions and memory. Despite these encouraging findings, more studies must be conducted to prove ayahuasca’s efficacy in other mood and behavioral disorders. Lysergic Acid Diethylamide (LSD) is a classical hallucinogen more specifically characterized as an entheogen. Some of its characteristic mental effects include distortion of the sense of time and identity, visual hallucinations, and states of euphoria or dysphoria. Beyond these short-term effects on the brain, LSD may play an overlooked role in neurogenesis and possible long-term nervous system health. A recent clinical study indicates that the drug may help the brain grow cells and construct novel connections in brain regions that typically exhibit cell death in mental health disorders such as anxiety and depression41. The drug acts on the brain by interacting with the serotonin 5-HT2A receptor in an agonist capacity42. Thus, the drug is analogous to serotonin chemically, which has been associated with numerous brain-boosting and physiologically regulating benefits. Studies have implicated serotonin receptors specifically in promoting promnesic effects and regulating emotional behaviors43. Compared to other traditional antidepressant drugs that focus on inhibiting serotonin reuptake, LSD is both faster-acting and longer-lasting in the human body44. One current research trial presents that LSD promotes social behavior through mTORC1, a protein complex activating the translation of other proteins- in excitatory neurotransmission45.LSD was shown to potential both AMPA and 5-HT2A synaptic responses in the mPFC (medial prefrontal cortex) and increase the phosphorylation of protein kinases Akt and mTOR in a rodent model. This effect on signaling in the mTOR pathway was hypothesized as the rationale behind the increase in prosocial behaviors like Ketamine. Another recent clinical trial utilized the administration of LSD and placebo to 20 healthy volunteers and subsequently measured the emotional behaviors of the participants 2 weeks after administration46. The results indicated that LSD was responsible for the heightened mood, optimism, and trait optimism of the participants. Another important ongoing clinical trial will measure the efficacy of LSD administration in patients suffering from MDD. Berkeley Pharma Tech Journal of Medicine | 36 By targeting the 5-HT2A receptor, LSD functions as a serotonin-like chemical in an agonist role. This may be advantageous to other antidepressants due to its rapid and longer-lasting effects. LSD also affects the mTORC1 pathway, which has been implicated in increasing sociality. Although much research was conducted regarding LSD’s therapeutic effects in the 1970s, government restrictions on psychedelic research have curtailed efforts in the past few decades46. The increasing rate of clinical trials, including psychedelics and LSD in psychiatric disorders, must continue to gather evidence of reproducibility and validity. Because of the prevalence of “bad trips” and the tendency of the drug to sometimes exacerbate existing psychiatric predispositions, trials testing the drug, in combination with therapy or trials focusing on micro-dosing the drug, may be an optimal focus47. 5.4. Natural Products Natural products encompass many possible treatment options, which all work to cure depression through different mechanisms. Most natural products act prophylactically and help to alleviate symptoms of depression while also benefiting internal organ functions7. Current natural products investigated as potential depression treatments include traditional Chinese medicine formula, herbs or their parts, and natural products that are either extracts or isolated compounds7. There are different types of natural products available for different types of depression, such as stress-induced depression, post-stroke depression, comorbidity depression, and more. Some products work well in conjunction with a good diet to prevent depression because some food components, such as omega-3 fatty acids and vitamin L1, can improve mood. Traditional herbal medicine has been used with multi- targets, multi-levels, and multi-ways48. Natural products differ from commonly prescribed antidepressants because they tend to originate from non-western medicine and focus on treating other mechanisms in the brain. For example, suppressing signaling pathways, treating internal heat depression, and protecting brain glial loss. Natural products also tend to be produced naturally, compared to most Berkeley Pharma Tech Journal of Medicine | 37 antidepressants which are produced in a laboratory environment. Some natural products have fewer adverse effects compared to conventional depression medication and can also reduce medication load and undesirable side effects49. Natural products provide many compounds with antidepressant-like effects, and their therapeutic impacts have been highlighted for a long time. Apart from using as-is, natural products are also a great source for future antidepressant drug discovery. There are in vitro, in vivo, nonclinical, and clinical/translational studies looking at the effectiveness of natural products in depression treatment. The potential of Tetragonia tetragonioides (TTK) was examined through a trial involving the animal model brain of depression50. Glial cells have a protective role within the CNS and PNS by helping to maintain homeostasis. Essentially, glial cells help to hold nerve cells in place so nerve cells can produce their appropriate function. Glial cells play a role in depression because the loss of glial functions has been shown to contribute to the pathophysiology of depression50. TTK is commonly called the New Zealand spinach and other local names. TTK is edible, both raw and cooked, and looks like a leafy plant51. In the research article, the team was able to protect glial loss (and hence loss of glial function) in the prefrontal cortex of a mouse brain by using TKK52, demonstrating that TKK is a potential candidate for depression treatment. However, further research is necessary. Xiaoyaosan, a mixture of dried plants and herbs, was shown to improve depressive-like behavior in rats52. Xiaoyaosan works by inhibiting immunoinflammatory activation and reducing the levels of inflammatory cytokines in the colon by suppressing the activation of the TLR4/NLRP3 inflammasome signaling pathway. Improvement in depression is likely due to the decrease in levels of various proteins, such as TLR4, TAK1, and IRAK1, which lead to a subsequent decrease in inflammatory cytokines, including IL-6, IL-1β, and TNF-α. Evidence shows that inflammatory cytokines contribute to the development of depression, and reducing the concentration of inflammatory cytokines alleviates depression symptoms52,53. Berkeley Pharma Tech Journal of Medicine | 38 Several natural products are effective in treating depression by reducing the likelihood of depression development, alleviating depressive symptoms, or accompanying conventional Western medicine. However, natural products are generally grouped under “alternative treatment," a treatment option used when Western medicine proves inadequate54. For natural products to gain more potential as novel therapeutic strategies, it is important for well- designed, more extensive clinical trials to be carried out. Only then more clinical trials using natural products can be carried out to prove the efficacy of natural products in depression treatment. Better integration of natural products in Western medicinal research is recommended. 5.5. Hormonal Treatment Thyroid, gonadal, pineal gland, and adrenal axis hormones are the four hormonal groups that have garnered the most recent attention in depression research. Some hormones play a direct role in the nervous system by acting as neurotransmitters and affecting neuronal signaling8. Other hormones regulate the production of proteins that affect both brain cell structure and synaptic neurotransmission. Sex hormones have even been proven to stimulate neuroprotection. Thyrotropin-releasing hormone, associated with the thyroid hormonal group, has been proven to stimulate locomotor activity, amongst other behavioral effects55. Additionally, thyrotropin is a pituitary hormone that stimulates the thyroid gland, and T4 and T3 are hormones secreted from the thyroid gland. Research studies have indicated that deficiency of these hormones in the central nervous system can result in fatigue, weight gain, and lack of energy-all common symptoms of depression56. The gonadal steroids estrogen and progesterone, beyond their neuroprotective effects, have been shown to affect brain regions involved in mood and behavior regulation57. Furthermore, Melatonin, the “sleep hormone,” has been implicated in mediating the circadian rhythm. Given the common occurrence of sleep disturbance and irregular sleeping patterns in MDD, melatonin replacement therapies have been gaining popularity58. Additionally, a link between hypersecretion of corticotropin-releasing hormone (CRH) and depression has been established. Higher levels of this Berkeley Pharma Tech Journal of Medicine | 39 hormone have been shown to reduce free cortisol levels and may be a therapeutic option for stress-induced depression59. Hormone therapy targets differ from traditional antidepressants as they focus on replacement therapies that increase levels of chemicals found naturally in the body8. Although hormone replacement therapies often have indirect effects on brain function and can thus result in unintended secondary effects, these therapies are much more targeted than novel drug treatments due to their natural prevalence in the human body. Furthermore, because such therapies often focus on the replacement of natural chemicals, they are much safer and likely to be approved for funding and distribution. In future research efforts, the three major endocrine systems—the hypothalamic-pituitary-adrenal (HPA) axis, the hypothalamic-pituitary- thyroid (HPT) axis, and the hypothalamic-pituitary-gonadal axis—should be studied more to enable hormones as research targets in depression. Table 3: Summary Table that displays all forms of antidepressants discussed– both conventional and novel. Berkeley Pharma Tech Journal of Medicine | 40 6. Practical Considerations Ketamine and psilocybin are the most thoroughly researched and promising therapeutic options for treating depression. Before their widespread implementation, however, greater efforts must be undertaken to reduce stigmas and influence public perceptions surrounding psychedelic treatments. Governmental action is needed to ease medicinal restrictions on psychedelic, natural, and hormonal treatments for mental disorders60. Reputable scientific journals and agencies should continue to publish and advertise content displaying the efficacy of these novel treatments to change public perception. However, some concerns regarding these treatments are valid—as high doses of certain drugs may cause adverse side effects and set back research efforts60. Thus, researchers must continue to prove the reproducibility of their clinical trials and consider the implementation of natural products in conjunction with conventional drugs. Such a strategy may prove to make therapeutic options more accessible for patients and more likely to be approved for medicinal use. 7. Future Directions Ketamine and Psilocybin have emerged as potential antidepressant therapeutic options through mechanisms that promote increased neuroplasticity. We have seen similar mechanisms in other psychedelic drugs, such as interaction with the 5-HT2A receptor and signaling on the mTOR pathway30,32. By better understanding what specifically contributes to Psilocybin’s long-term success, Ketamine’s rapid action, hormonal treatments’ direct targeted approach, and natural products’ reduction of neurotoxic side effects, researchers can not only guide the development of novel antidepressants with similar properties, but we can even perhaps go into how to personalize antidepressants to meet individual needs. We can also expand this study of Depression to other neurological disorders as well, such as Post-Traumatic Stress Disorder, which could benefit from similar novel antidepressant mechanisms. Berkeley Pharma Tech Journal of Medicine | 41 8. Conclusion Research on antidepressant therapies has significantly advanced in recent years while taking on a new approach to treating depressive symptoms in patients. While current antidepressant medications increase concentrations of serotonin and norepinephrine through reuptake inhibition, new research focuses on the direct manipulation of receptors, specifically targeting and improving neuroplasticity, which has emerged as a promising approach to treating depressive symptoms. Ketamine has been shown to rapidly reduce depressive symptoms by targeting glutamate, promoting the formation of synapses and new neural connections. Psilocybin has also shown numerous signs of improving neuroplasticity in clinical trials, with the potential for longer-lasting effects. While ketamine and psilocybin are at the forefront of current antidepressant research, much information remains to be known about the impact of long-term and repeated exposure to these drugs, and larger clinical trials are necessary to evaluate their efficacy. Psychedelic-related drugs, such as ayahuasca and LSD, display the potential to treat depressive symptoms as well. Ayahuasca inhibits default mode network activity to reduce stress-induced depression and anxiety, while LSD functions similarly to psilocybin and promotes cell growth and connections to improve neuroplasticity. However, concerns over side effects and government restrictions have limited research on the psychedelic approach. Natural products have also been found to work well in conjunction with current antidepressant drugs and therapies due to reduced side effects and medication loads. While recent clinical trials show signs of antidepressant effects, there is still an overall lack of research surrounding these products and their potential to treat depression. Hormonal treatment, which has been used for years to treat a variety of disorders, has recently emerged as a potential antidepressant therapy. Replacement therapies involving thyroid, gonadal, pineal gland, and adrenal axis hormones specifically have shown signs of reducing depressive symptoms by adjusting the naturally occurring chemicals to their optimum levels. While hormonal treatment offers a targeted approach due to the knowledge surrounding hormones and their effect on the body, there are concerns about unintended secondary effects that can occur. Due to the relative inconsistency and inefficiency of current Berkeley Pharma Tech Journal of Medicine | 42 antidepressants, many novel therapeutic strategies, and approaches to treat depression have emerged in recent years. Larger and more diverse clinical trials are needed for all the potential therapies discussed in this review to determine their efficacy in treating depression and whether they offer significant improvements compared to current reuptake inhibitors. 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Frontiers in Psychiatry. 2021;12. doi:10.3389/fpsyt.2021.638981 29. doi:10.1177/1179573520907397 https://www.ncbi.nlm.nih.gov/books/NBK500006/ https://www.ncbi.nlm.nih.gov/books/NBK500006/ https://www.ncbi.nlm.nih.gov/books/NBK500006/ FRONT PAGE - Sharma et al. Body Template_Sharma et al. 2. Pathophysiology of Depression 4. Molecular Mechanisms of Antidepressants 5.1. Ketamine as a Short-Term Therapeutic Option 5.2. Psilocybin as a long-term treatment option 5.3. Psychedelic-related drugs We have already seen an example of a popular, effective psychedelic-related drug– Psilocybin. Other drugs of similar properties will be discussed in this section. Ayahuasca is a psychoactive drink shown to have medicinal potential in treating psycholo... 5.5. Hormonal Treatment 6. Practical Considerations 7. Future Directions 8. Conclusion References_Sharma et. al.