Steps Forward in the Treatment of Depression

Depressed man

The neurotransmitter serotonin has an essential role in behavior and cognition. It has been seen as having a big part of common neuropsychiatric diseases such as major depressive disorder and anxiety disorders. This study added to the increasing evidence for a direct interaction between serotonin and brain-derived neurotrophic factor. There continues to be insufficient data for the interaction of serotonin and BDNF.

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Effective treatment of clinical depression remains a major mental health issue. Roughly 30% of patients with depression don’t respond to any available treatment. University of Maryland School of Medicine has discovered a crucial receptor called mGlu2 that is critical to the mechanism of fast-acting antidepressants like Ketamine when used for depression. Finding out how this kind of receptor in the brain works with fast-acting antidepressants is needed to open the way for research into how to approach those with treatment-resistant depression (TRD). The reason for this is because existing treatments can take weeks to show any noticeable difference. This lag time for depressed patients, especially suicidal patients can be a difference in life or death. In addition, the effects of the Ketamine can last up to a few weeks after just one dose. On the downside, it can cause hallucinations and has high abuse potential. Understanding how the brain reacts to Ketamine is a critical direction toward furthering treatment for depression (UMD, 2019).

What is the present treatments
The currently available antidepressants can be classified into 13 different distinct classes based on their unique pharmacological mechanism of action. Eleven of the 13 work, by blocking one or more of the reuptake transporter ports and/or receptors for the three monoaminergic neurotransmitters; serotonin, dopamine, and norepinephrine. The 12th class inhibits monoamine oxidize inhibitors (MAOIs), an enzyme and the 13th works by blocking the NMDA-glutamatergic ionoceptor. In this last group, there have been recent studies showing the effectiveness of Ketamine in sub-anesthetic doses on otherwise hard to treat depression. A number of studies have demonstrated rapid antidepressant effects of Ketamine. It not only relieves immediate depression, but the effect has been to persist up to a week or longer. Unfortunately, because of its own long-term side effects, it is imperative it be followed up with something less destructive. Studies on rats/mice being done presently looking at combining Ketamine with other treatments to see if it can enhance the other treatment, more proactive research is needed to synthesize rapid-onset novel antidepressant agents with other agents without producing neurocognitive dysfunction or hallucinogenic effects of Ketamine (Fesipe, O.J., 2019).

Depression is defined as a complex mental disorder which is characterized by a pervasive low mood and aversion to activity. There are several types of neurotransmitters like glutamatergic and cannabinoid systems play a role in the modulation of depression. Ketamine is an anesthetic that has found several non-anesthetic applications. Ketamine has rapid and sustained antidepressant properties following a single dose below its anesthetic range. And while this property of Ketamine has been demonstrated, the mechanism at work is not fully understood. The endocannabinoid system implicated in the modulation of many emotional-related responses in the CNS including stress anxiety, depression, and aggression. In addition, studies have indicated there is an interaction between glutamatergic and endocannabinoid systems in the modulation of schizophrenia dissociative states and other psychiatric conditions. Ketamine has found to be an effective and rapid antidepressant. It can be administered oral, nasal, sublingual (under the tongue), IM (into a muscle) or subcutaneous. These antidepressant properties have also been noted effective in the treatment of patients with major depression and bipolar disorders resistive to anything else. Further study is needed to discover the exact mechanism involved in the antidepressant property of Ketamine (Khakpai et al, 2019).

Where future study needs to focus
The rapid and profound antidepressant effects of Ketamine seem poised to transform the treatment of depression. At the same time the mechanisms by which it works and turning the medical understanding of how depression treatment actually works on its ear. Depression is among the most disabling medical condition. Despite progress, too few patients respond to present antidepressants or improvement is too slow among the individuals who actually respond. In addition, certain individuals like those who are bipolar, have a poor response to currently available treatment. Part of the issue is that since the discovery of antidepressants in the 1950s, there was a failure to identify new treatment mechanism. And while the meds worked on monoamine transiently decreasing depression, depletion of monoaminergic didn’t reliably induce depression. Nor did it make depressed un-medicated people worse. Ketamine, however, reduces all symptoms of depression, notably ideation of suicide. Studies are currently being conducted to find the optimal dosage of Ketamine. It is challenging because while 0.2mg/kg is subtherapeutic, 0.5mg/kg causes disassociative and effective. There is hope that with Ketamine-like antidepressants this can become a transformative treatment (Krystal et al, 2019).

For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems. They typically take weeks, for effects to be noted and more weeks to months to have a remission of symptoms. Low subanesthetic doses of Ketamine have resulted in rapid improvement of core depressive symptoms, including mood, anhedonia (not able to experience pleasure) and suicidal ideation. The effects can be documented within hours and one dose can bring relief noted by patients for up to one week. Depression is chronic, severe and often life-threatening affliction. Each person manifests depression in different ways causing the treatment to envelop many facets. Typical treatment of depression can take weeks to have any measurable effect and up to a month before symptoms are controlled. This lag time can potentially have life-threatening results. Thus the current push has been for faster-acting medicines with the fewest side effects. Traditionally, non-pharmacological treatment of TRD has been electroconvulsive therapy (ECT) but it is limited by the time-consuming nature of the procedure and the common side effect of cognitive deficits. Ketamine has been used as anesthesia induces for over 50 years. No other treatment for TRD has demonstrated comparable results in terms of the magnitude of response following a single administration. Novel or more effective with fewer side effects are being developed that mimic ketamine’s mechanism of action has proven difficult. Improved understanding of the mechanism of Ketamines effect on depression has provided insight on where new studies need to be focused (Gould, Zarate, & Thompson, 2019).

Conclusion
The same neural mechanisms underlying the effects of Ketamine need closer examination. Accumulating evidence has shown dysfunctions for glutamate transmission plays a key role in the etiology and pathophysiology of depression. The importance of this for developing novel antidepressants has been highlighted by recent findings of the antidepressant effects of Ketamine. This substance has shown to exert rapid and lasting antidepressant on patients; especially useful in TRD. Ketamine, however, has serious effects with long-time use like hallucinations and has high abuse potential. Therefore the focus of research has now shifted to finding novel treatment with the same mechanism of Ketamine but devoid of the side effects (Chaki & Fukumoto, 2019).

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Work Cited
Chaki,S. & Fukumoto, K. (2019). Role of serotonergic system in antidepressants actions of mGlu2/3 receptor antagonists: Similarly to Ketamine. International Journal of Molecular Sciences,20(6).

Fasipe, O.J. (2019). The emergence of new antidepressants for clinical use: Agomelatine paradox versus other novel agents. IBRO Reports, 6(2019).

Gould, T.D., Zarate Jr., C.A., & Thompson, S.M. (2019). Molecular pharmacology and Neurobiology of rapid-acting antidepressants. Annual Review of Pharmacology and Toxicology, 59(2019).

Khakpai, F. et al. (2019). Ketamine-induced antidepressant-like effects in mice: A possible involvement of the cannabinoid system. Biomedicine and Pharmacotherapy,112 (2019).

Krystal, J.H. et al. (2019). Ketamine: A paradigm shift for depression research and treatment. Neuron 101. Cell Press.

Kutzky, A. et al. (2019). Epistasis of HTR1A and BDNF risk genes alter cortical 5-HT1A receptor binding: PET results link genotype to molecular phenotype in depression. Translational Psychiatry, 9(5).

UMD. (2019). Researchers discover a critical receptor involved in response to antidepressants like Ketamine. University of Maryland School of Medicine.

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