Depression or Major Depressive Disorder is a common and serious medical illness that negatively affects how you feel, the way you think and how you act. Its big impact on the social life is seen as MDD affects nearly 20% of the population at some point during the life span and it is estimated to be the number one cause of disability by 2020.
The clinical presentation of the disease consist in symptoms such as depressed mood, loss of pleasure in almost all activities (anhedonia), significant weight change, sleep disturbance (insomnia or hypersomnia), psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness, diminished ability to think or concentrate, recurrent thoughts of death.
The disease is diagnosed when at least five of the symptoms are present during the same two weeks period.(and at least 1 of the symptoms must be depressed mood and/or loss of pleasure).
This figure is adapted from (Ref 1).
To explain the pathophysiology of the disease first we have to mention that the normal physiology of patient’s mood, perception, emotion and behavior focuses majorly on neurotransmitters in the brain. Neurotransmitters are chemical messengers that are released and received by synapses of neurons to mediate intracellular communication in the nervous system. Serotonin is involved with mood, happiness, anxiety, and sleep induction. These are Norepinephrine, Dopamine, Serotonin. Sufficient levels are needed for the brain to function properly and decreased levels have been found in patients with depression.The main mechanism of pathophysiology consist in neurochemical dysregulation. In the last decades, an important role of glutamate in mood modulation has been hypothesized and ketamine, has been demonstrated to be effective in both MDD and TRD. But how does it work?
Ketamine is an NMDA receptor antagonist, and AMPA stimulator. The idea is that ketamine blocks the NMDA receptors on the GABA neurons. Because of that, there is less inhibition and more glutamate. AMPA stimulation results in increased BDNF (brain derived neurotrophic factor). BDNF stimulates the formation of new receptors and synapses by triggering a cascade of events (via mTOR) which causes more AMPA receptors to be inserted into the synapse, making the synapse stronger, more stable, and more mature. This is the key reason behind ketamine’s antidepressant effect. It is shown that when they block mTOR with the drug Rapamycin, the effects of ketamine on new spine growth disappear and its anti-depressant effects disappear. So the claim here is tha ketamine it could help new neurons become synaptically mature, and thus functionally useful.
First-line treatments for MDD include oral antidepressant medications, such as Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors, and Tricyclic antidepressants, in conjunction with psychotherapy if needed. Those who have tried two or more antidepressants without success are considered to have Treatment Resistant Depression. (TRD)
For decades, there has been a long-standing need for additional effective treatments for MDD and today, the new hope for that, is called Spravato. Spravato is the brand name of the new medicine. The generic name is Esketamine. It is launched by Janssen Pharmaceutical Companies of Johnson & Johnson and it is approved by FDA on 5 March 2019. Spravato is the first major advance in depression drugs. It uses the first new mechanism of action in 30 years, to treat MDD and TRD.
The mechanism of action of the new drug consists in Esketamine, the S-enantiomer of racemic ketamine role, as a non-selective, non-competitive antagonist of the NMDA receptor. The mechanism by which esketamine exerts its antidepressant effect is unknown. It works differently than currently available therapies for depression. The major circulating metabolite of esketamine (noresketamine) demonstrated activity at the same receptor with less affinity. The medicine is administered as a nasal spray. The mean absolute bioavailability is approximately 48% . The time to reach maximum esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of a treatment session. That is absorbed by the lining of the nasal passages into the blood stream. Protein binding of esketamine was approximately 43% to 45%. Esketamine is primarily metabolized to noresketamine metabolite via P450 (CYP) enzymes CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19.
Noresketamine is metabolized via CYP-dependent pathways and certain subsequent metabolites undergo glucuronidation. Less than 1% of a dose is excreted as unchanged drug in urine. Spravato mainly effects Cardiac Electrophysiology. A large increase in heart rate (i.e. >10 bpm) was observed in both intranasal and intravenous esketamine treatment groups. The totality of evidence from the nonclinical and clinical data indicates a lack of clinically relevant QTc prolongation at the therapeutic dose of esketamine.
The side effects of the new drug consists in: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting. It is important to know that three adverse events were particularly concerning: sedation, dissociation, and increased blood pressure. The majority of these events happened during the first 2 hours after drug administration. That’s why the medicine Spravato should be self-administered under the supervision of a health care professional. Patients must be monitored for at least two hours after receiving a dose. The spray cannot be taken home.
COPYRIGHT: This article is the property of We Speak Science, a nonprofit institution co-founded by Dr Detina Zalli . The article is written by Dr. Klaudia Stajka (University of Tirana, Albania).
REFERENCES:
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Fifth edition. 2013.
- Garcia-Arocena, D. (n.d.). Happy or SAD: The chemistry behind depression. Retrieved October 29, 2018.
- WHO: WHO | Depression [Internet]. Depression. 2017.
- Kessler RC, Chiu WT, Demler O, et al.: Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry.2005; 62(6): 617–27.
- Kessler RC: The costs of depression. Psychiatr Clin North Am.2012; 35(1): 1–14. Murray CJ, Atkinson C, Bhalla K, et al.: The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. JAMA.2013; 310(6): 591–608.
- Duman RS. Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide. F1000Research. 2018;7:F1000 Faculty Rev-659. doi:10.12688/f1000research.14344.1.
- Dubovsky SL. What Is New about New Antidepressants? Psychotherapy and Psychosomatics. 2018;87(3):129-139. doi:10.1159/000488945.
- SPRAVATO™ [Prescribing Information]. Titusville, N.J., Janssen Pharmaceuticals, Inc.
- Thase ME. Update on partial response in depression. J Clin Psychiatry. 2009;70[suppl 6]:4-9.
- Duman RS, & Li N (2012). A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367(1601), 2475-84 PMID: 22826346
- Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, & Duman RS (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science (New York, N.Y.), 329(5994), 959-64 PMID: 20724638
