Peptides for Depression

[01dragonslayer]

Peptides for Depression | What to Know in 2023​

For decades scientists and doctors have operated under the premise that a “chemical imbalance” is the underlying cause of depression. The prevailing theory has been that if a person’s serotonin, norepinephrine, or dopamine levels were out of balance then that person would develop depression. It seemed logical then that correcting those levels, usually by raising them, was the best way to treat depression.

The result of the “chemical imbalance” hypothesis was an explosion of selective serotonin reuptake inhibitors (SSRIs), like Prozac and Zoloft, in addition to MAOIs, SNRIs, tricyclic antidepressants, and drugs targeting norepinephrine and dopamine levels. In the early 1990s, these drugs were touted as being 80-90% effective in treating depression and related conditions. As a result, they quickly became some of the most-prescribed drugs in the western world. Unfortunately, these wounder drugs were given far more credit than they were due, perhaps in no small part because people and their medical providers were desperate to have anything they could use to fight back against the symptoms of depression.

As it turns out, more recent studies have shown that drugs like Prozac are no more effective in treating depression than placebo[1]. For a long time, no one wanted to talk about this because, well, there wasn’t much of an alternative. Over time, however, doctors were forced to face the fact that SSRIs and similar drugs simply weren’t up to the task they were developed for. Far from being a nadir in depression research, however, this revelation spurred the development of new hypotheses and resulted in the investigation of multiple new treatments for depression including peptides, electroconvulsive therapy, and even drugs like ketamine.

Peptides for Depression​

Neuropeptides, which is to say peptides that are active in the central nervous system, likely play an important role in the etiology and pathophysiology of depression[2]. Research shows that peptides like vasopressin, galanin, neuropeptide Y, and others are critical in the modulation of monoaminergic receptor transmission. In other words, peptides likely provide the underlying control of neurotransmitters like serotonin and dopamine. Thus, the problem of depression is not one of “chemical imbalance,” but rather one of incorrect chemical regulation and signaling.

Neuropeptide systems appear to be involved in several neuropsychiatric conditions, suggesting that there is legitimate physical dysfunction of certain receptors or their ligands that accounts for many neuropsychiatric symptoms. For example, schizophrenia has been tied to alterations in neuropeptides systems including arginine-vasopressin, cholecystokinin, corticotropin-releasing factor, neuropeptide Y, and more[3].

Further adding to the link between peptides and depression is the fact that electroconvulsive treatment (ECT) appears to significantly alter certain peptide levels in the brain. ECT has been shown to have tremendous benefit in the treatment of mood disorders like depression, but because of potential side effects is often limited in use to only refractory, severe cases. Research shows that a number of peptides like neuropeptide Y, galanin, and somatostatin are all impacted by ECT treatment thus suggesting that the real benefit of ECT is in its ability to help the brain regulate neuropeptides[4].

Research into the role of peptides in the treatment of depression is in relatively early stages and there is much to be done, particularly where animal studies are concerned. Still, there is some promising research showing that certain peptides may provide a legitimate, measurable, statistically, and clinically relevant benefit in depression and anxiety. Here is a look at a handful of those peptides.

Ghrelin​

Ghrelin, often called the hunger hormone, has a natural anti-depressant effect. It is thought that this peptide, which regulates growth hormone levels and energy balance, rises in response to elevated cortisol levels. Cortisol itself rises in response to stress and thus high cortisol levels are associated with depression and anxiety, though it isn’t clear that cortisol itself is the causative agent in these conditions.

Stimulation of the ghrelin receptor (aka growth hormone secretagogue receptor) has been shown to alleviate depression-like behavior and hypomotility in rats while driving down cortisol levels[5]. Additionally, deletion of ghrelin in mice has been shown to alter tryptophan metabolism. Tryptophan is a precursor to many of the neurotransmitters implicated in the pathophysiology of depression[6], [7]. Ghrelin analogues, like ipamorelin, GHRP-2, and GHRP-6, may have similar benefits to ghrelin where depression is concerned. Anecdotal evidence suggests this link, but the research has yet to be done. Most of the work on these peptides has focused on their ability to stimulate growth hormone secretion, wound repair, and bone building. It is only recently that more serious attention has been given to their potential effects on the central nervous system.

Melanocyte-Stimulating Hormone-Release Inhibiting Factor (MIF-1)​

MIF-1 is a synthetic peptide derived from the c-terminal peptides (proline-glycine-leucine) of oxytocin. First studied in the laboratory of Abba Kastin in 1974, MIF-1 has been shown to have a biphasic effect in the setting of depression. At low levels, MIF-1 causes s significant improvement in the symptoms of depression after a very short period. Higher doses of this peptide do not produce better results, however, but instead seem to impair the anti-depressive effects seen at lower doses. Doses on the order of 0.1 mg/kg have far greater effect than either placebo or higher doses[8]. When given via subcutaneous injection for just 5 days, fully 89% of subjects show substantial improvement on the Hamilton Scale of depression, as compared to just 20% of those given placebo[9]. According to Dr. Kastin, a neuroendocrinologist and early researcher of neuropeptides, the use of peptides to treat depression has shown far greater promise in research settings than any other approach used to date.

Pinealon​

Pinealon is a short, natural peptide known to directly interact with DNA to alter gene expression. Research has shown that pinealon administration can lead to behavioral modification in animals and plays important roles in circadian rhythm disorders. Given that sleep and depression are closely linked, it should come as no surprise that pinealon has shown some promise in animal models of depression.

Pinealon has been shown to boost expression of 5-tryptophan hydroxylase in the brain. This enzyme plays a critical role in the production of serotonin and can therefore alter concentrations of serotonin in the brain[10]. Additionally, pinealon has been shown to correct neuropsychiatric symptoms resulting from disordered sleep and sleep deprivation[11].

Selank​

Anxiety and depression are closely related conditions and, often, where one is found the other is diagnosed as well. Research in patients with both anxiety and depression suggests that the inflammatory cytokine IL-6 may play a role in both conditions. IL-6 appears to be particularly important in those who suffer from anxiety-asthenic disorder and other psychosomatic conditions in which nerve pain, fatigue, headache, heart palpitations, and high blood pressure accompany the symptoms of depression and complicate treatment. In fact, IL-6 is of interest in research on fibromyalgia and chronic fatigue syndrome. In both conditions, which have strong elements of depression and which respond to anti-depressives in some cases, IL-6 appears to be elevated[12]. Selank can suppress the expression of the gene responsible for the production of IL-6 and as such is of interest in the treatment of anxiety and depression[13].

Semax​

Research has shown that BDNF (brain-derived neurotrophic factor) levels are decreased in people with depression. BDNF is important in the maintenance, survival, and growth of neurons and the synaptic connections between them. It isn’t clear whether lower BDNF levels are a consequence of depression or a cause of depression, but abnormalities in BDNF levels and BDNF receptors have been strongly linked to both depression and suicidality[14].

Enhancement of BDNF levels has been proposed as a potential treatment for depression[15]. Semax, a short synthetic derivative of adrenocorticotrophic hormone (ACTH), has been shown to stimulate BDNF levels in specific areas of the rat brain (e.g. basal forebrain)[16]. Furthermore, administering BDNF to rats increases their exploratory activity and decreases both anxiety and depression-like behavior[17], [18]. There has even been research to suggest that Semax might play a role in the treatment of attention-deficit hyperactivity disorder (ADHD), suggesting that BDNF may be a final common pathway in a number of neuropsychiatric conditions[19].

Peptides for Depression: Summary​

As noted above, the research into peptides for depression is in its infancy. This is likely because so much time and so many resources have been devoted to drugs targeting serotonin, norepinephrine, and dopamine. Despite the relative dearth of information on this topic, there is still compelling research to suggest that peptides like ghrelin, MIF-1, and others may offer important clues to the etiology of depression. More than a few animal studies have also suggested that these peptides may offer potent and relatively side-effect-free treatment options for depression, anxiety, and other neuropsychiatric conditions. While more work needs to be done, the research that does exist bodes well for future research into peptides for depression.