THE GOOD DRUG GUIDE
Depressive illness devastates millions of lives. Tianeptine (Stablon, Coaxil, Tatinol) is a neuroprotective antidepressant that reverses the neuronal damage and lasting misery caused by chronic, uncontrolled stress. Tianeptine acts both as a non-sedating anti-anxiety agent and a non-stimulating mood-brightener. Uniquely in clinical medicine, tianeptine acts as a selective serotonin reuptake enhancer. Its puzzling efficacy as an antidepressant illustrates how little modern psychiatric medicine really understands about mind, mood and depression.
A breakthrough in tianeptine research was announced in July 2014 with the unexpected discovery that tianeptine is a full agonist at the mu and delta opioid receptors with negligible effect at the kappa opioid receptors. Selective mu opioid agonists in the brain's "hedonic hotspots" typically induce euphoria. Selective kappa agonists typically induce dysphoria. The role of central delta opioid receptors is poorly understood. Dual activation of the mu and, less potently, delta opioid receptors may be critical to tianeptine's mood-brightening and anxiolytic effect - a therapeutic action seemingly unaccompanied by the physiological tolerance and dependence that have plagued traditional opioids. All previous research into tianeptine may need to be re-evaluated in this light. Neonatal Abstinence Syndrome following heavy use of tianeptine during pregnancy has been reported. The recently popular sulfate salt (tianeptine sulphate) is less readily absorbed and excreted from the body than the sodium salt, allowing one-per-day dosing, smoother plasma concentrations, and minimal risk of abuse. More research is urgently needed.
An inverse correlation exists between the suicide rate and dietary intake of the essential amino acid l-tryptophan, the rate-limiting precursor of serotonin synthesis. The widely prescribed selective serotonin reuptake inhibitors [i.e. the SSRIs fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), paroxetine (Paxil) and citalopram (Celexa)] block the reuptake of the neurotransmitter serotonin into the presynaptic nerve cells by interfering with the serotonin transporter. They thereby increase the availability of serotonin in the synapse. SSRIs are marketed primarily as antidepressants. They are prescribed for a host of off-label indications too. In contrast to SSRIs, tianeptine facilitates the reuptake of serotonin into serotonergic terminals both in the cortex and hippocampus - confounding simplistic "low serotonin" theories of depression. Tianeptine lacks any significant activity at monoamine transporters or neurotransmitter receptors. How it actually accelerates serotonin reuptake, both acutely and chronically, is unclear. Like other contemporary antidepressants, its therapeutic action presumably depends on downstream adaptations both between and within neurons occurring over a period of several weeks. But again the precise molecular mechanisms are obscure.
Tianeptine was first synthesised in 1981[?] by French researchers Antoine Deslandes and Michael Spedding. It has been developed and marketed since the late 1980s as the antidepressant Stablon by secretive, privately-owned Servier, the innovative French drug giant. Tianeptine is sold in Europe, Latin America and Asia. It is not marketed in North America because its patent has expired. To gain a US product license, a raft of costly new clinical trials would be needed by the FDA. Unfortunately, American regulators are habitually sceptical of the calibre of European medical science. Even after FDA approval, tianeptine/Stablon could be sold only cheaply due to generic competitors. Commercially, this might not seem an insoluble problem: structurally, tianeptine may be considered a modified tricyclic, and patentable analogues of tianeptine do exist, notably hetero[2,1]benzothiazepine derivatives. But if and when any such analogues will be commercialised is uncertain. No evidence exists that they are therapeutically superior to tianeptine. Another option might exploit how tianeptine sold as Stablon (etc) is a racemate; the l-isomer is more therapeutically active than its molecular sister. The design of single-isomer "chiral" drugs allows corporate patent lawyers to extend the patent life of old medicines. Thus tired SSRI antidepressant citalopram/Celexa was relaunched in 2002 as expensive new s-citalopram/Lexapro; and patent-expired modafinil/Provigil will soon be relaunched as expensive new r-modafinil/Nuvigil. This route hasn't been pursued yet with Stablon. In fact tianeptine may finally reach the USA branded not as an antidepressant, but in the guise of a treatment of Irritable Bowel Syndrome (IBS). For in 2004 Vela Pharmaceuticals registered a patent for the use of tianeptine to treat IBS. In March 2006 Pharmos Corporation acquired Vela. Tianeptine for IBS is now in "late-preclinical development". If and when a medicine gains a US product license, physicians can then prescribe it "off-label" for whatever they see fit, including depression. But this prospect is several years away at best.
Some indication of tianeptine's potential range of application can be gleaned from its various patents. Thus patent US6599896 proposes "...use of tianeptine in the production of medicaments to treat neurodegenerative pathologies...cerebral ischaemia, cerebral traumatism, cerebral aging, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, demyelating pathologies, encephalopathies, chronic fatigue syndrome, myalgic encephalomyelitis post-viral fatigue syndrome, the state of fatigue following a bacterial or viral infection, and the dementia syndrome of AIDS”. A prospective, double-blind, randomised, placebo-controlled trial of tianeptine for fibromyalgia is currently under way in Spain. Regular tianeptine use may even be good for one's teeth, though it's unlikely to become a staple of orthodox dentistry. Despite this cornucopia of possibilities, tianeptine is not well known in Anglo-American psychiatry or among the English-speaking lay public. Much of the early literature was published only in French. Servier's present focus is not on tianeptine but the novel melatonin receptor agonist and serotonin 5-HT2C receptor antagonist agomelatine (Valdoxan), EC-licensed from February 2009 as an antidepressant. Unlike tianeptine, agomelatine is comprehensively patent-protected.
How does tianeptine/Stablon work? No one really knows. So the story below will soon be superseded. Tianeptine is neuroprotective via multiple neurochemical and cellular mechanisms. When an organism is under stress, or perceives itself under stress, the hypothalamus secretes corticotropin-releasing hormone/factor (CRH/CRF). CRH/CRF in turn increases secretion of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. ACTH in turn stimulates the release of glucocorticoids from the adrenal cortex. Persistent, uncontrolled physical and psychosocial stress causes excess cortisol secretion from the adrenal glands. Excess cortisol causes dendritic shrinkage in the hippocampus and a contrasting growth of dendrites in the lateral amygdala. These stress-induced changes tend to lower mood; they can cause clinical depression in the genetically vulnerable. Current evidence suggests that tianeptine acts to prevent and even reverse stress-induced neural damage, promoting both neuronal survival and synaptic plasticity. Sustained use of tianeptine tends to "normalise" the hypothalamic-pituitary-adrenal (HPA) system. Tianeptine reduces basal and stress-evoked activity of the HPA, helping its users cope in a stressful environment. Treatment with tianeptine inhibits corticosterone-induced gene transcription. Stress-induced increases in plasma ACTH, and corticosterone levels are diminished. So too is basal activity of corticotropin-releasing factor (CRF) neurons and their sensitivity to stress. Prolonged tianeptine use also reduces some forms of stress-induced apoptosis ("programmed cell-death"), notably in the temporal cortex and dentate gyrus of the hippocampus. At the molecular level, tianeptine exerts profound effects on the glutamate system. The amino acid glutamate serves as the main excitatory neurotransmitter in the brain. Its excitatory action is mediated by via multiple receptor subtypes. The three main subtypes of glutamate-gated ion channel are kainate, ampa, and N-methyl-D-aspartate (NMDA). Tianeptine prevents overstimulation of AMPA/kainate type glutamate receptors in the hippocampus that regulate Ca2+ entry into the nerve cell; excess Ca2+ entry into nerve cells is toxic. Tianeptine also modulates the NMDA glutamate receptors. NMDA receptors for glutamate play a critical role in mediating the functional and intracellular effects of stress. Tianeptine reportedly targets the phosphorylation-state of glutamate receptors in the hippocampus, "normalising" stress-induced changes in the amplitude ratio NMDA glutamate receptor to AMPA/kainate glutamate receptor-mediated excitatory post-synaptic currents. Selective glutamate receptor antagonists, including sub-anaesthetic doses of the dissociative anaesthetic ketamine, can act as analgesics and neuroprotective antidepressants, despite dose-limiting side-effects. Their mind-altering properties deter wider clinical psychiatric use. Tianeptine, on the other hand, is an analgesic and antidepressant that lacks psychotomimetic side-effects at any sensible dose.
In theory, tianeptine's neuroprotective action makes it a potential life-extension drug for the wider "euthymic" population. This hypothesis remains untested in prospective clinical trials.
Chronic administration of tianeptine increases the density of serotonin innervation in the forebrain. Different categories of antidepressant may converge on the same molecular and cellular targets: like SSRIs, tianeptine promotes growth of serotonergic axons in the layer IV of the neocortex and forebrain limbic structures, notably the shell region of the nucleus accumbens. The shell region is important because it contains the ultimate "hedonic hotspot" of the brain. Latent in the architecture of medium spiny neurons in the rostrodorsal region of the medial accumbal shell is the molecular essence of pleasure - and what makes it feel good to be alive. By contrast, anhedonia i.e. the diminished or absent capacity to experience happiness, is a marked feature of clinical depression. Sadly, today's antidepressants are more often effective at relieving misery than promoting expression of the molecular substrates of well-being. Misplaced optimism over their therapeutic efficacy arises when rates of antidepressant "response" and remission are conflated in the medical marketing literature. Ironically, agents that do banish depression and induce bliss, notably mu opioid agonists, are not categorised as antidepressants by mainstream Western medicine. By comparison, the results from trials of putative antidepressants pushed by Big Pharma often struggle to achieve statistical significance. The outcome of unpublished trials is normally worse; "publication bias" is endemic to the drug industry and its academic satellites. So a large minority of patients treated with "antidepressants" either continue to feel depressed or remain haunted by "residual" symptoms. Tianeptine itself has no affinity for the opioid receptors which regulate basal hedonic tone, though it increases Met-Enkephalin and mRNA coding for proenkephalin in the adrenals and pituitary gland. Tianeptine's mood-lifting action is not as effective - or addictive - as mu-selective opioids. Tianeptine is nonetheless a useful medication for depressed ex-opiate users. It acts as an analgesic, possibly via a serotonergic mechanism, but possibly too via its poorly understood indirect effects on the endogenous opioid system. The pain-relieving action of tianeptine is especially important because many depressives are also chronic pain sufferers. Numerous other depressed and dysthymic people suffer bodily aches and an ill-defined malaise. When untreated, somatic symptoms are liable to exacerbate depression. Tianeptine combats malaise partly by interfering with the cytokine-induced behavioural and psychological effects of stress. Elevated proinflammatory cytokines accompany the chronic stress response. Cytokines typically trigger feelings of malaise and a deep sense of ill-being; a common side-effect of interferon therapy of Hepatitis C, for instance, is severe depression. More generally, the malaise theory of depression proposes that many forms of depressive disorder should be seen as a form of sickness behaviour. Tianeptine reverses sickness behaviour. Typically, tianeptine helps its users feel well but not euphoric.
Unlike its cousin amineptine, tianeptine doesn’t ordinarily give rise to a degree of subjective inner tension. Noradrenergic/dopaminergic mood-brighteners may boost motivation and dispel melancholia; but subjectively, such well-being as they may induce is often of a harder-edged texture than is characteristic of tianeptine. Anecdotally, people on the noradrenergic/dopaminergic antidepressant bupropion (Wellbutrin), for example, have a reputation among their physicians for being irritable. Tianeptine users are more likely to be mellow. Taking tianeptine reduces irritability and impulsiveness. It's also a treatment option in panic disorder and social phobia. Tianeptine reduces acute stress-induced noradrenaline release in the frontal cortex. Unlike most tricyclics, tianeptine doesn't have a sedating action because it has no affinity for the histamine receptors. Nor does tianeptine tend to flatten emotions like the SSRIs. Unlike the SSRIs, tianeptine doesn't induce serotonin 5-HT1A receptor subsensitivity as seen with many other antidepressants, including the archetypal tricyclic imipramine (Tofranil); but the significance of this finding is obscure. At their best, SSRIs buffer the user against the effects of chronic uncontrolled stress. Ideally, SSRIs promote resilience and greater emotional self-sufficiency in the vulnerable. They swiftly treat "emotional incontinence". But SSRIs can also cause emotional blunting. Long-term SSRI use may induce a sense of emptiness and apathy. Tianeptine doesn’t exert this dulling action, but the extent of the emotion-deepening effect sometimes reported (by e.g. Claude Rifat) is unclear and possibly short-lived: tianeptine certainly doesn't trigger the emotional soul-baring of a serotonin-and-dopamine releaser like MDMA or a sociabiliser like GHB. Indeed drug discrimination studies suggest that some of its subjective effects in rodents may be quite similar to fluoxetine (Prozac); though the significance of this result is muddied by the fact that Prozac is the dirtiest and least selective of the SSRIs. Tianeptine has been used experimentally in the symptomatic treatment of autistic spectrum disorders. A modest benefit has been claimed, but this study needs following up.
Unlike SSRIs and other "serotonergic" antidepressants, tianeptine does not dampen libido or sexual performance. Indeed sexual function may even be enhanced. Depression, dysthymia and the spectrum of "subclinical" depressive disorders damage not just millions of afflicted individuals, but their partners and wider circle of friends and family. Unfortunately, no controlled studies have been done on the effects of existing psychotherapeutic drug treatments on the user’s personal relationships. Thus SSRIs have helped save many intimate relationships, yet they have also broken them. For SSRIs can diminish both the intensity of being in love and the ardour with which to express it. One makeshift option is to correct SSRI-induced sexual and romantic deficits with cautious polypharmacy. Authentic aphrodisiacs like Palatin's melanocortin agonist PT-141 (bremelanotide) are already circulating in the scientific counterculture and beyond. A veritable cultural revolution may be brewing. Yet the likelihood of ubiquitous recreational use of inhalable sex-drugs may discourage an FDA product license.
Unlike its pro-sexual cousin amineptine, tianeptine does not significantly inhibit the synaptic reuptake of dopamine when taken at normal doses. But tianeptine does acutely increase extracellular dopamine concentration in the nucleus accumbens and, at higher doses, in the frontal cortex. The functional responsiveness of dopamine D2/D3 receptors is also enhanced. "Supra-therapeutic" doses of tianeptine are mildly stimulating and noticeably mood-lifting. But tianeptine is (almost) without a tendency to uncontrolled dose-escalation; rare chronic high-dosage tianeptine use is pursued for a gentle stimulant effect that is virtually absent at approved and divided doses. High-dose tianeptine also feels smoother than high-dose amineptine. In common with the SSRIs, tianeptine is (relatively) safe even in massive overdose. It's certainly less hazardous than its cardiotoxic tricyclic relatives.
Tianeptine inhibits activity of the enzyme nitric oxide synthase (NOS) in the hippocampus. This is an important subcellular signalling system for the glutamate-NMDA receptor. NOS inhibitors have distinct antidepressant properties. NOS levels are higher in depressives than "euthymic" normals. The effects of tianeptine on the glutamate-NO pathway explain the improved cardiovascular status of tianeptine-using patients with ischaemic heart disease. There is a poorly understood association between coronary heart disease and depression; disturbances in nitric oxide production may play a role in both.
Triiodothyronine (T3) levels in the amygdala are elevated during tianeptine use. A central thyroid action has been hypothesised for many antidepressant drugs; and thyroid supplementation may augment and accelerate therapeutic response to antidepressants. A thyroid mechanism may even be partly responsible for the mood-elevating effects of acute sleep-deprivation in depression, though dopamine plays a role here too. But quantifying the contribution of a thyroid mechanism to tianeptine's therapeutic effect is difficult.
Interestingly, rats on tianeptine show reduced susceptibility to serotonin breakdown by central monoamine oxidase type A, but not by MAO type B. Such MAO-A inhibition may conceivably contribute to tianeptine's mood-brightening effect. But all sorts of agents e.g. coffee and tobacco smoke, have potentially mood-brightening MAO-inhibiting properties too. Perhaps the easiest and least risky way of achieving therapeutically effective unselective MAO inhibition is via EMSAM, the newly-licensed (2006) transdermal selegiline patch.
Tianeptine is reported to be moderately useful in treating Attention Deficit Hyperactivity Disorder (ADHD). At present, millions of (mainly) American school students diagnosed with ADHD take amphetamines under different guises and innocent-sounding labels. Amphetamine adverts can be alluring: "Try Adderall" [amphetamine/dextroamphetamine salts] and "soar confidently into summer and the new year". Drug-induced bouts of focused intensity may perhaps be educationally useful, occasionally; but critics argue that such products are prescribed at least in part as instruments of social control. ADHD itself may not wholly be a diagnostic artefact of modern medicine; yet nor is ADHD a recognised diagnostic entity in cultures where children aren't compelled to sit unnaturally immobilised in classrooms for 6-8 hours each day performing rituals alien to their ancestral environment. As if to feed the darkest suspicions of anti-psychiatry advocates, the majority of the medical elite involved in classifying psychiatric disorders via DSM-IV have close ties to the drug companies. In consequence, American children consume some 90% of the world's Ritalin. In fairness, a powerful case can be made that all forms of distress should be pathologised and treated. The medicalisation of everyday life may ultimately lead to a happier world. But with ADHD, potentially toxic amphetamine-based products are commonly (ab)used to curb the exuberance and crush the spirit of innumerable school students for purposes beyond the welfare of the "paediatric patient". The long-term effects of tianeptine use on high-spirited children have not been properly evaluated. Its administration is known to promote attentional focus in cats. At worst, tianeptine may be a less harmful option than existing amphetamine-based drugs. A more radical alternative might be to stop pharmaceutical experimentation on children until the neurobiology of ADHD is adequately understood.
In common with amineptine, but unlike classic tricyclic antidepressants, tianeptine does not normally impair cognitive function. On some measures, memory consolidation and intellectual performance may be improved; but this claim for humans is problematic, at least in unstressed non-depressives. The effects of tianeptine on cognition are complicated. Most tricyclics have "dumb-drug" anticholinergic effects consequent on their antimuscarinic action, aggravated by their sedative action due to anti-histamine effects. Their use in the elderly prior to the SSRI revolution contributed to the misdiagnosis of dementia in depressed seniors. "Typical" tricyclics can subtly impair concentration, language facility, and memory even in the healthy and "euthymic" young. Among the SSRIs, only paroxetine (Paxil, Aropax) has significant anticholinergic effects; but all SSRIs can induce subtle cognitive deficits. Tianeptine is not a cholinergic antagonist; yet acute, high-dose tianeptine treatment does indirectly inhibit acetylcholine release in the dorsal hippocampi and frontal cortex. This may weakly and indirectly contribute to acute mood-elevation, but it might also be expected acutely to impair intellectual performance. However, this hasn't been borne out in controlled experiments. Rather than being a classic tricyclic dumb drug, tianeptine may serve as a long-acting nootropic. It counteracts serotonin-induced inhibition of cholinergic medial septal neurons. Chronic tianeptine desensitises serotonin 5-HT1B presynaptic heteroreceptors which inhibit acetylcholine release. Experimentally, tianeptine improves working and reference memory in depressed rats, probably due to its neurotrophic action. Tianeptine prevents stress-induced memory deficits and restores synaptic plasticity. Even a single dose of tianeptine measurably increases growth hormone (GH) secretion; long-term GH enhancers tend to improve intellectual performance. Clearly, there is a need for more research in humans and maybe a subtler battery of tests measuring cognitive function.
Dosage of tianeptine in most clinical trials has ranged from 25mg to 50mg per day. Currently, 3 x 12.5mg = 37.5mg daily is standard. "Patients"/healthcare consumers are rarely encouraged to explore the optimal dosage of their prescribed psychotherapeutic agent by their doctor. This is regrettable because individual optimal dosage regimen can vary a lot. Obviously, there are risks as well as advantages to encouraging self-titration. A post-genomic era of truly personalised medicine is probably decades away. In the meantime, not everyone is temperamentally or educationally well-equipped to perform the incremental dosage increases or decreases over time that are needed to identify what regimen personally works best, especially when there is a pronounced therapeutic time-lag. One consequence is that very few people ever receive their optimal dosage of psychotropic medication - or for that matter "lifestyle drug" of choice. This failure exacerbates the poor response-and-remission rates to antidepressant drugs and other psychoactive pharmaceuticals. The actual therapeutic dosage range of tianeptine probably ranges from less than 12.5mg to as much as 300 mg daily; but these figures depend on "animal models" and the usual horrible experiments.
The side-effect profile of tianeptine is unusually benign. To ask what licensed antidepressant has least troublesome side-effects is doubtless naïve; but if adverse side-effect league-tables were possible, then tianeptine would be a contender for the pharmaceutical crown. "Patient compliance" is high. Tianeptine is oxidised into reactive metabolites and rapidly eliminated, mainly by the kidneys. Tianeptine has an identical heptanoic acid side chain to amineptine; and their metabolism is similar. However, at standard dosage tianeptine is less likely to produce the rare high-dose side-effect of microvesicular steatosis than amineptine; in mice at least, this occurs through inhibition of mitochondrial beta-oxidation of fatty acids.
Insomnia occasionally occurs on starting tianeptine. It soon subsides. Complex, vivid dreams on tianeptine are common; but paradoxically, tianeptine can also be effective against posttraumatic stress disorder (PTSD). The mechanism behind tianeptine-induced altered dreaming patterns is unknown. Possibly such dreams reflect a cholinergic rebound due to its short (c. 2.5 hour) plasma half-life; alternatively, they may be a dopaminergic effect. Or neither, or both. Hippocampal remodelling may well be involved in tianeptine-driven dreams too.
Taken both acutely and chronically, tianeptine is a helpful medication for heavy drinkers. Tianeptine use alleviates the signs and symptoms of alcohol withdrawal. It may also be taken by drinkers who simply want to drink less. Many alcoholics are, in effect, self-medicating; abstinence from alcohol entails a reversion to anxious depression or social anxiety disorder. Switching to tianeptine can induce a similar degree of well-being to liquor without the intoxication and subsequent hangover. Moreover, unlike ethyl alcohol, tianeptine consumption is not associated with marital breakdown and crimes of violence. Tianeptine tends to reduce aggression.
Tianeptine is also useful for asthmatics. It's a fast-acting bronchodilator. There is a positive association between free serotonin in plasma and severity of asthma in patients undergoing asthma attacks. Tianeptine is the only licensed psychoactive agent known to reduce free serotonin in plasma. People with atopic allergies are also more prone to mood disorders. Indeed for pain-wracked alcoholic asthmatics with anxious depression, tianeptine may be considered a first choice of treatment.
To date tianeptine has been mercifully free from the moral panic that befell another useful psychoactive medication whose patent had expired (cf. amineptine). Thus despite tianeptine's unlicensed status, North Americans and UK residents can lawfully order it for personal use from overseas. Somewhat bizarrely, the Gulf state of Bahrain has designated tianeptine a controlled substance. Singapore has restricted its prescription to practising psychiatrists. But tianeptine is widely available on prescription in Europe, Latin America and Asia. It's increasingly sold globally over the Net via online pharmacies. For many people prefer to cast themselves in the role of autonomous healthcare consumers rather than as disempowered "patients" - a status that can lower the spirits of even the most psychologically robust.
As with all of today's psychoactive medicines, tianeptine doesn't work for everybody: perhaps up to a third of users don't appreciably respond, though the results of other studies are rosier. Tianeptine has been used by creative clinicians in a variety of antidepressant cocktails when monotherapy has failed. Melancholic depressives may do better on amineptine; inevitably a few users combine both, though controlled trials are lacking, and amineptine is now hard to obtain. Since melancholic depression is strongly associated with hypercortisolaemia, which tianeptine reverses, tianeptine may in fact offer comparable long-term protection against relapse and recurrence. Either way, anyone ploughing their way through the published literature might conclude that depressive illness is an impossibly complex disorder - or an inescapable part of the human predicament that will never be cured. Some "treatment-refractory" depressives do indeed remain chronically in despair despite being subjected to a dozen or more "antidepressants" over years or even decades. Undoubtedly, multiple different genes/allelic variants and signalling pathways are involved in mood disorders; and there are multiple sub-types of depression. In the ancestral environment, a conditionally-activated capacity for depressive behaviour may have been genetically adaptive, albeit personally tragic. But for contemporary humans, depression is personally maladaptive and pointlessly unpleasant. In the first decade of the 21st century, the neurogenic hypothesis of depression and antidepressant action is in the ascendant. Among researchers, the neurogenic paradigm is eclipsing variants of the older "monoamine hypothesis" dominant over the past forty years. Depression is increasingly conceptualised as a disorder of neuroplasticity, not just neurochemical "imbalance". Nevertheless the immediate pharmaceutical product pipeline of antidepressants isn't wholly encouraging. Most of the investigational drugs under commercial development are CRF1 antagonists, glucocorticoid receptor antagonists, NMDA glutamate receptor antagonists, "triple" monoamine reuptake inhibitors, and other agents designed to combat the depressogenic effects of chronic stress. Unfortunately, none of the new candidate treatments seriously promise to raise response-and-remission rates above the mediocre figures of the past few decades. The dysfunctional opioid system of many depressives is still off-limits. Moreover, currently proposed antidepressant mechanisms might be more convincing in detail if the drugs used to elucidate them were actually reliably effective antidepressants in human beings as well as tormented rodents. Thus SSRIs etc increase hippocampal neurogenesis, whereas mu and delta opioid receptor agonists decrease it; but it's debateable which category of agent is better classed as an antidepressant.
However, the future is bright. Like smallpox in the 20th century, depression can be abolished in the 21st. This bold claim may be less extravagant than it sounds. For the homeostatic mechanisms of unhappiness bequeathed by evolution can be dismantled and replaced as the biotech revolution unfolds. Common to all forms of depression is inadequate stimulation of the mesolimbic pleasure centres of the brain. Sustained activation of the reward pathways is 100% effective at defeating depressive illness. Unlike "drugs of abuse", direct neurostimulation exhibits no physiological or psychological tolerance; pure pleasure never palls. So the medical and ethical challenge ahead is to devise pharmaceutical and autosomal gene therapies that avoid the social taboo against wireheading - or the risk of uncontrolled mania - while delivering high-functioning and socially responsible well-being over a lifetime. More controversially, prospective parents in the era of post-genomic reproductive medicine will need to choose whether they want to produce babies genetically susceptible to mood disorders at all. In future, responsible parents may opt to ensure the heritable well-being of their offspring via germline therapy. Our hedonic "set-point" can be genetically raised. Inevitably, advocacy or prediction of hedonic enrichment across the lifespan invites emotive talk of "designer babies". For aren't such scenarios a recipe for "Brave New World"? Yet ethically, are the cruelties of human reproduction via genetic roulette really preferable to lifelong mental super-health? It's worth recalling that the idea of painless surgery was once judged hopelessly utopian too.
The 20th century antidepressant tianeptine is no wonderdrug. Historically, it may be remembered as a very minor player; its use offers only a crude chemical stopgap on the route to a suffering-free world. But tianeptine is still a unique and valuable mood-brightener whose neglect by Anglo-American psychiatry is ill-deserved.
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further reading about tianeptine
THE GOOD DRUG GUIDE
Tianeptine (sodium salt)
Another Tianeptine source
International Pharmacies 2018
World Transhumanist Association/H+
Tianeptine (Stablon): product info from manufacturer