Serotonin–norepinephrine–dopamine reuptake inhibitor


A serotonin–norepinephrine–dopamine reuptake inhibitor, also known as a triple reuptake inhibitor, is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. Monoamine structures contain a singular amino group linked to an aromatic ring by a chain of two carbons. SNDRIs prevent reuptake of these monoamine neurotransmitters through the simultaneous inhibition of the serotonin transporter, norepinephrine transporter, and dopamine transporter, respectively, increasing their extracellular concentrations and, therefore, resulting in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. SNDRIs were developed as potential antidepressants and treatments for other disorders, such as obesity, cocaine addiction, attention-deficit hyperactivity disorder, and chronic pain. The increase in neurotransmitters through triple reuptake inhibition has the potential to heighten therapeutic effects in comparison to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, reducing symptoms of depression and anxiety in people struggling with mental illness, as well as potentially combating other ailments such as those listed above.
However, increased side effects and abuse potential are concerns when using these agents relative to their SSRI and SNRI counterparts. Additionally, SNDRIs include the naturally occurring drug cocaine, a widely used recreational and often illegal drug for the euphoric effects it produces. Ketamine and phencyclidine are also SNDRIs and are similarly encountered as drugs of abuse. To a lesser extent, MDMA also acts as a SNDRI.

Indications

Depression

is the foremost reason supporting the need for development of an SNDRI. According to the World Health Organization, depression is the leading cause of disability and the 4th leading contributor to the global burden of disease in 2000. By the year 2020, depression is projected to reach 2nd place in the ranking of DALYs.
About 5% of the population is estimated to be affected by depression, and in 2019, another 0.53% was affected by bipolar disorder. The ability to work, familial relationships, social integration, and self-care can all be severely disrupted by MDD. The presence of the common symptoms of these disorders are collectively called 'depressive syndrome' and include a long-lasting depressed mood, feelings of guilt, anxiety, poor concentration, a disturbance of sleep rhythms, severe fatigue, and recurrent thoughts of death and suicide. Over 700,000 people commit suicide each year worldwide, and people from age 15-29 are the demographic at the highest risk. Individual patients present differing subsets of symptoms, which may change over the course of the disease highlighting its multifaceted and heterogeneous nature. Depression is often highly comorbid with other diseases, e.g. cardiovascular disease, diabetes, and cancer. Depressed subjects are prone to smoking, substance abuse, eating disorders, obesity, high blood pressure, pathological gambling and internet addiction, and on average have a 15 to 30 year shorter lifetime compared with the general population.
Major depression can strike at virtually any time of life as a function of genetic and developmental predisposition in interaction with adverse life-events. The genetic contribution has been estimated as 40-50%. However, combinations of multiple genetic factors may be involved considering a defect in a single gene usually fails to induce the multifaceted symptoms of depression. Although common in the elderly, over the course of the last century, the average age for a first episode has fallen to around 18–24 years. However, depressive states are now frequently identified in adolescents and even children. The differential diagnosis and management of depression in young populations requires considerable care and experience; treatment can include therapy or institutionalization along with medication; SNDRIs could potentially become one of the drugs available to combat depression.

Pharmacotherapy

There remains a need for more efficacious antidepressant agents. Although two-thirds of patients will ultimately respond to antidepressant treatment, one-third of patients respond to placebo, and remission is frequently sub-maximal. In addition to post-treatment relapse, depressive symptoms can even recur in the course of long-term therapy. Also, currently available antidepressants all elicit undesirable side-effects, and new agents should be divested of the distressing side-effects of both first and second-generation antidepressants.
Another serious drawback of all antidepressants is the requirement for long-term administration prior to maximal therapeutic efficacy. Although some patients show a partial response within 1–2 weeks, in general one must reckon with a delay of 3–6 weeks before full efficacy is attained. In general, this delay to onset of action is attributed to a spectrum of long-term adaptive changes. These include receptor desensitization, alterations in intracellular transduction cascades and gene expression, the induction of neurogenesis, and modifications in synaptic architecture and signaling.
Depression has been associated with impaired neurotransmission of serotonergic, noradrenergic, and dopaminergic pathways, although most pharmacologic treatment strategies directly enhance only 5-HT and NE neurotransmission. In some patients with depression, DA-related disturbances improve upon treatment with antidepressants, it is presumed by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure.
Preclinical and clinical research indicates that drugs inhibiting the reuptake of all three of these neurotransmitters can produce a more rapid onset of action and greater efficacy than traditional antidepressants.
DA may promote neurotrophic processes in the adult hippocampus, as 5-HT and NA do. It is thus possible that the stimulation of multiple signalling pathways resulting from the elevation of all three monoamines may account, in part, for an accelerated and/or greater antidepressant response.
Dense connections exist between monoaminergic neurons. Dopaminergic neurotransmission regulates the activity of 5-HT and NE in the dorsal raphe nucleus and locus coeruleus, respectively. In turn, the ventral tegmental area is sensitive to 5-HT and NE release.
In the case of SSRIs, the promiscuity among transporters means that there may be more than a single type of neurotransmitter to consider as mediating the therapeutic actions of a given medication. MATs are able to transport monoamines other than their "native" neurotransmitter. It was advised to consider the role of the organic cation transporters and the plasma membrane monoamine transporter.
To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout mice and wild-type littermates were studied in the forced swim test, the tail suspension test, and for sucrose consumption. The effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support reevaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.
The SSRIs were intended to be highly selective at binding to their molecular targets. However it may be an oversimplification, or at least controversial in thinking that complex psychiatric diseases are easily solved by such a monotherapy. While it may be inferred that dysfunction of 5-HT circuits is likely to be a part of the problem, it is only one of many such neurotransmitters whose signaling can be affected by suitably designed medicines attempting to alter the course of the disease state.
Most common CNS disorders are highly polygenic in nature; that is, they are controlled by complex interactions between numerous gene products. As such, these conditions do not exhibit the single gene defect basis that is so attractive for the development of highly specific drugs largely free of major undesirable side-effects. Second, the exact nature of the interactions that occur between the numerous gene products typically involved in CNS disorders remain elusive, and the biological mechanisms underlying mental illnesses are poorly understood.
Clozapine is an example of a drug used in the treatment of certain CNS disorders, such as schizophrenia, that has superior efficacy precisely because of its broad-spectrum mode of action. Likewise, in cancer chemotherapeutics, it has been recognized that drugs active at more than one target have a higher probability of being efficacious.
In addition, the nonselective MAOIs and the TCA SNRIs are widely believed to have an efficacy that is superior to the SSRIs normally picked as the first-line choice of agents for/in the treatment of MDD and related disorders. The reason for this is based on the fact that SSRIs are safer than nonselective MAOIs and TCAs. This is both in terms of there being less mortality in the event of overdose, but also less risk in terms of dietary restrictions, hepatotoxicity or cardiotoxicity.

Applications other than depression

Approved pharmaceuticals

  • Mazindol — anorectic; ki is 50 nM for SERT, 18 nM for NET, 45 nM for DAT
  • Nefazodone — antidepressant; non-selective; ki is 200 nM at SERT, 360 nM at NET, 360 nM at DAT
  • Nefopam — analgesic, Ki SER/NE/DA = 29/33/531 nM)
  • Toludesvenlafaxine. Completed Phase 2 & 3 trials. FDA accepted NDA application. Approved in China.
Sibutramine is a withdrawn anorectic that is an SNDRI in vitro with ki values of 298 nM at SERT, 5451 at NET, 943 nM at DAT. However, it appears to act as a prodrug in vivo to metabolites that are considerably more potent and possess different ratios of monoamine reuptake inhibition in comparison, and in accordance, sibutramine behaves contrarily as an SNRI in human volunteers with only very weak and probably inconsequential inhibition of dopamine reuptake.
Venlafaxine is sometimes referred to as an SNDRI, but is extremely imbalanced with ki values of 82 nM for SERT, 2480 nM for NET, and 7647 nM for DAT, with a ratio of 1:30:93. It may weakly inhibit the reuptake of dopamine at high doses.