With the gradual acceleration of the pace of people’s lives and increasing mental stress, the incidence of depression is rapidly rising and is expected to become the 2nd most common disease in the world after coronary heart disease by 2020 [1]. The disorder is characterized by an affective mental disorder as the main type of presentation, with persistent and significant depressed mood as the main feature. It is characterized by symptoms such as little speech, low mood, mental and motor retardation, and even suicide attempts. The pathogenesis of the disorder is unknown, but it may be related to the reduction of central norepinephrine (NE) and 5-hydroxytryptamine (5-HT) monoamine neurotransmitters and the down-regulation of their receptor functions induced by genetic and neuroendocrine factors, and pharmacological treatment is still the main method. This paper reviews the current status of pharmacological treatment.
1. monoamine oxidase inhibitor (MAOI)
MAOI is a class of drugs that specifically inhibit the activity of MAO in the body, and was first used to treat depression in the 1950s. Its mechanism is to reduce the degradation of monoamine neurotransmitters in the central nervous system by inhibiting MAO, which relatively increases the concentration of central monoamine transmitters and enhances mood and produces antidepressant effects. MAOIs can be classified into 3 categories based on their selectivity for enzymes. ① Non-selective MAOI (MAOI-AB): These drugs have inhibitory effects on both MAO-A and MAO-B at low doses, and their representatives are hydrazine MAOIs, such as isocarbohydrazide, phenelzine, cycloamphetamine, nialamide, etc. Because of the low selectivity of this class of drugs, there are many side effects. At present, only isocarbohydrazide (isocarboxzine, boring cola) is still in clinical use. ②A-type MAOI (MAOI-A): This class of drugs can selectively inhibit the activity of MAO-A at low doses, and its representative drugs are aromatic MAOI moclobemide (moclobemide, Lantian) and toloxadone (toloxatone). It has the characteristics of fast enzyme inhibition and fast recovery of MAO activity after discontinuation, and has good antidepressant effect clinically. The side effects are similar to MAOI-AB, but the degree is mild and the incidence is low. (3) Type B MAOI (MAOI-B): The representative drug is selagiline (selagiline), which belongs to the aromatic amine class and is a newly marketed MAOI in recent years. these drugs selectively inhibit the activity of MAO-B at low doses and inhibit the activity of MAO-A and MAO-B at medium to high doses. Due to the lesser effect on peripheral MAO-A, their side effects are milder, and their clinical application is safer and more efficacious than traditional drugs, and they do not cause case reaction [2].
2. tricyclic antidepressants (TCA /Tetracyclic antidepressants)
The mechanism of action is to inhibit the reuptake of NE and 5-HT in the presynaptic brain and to increase the concentration of NE and 5-HT in the synaptic gap. The representative drugs are promethazine, amitriptyline, doxepin, clomipramine of tertiary amines and norethindrone and nortriptyline of secondary amines. Although they are effective in depressive disorders, their application is more limited in patients with depression. The main reason is that TCA has poor selectivity for NE and 5-HT reuptake, high affinity for CNS muscarinic cholinergic receptors and histamine receptors, and is prone to upright hypotension, arrhythmias, urinary difficulties, cognitive dysfunction and other toxic side effects. Although the new tetracyclic antidepressants maprotiline and mianserin have improved the safety and tolerability of depression in recent years [3], they cannot avoid being replaced by drugs with better efficacy and fewer adverse effects.
3. selective serotonin reuptake inhibitor (SSRI)
The SSRI fluoxetine, first introduced by Eli Lilly and Company in the 1980s, became a milestone in the treatment of depression and led to a breakthrough in antidepressant treatment. This class of drugs has less effect on choline, dopamine (DA) and NEergic nerves, but is highly selective for 5-HT. SSRIs should not be used in combination with MAOIs, as this may lead to 5-HT syndrome. When an MAOI is needed, the SSRI should be discontinued for more than 2 weeks, and vice versa at least 1-5 weeks apart. The following SSRIs are currently used in clinical practice, and although their chemical structures are not identical, their pharmacological characteristics are similar. Fluoxetine (Prozac): The oral dose is 20-40 mg per day, with a maximum of 80 mg, which is particularly suitable for elderly patients with depression because of its low impact on the function of internal organs. Paroxetine (Seroxate): 20mg per dose, taken once daily in the morning. 2-3 weeks later, the dose can be increased by 10mg, and should not exceed 50mg per day. 40mg per day for elderly patients. The maximum dose should not exceed 60mg per day, taken in the morning or evening. Side effects are less frequent, mainly sweating, drowsiness, dry mouth, nausea and vomiting, and other mild symptoms [4]. Sertraline (Setraline, Zoloft): 50-10 mg daily in the morning and gradually increase to 200 mg after a few weeks depending on the condition. it has no significant anticholinergic effect due to less interaction with P450 enzyme system and can improve cognitive function and quality of life, which is especially suitable for elderly patients [5]. ⑤ Fluvoxamine (fluvoxamine, luvox, lanrelease): it is taken at bedtime, and 100 mg per night is its regular dose. It has no anticholinergic and antihistamine effects, no excitatory or sedative effects, and no effect on MAO, and can effectively treat various types of depression. (6) Escitalopram (Escitalopram, Lexapro, Lexapro): the starting dose is 10 mg once daily, which can be increased to 20 mg once daily by mouth in the morning or evening after 1 week, depending on the condition. A meta-analysis [6] concluded that escitalopram is more effective than citalopram, mainly in terms of rapid onset of action, with significant efficacy in about 1 week, more pronounced symptom improvement, and better remission rate and efficiency.
4. Selective NE reuptake inhibitor (NARI, NRI)
NARI has a significant blocking effect on NE reuptake in the presynaptic membrane of the central nervous system, but does not affect 5-HT reuptake, so that the function of the NE system is restored to balance. It is indicated for various depressive disorders. The first fully clinically significant NARI is Reboxetine (Yero loom). It exerts antidepressant effects by inhibiting the reuptake of NE by the presynaptic membrane of neurons and enhancing the NE function of the central nervous system. The drug has weak anticholinergic activity, little affinity for 5-HT and other brain receptors, no sedative effect, and no effect on cognitive function. Data [7] indicate that the antidepressant treatment is well tolerated, has a low relapse rate, and is safe and effective. Side effects are few and commonly include dry mouth, constipation, sweating, insomnia, fatigue, and vertigo.
5. selective serotonin and noradrenaline reuptake inhibitor (SNRI )
SNRIs are dual inhibitors of 5-HT and NE reuptake, and studies have shown [8] that SNRIs with dual action are more characteristic than single-action antidepressants. The representative drugs are: ①Vanlafaxin (venlafaxin, venlafaxine) has little affinity for M1 cholinergic, histamine H1 and adrenergic receptors, so it has fewer adverse effects and has a faster clinical onset of action due to its rapid downregulation of β receptors. It can be used clinically for depression, anxiety and obsessive-compulsive disorder. It is available in both immediate-release and sustained-release formulations. Sustained-release formulations have a slower release in the gastrointestinal tract, less fluctuation in blood levels, fewer side effects, and better treatment compliance than immediate-release formulations. Adults take 75 mg of oral venlafaxine extended-release daily, which can be increased to 150 mg daily within 1 week according to the condition, with a maximum dose of 225 mg daily, and the dose is reduced in the elderly or those with hepatic or renal insufficiency. A meta-analysis [9] showed that vanlafaxine has a shorter healing time and a higher healing rate than SSRIs. Adverse effects are less common and can be seen as nausea and dry mouth, dizziness, sleep disturbance and hypersensitivity. ②Milnacipran inhibits the reuptake of both 5-HT and NE neurotransmitters with almost equal intensity, and increases the extracellular level of NE in vivo. It also has no effect on DA reuptake and cholinergic receptors. Adults take 100-200 mg orally daily in 2 divided doses; elderly people and patients with impaired renal function require lower doses. Clinical data suggest [10] that milnacipran can be used not only for the acute and maintenance treatment of depression, but also for the treatment of chronic pain syndromes. In terms of adverse effects, except for tremor and dyspareunia, there is no drowsiness, fatigue and anticholinergic effect common to TCA class, and the side effects such as gastrointestinal nausea and vomiting are less than those of SSRI class. The FDA approved the drug in August 2004 for the treatment of major depression and in September of the same year for the treatment of peripheral neuropathy in diabetic patients, while the drug was approved in Europe for the treatment of stress urinary incontinence. The drug has a strong inhibitory effect on the reuptake of 5-HT and NE, significantly increasing the concentration of 5-HT and NE in the brain and spinal cord and improving the symptoms of depressed patients. It also increases the role of 5-HT and NE in regulating emotion and sensitivity to pain, resulting in increased somatic tolerance to pain. In addition it stimulates pubic motor neurons adrenergic α1 and 5-HT2 receptors, increases bladder function and electrical activity of urethral striated muscles, and increases the level of sphincter contraction to prevent urinary leakage. Trials have demonstrated [11] that duloxetine inhibits the absorption and transit binding process of 5-HT and NE, which is more effective than vanlafaxine therapeutically, and that the therapeutic effect is more rapid. Side effects include nausea, loss of appetite, dry mouth, drowsiness, insomnia, dizziness, constipation and fatigue, which are mild to moderate and disappear in about a week.
6. NE and DA reuptake inhibitor (norepinephrine and dopamine ruptake inhibitor, NDRI)
The representative drug of NDRI is bupropion [12] (bupropion, bupropion, bupropion,), which is a monocyclic aminone structure with a chemical structure similar to that of the psychostimulant amphetamine. It exerts antidepressant effects by inhibiting the reuptake of DA and NE and increasing the function of DA and NE in the central nervous system. It has no anticholinergic or 5-HT reuptake inhibitory effects. The regular daily oral dose for adults is 300mg-450mg in 3 divided oral doses for regular tablets and 2 divided oral doses for extended release tablets. The drug has good efficacy in depressed patients with somatic disorders or refractory depression and other depressive disorders, comparable to that of SSRIs, reducing relapse and improving quality of life [13]. This drug is also used for smoking cessation, reducing the desire to smoke and withdrawal symptoms. Severe side effects of regular tablets include seizure-like epileptic seizures, and other common ones include headache, dry mouth, constipation, tremor, sweating, and insomnia. The side effects of extended-release tablets are relatively mild and no serious adverse effects have been observed.
7. 5-HT antagonist and reuptake inhibitor (SARI)
This class of drugs has a dual effect of 5-HT antagonist and reuptake inhibition, and its antidepressant effect is comparable to TCA and SSRI, and has certain advantages in improving depression with anxiety, insomnia, decreased libido, etc., and is more widely used in clinical practice. The representative drugs are trazodone and nefazodone. It is not only an effective antidepressant, but also a good hypnotic and anxiolytic, and has a good therapeutic effect on erectile dysfunction. The drug can inhibit the reabsorption of 5-HT, and its metabolite m-chlorophenylpiperazine (mCPP) has antagonistic effects on 5-HT, and the two effects together produce antidepressant effects [14]; in addition, it can selectively block H1 and adrenergic α1 receptors, so it has a good sedative effect; in addition, it can also block adrenergic α2 receptors, which significantly increases the hardness and duration of erection. The starting oral dose for adults is 50-100mg/day, divided into 3 oral doses. Increase by 50mg/day every 3-4 days. Generally 50-100mg/day for improving sleep; 50-150mg/day for anti-anxiety; 150-400mg for anti-depression; and 100-200mg/day for impotence. Side effects are less frequent and milder than TCA and SSRI, including headache and dizziness, tinnitus and drowsiness, dry mouth and constipation, tremor and abnormal penile erection. ②Nefazodone (NEF) is a chemically synthesized phenylpiperazine derivative, whose chemical structure is similar to that of trazodone. It has the function of inhibiting the reabsorption of 5-HT, inhibiting the action of 5-HT1A and 5-HT2A receptors and blocking the postsynaptic 5-HT receptors, producing antidepressant and relieving symptoms of anxiety and insomnia. Its antidepressant active ingredients are NEF, nefazodone hydroxychloride (OH-NEF) and mCCP. adult therapeutic doses range from 200-500 mg in 2 divided doses, usually increased to the therapeutic dose within 10 days. the starting dose for people over 65 years of age is 50 mg twice a day. Adverse reactions are minor, mainly nausea and vomiting, headache and dizziness, with no significant effect on the heart, liver and kidney.
8. NE and specific 5-HT antidepressant (noradrenergic and specific serotonergic antidepressant, NaSSA)
NaSSA is a new class of antidepressants developed in recent years, with a dual mechanism of strengthening NE and 5-HT neurological function. The representative drug is mirtazapine (mirtazapine, Rmeron, Remeron), the first NaSSA in the world, which belongs to the piperazine-azepine class. The drug can block the α-adrenergic receptors on the cell bodies of NEergic neurons and nerve terminals, which can enhance the firing activity of NEergic neurons terminals and promote the release of NE from NEergic neurons terminals; in addition, it also increases the release of NE by blocking the α2-adrenergic receptors of NEergic neurons, and NE acts on the α1-adrenergic receptors on the cell bodies of 5-HTergic neurons, which leads to the 5-HTergic neuronal firing is enhanced and 5-HT release is increased. Ultimately, the antidepressant effect is exerted through the above unique dual mechanism of action [15], which is the main reason for the faster onset of action of this drug. Mirtazapine also produces anxiolytic effects by selective excitation of 5-HT1 receptors and blocks 5-HT2 and 5-HT3 receptors, thus avoiding the adverse effects of insomnia and sexual dysfunction. Mirtazapine is characterized by rapid onset of action, good tolerability, broad antidepressant spectrum, as well as anxiolytic and sleep improving effects, and is suitable for various depressive disorders. The starting oral dose for adults is 15mg per day, and the effective dose is usually 15-45mg, which is suitable to be taken in one dose at night. Adverse effects may include dry mouth, sedation, drowsiness, increased appetite and weight gain.
9.5-HT reuptake agonist (selective serotonin reuptake accelerator SSRA)
As research into the pathogenesis of depression continues, it has progressed from the monoamine hypothesis theory to the neuroplasticity theory. The monoamine hypothesis suggests that depression occurs due to decreased levels of NE and 5-HT in the synaptic gap of the brain, and drugs produced under this hypothesis to increase NE and 5-HT in the synaptic gap have produced undeniable efficacy in clinical applications. However, in recent years, it has been found that drugs that do not increase or decrease synaptic NE and 5-HT levels also have strong antidepressant efficacy, suggesting that depression may be caused by instability or even excess of synaptic NE and 5-HT. Tianeptine (Tianeptine, Tatinol, Daptilan) is its representative drug. The antidepressant mechanism is the exact opposite of SSRI. The drug promotes the reuptake of synaptic gap 5-HT, reduces the level of synaptic gap 5-HT, increases the catabolism of intra-neural 5-HT, and elevates the 5-HT metabolite 5-hydroxyindoleacetic acid [16]. In addition neuroplasticity theory suggests that the drug regulates dendritic remodeling in hippocampal and amygdala cells, blocks dendritic atrophy in hippocampal neurons, and enhances functional regulation of the hippocampus. These special pharmacological effects of tianeptine make it produce good antidepressant effects in clinical practice with significantly less adverse effects than tricyclic antidepressants. The drug is not only suitable for various depressions, but also effective for post-abstinence depression and depressive neurosis. And long-term application can prevent depression relapse. The oral dose for adults is 12.5 mg three times a day. No dose adjustment is necessary for patients with chronic alcoholism, but the dose should be limited to 2 times daily for renal insufficiency and the elderly. It is well tolerated by patients, and the adverse effects are only mild insomnia, drowsiness, tremor and dry mouth, with no effect on sexual function.
10. selective serotonin receptor accelerant (SSRA)
The representative drug of SSRA is tandospirone (Tandospirone, Xidexing), which belongs to the class of azospirone. It is mainly used clinically as anxiolytic and, to a lesser extent, antidepressant [17]. The drug selectively binds to 5-HT1A receptors in the hippocampus, amygdala and other parts of the limbic system of the brain, as well as the septal nucleus, which projects 5-HTergic nerves, agonizes 5-HT1A self-receptors, regulates 5-HT projecting from the septal nucleus to the hippocampus, inhibits 5-HTergic nerve activity, and exerts anxiolytic effects. The mechanism of its antidepressant effect is due to the significant downregulation of 5-HT1A receptors after long-term application of tandospirone, and it has also been shown in animal tests that tandospirone can inhibit aggressive behavior in rats with destroyed septal nucleus, which also suggests that the drug has antidepressant effect. The oral dose for adults is 30mg or 60mg per day in 3 divided doses. The dose should be reduced for hepatic and renal insufficiency and the elderly. It is well tolerated by patients, and the incidence of adverse reactions is low and mild. The main ones are drowsiness, tremor, nausea, staggering gait and lethargy.
11. Other antidepressants
①Tianeptine (Dianeptine) [18] is a new formulation that can exert both anxiolytic and antidepressant effects, which is a combination of trifloxystrobin dihydrochloride 0.5 mg and tetramethyl anthranilamide 10 mg. Trifluthione belongs to the class of thiacetin, which is a dopamine receptor antagonist and has antagonistic effects on postsynaptic dopamine D1 and presynaptic dopamine D2 receptors at high doses. However, at low doses, it has no effect on the postsynaptic membrane, but only blocks D2 receptors in the presynaptic membrane, promotes the synthesis and release of dopamine, and increases the amount of dopamine in the synaptic gap, thus achieving antidepressant and anxiolytic effects. Tetrazolium anthranilamide is a novel cyclic drug that acts on the presynaptic membrane to inhibit the reuptake of presynaptic membrane monoamine oxidase-like neurotransmitters, increasing the content of NA and 5-HT in the synaptic gap and producing antidepressant effects. In addition tetramethylphenidate counteracts the extrapyramidal symptoms produced by trifloxystrobin. The synergistic and combined action of the two active ingredients of the drug simultaneously acts on the three neurotransmitters associated with anxiety and depression, resulting in a further increase in synaptic gap neurotransmitters, enhancing the antidepressant effect, shortening the onset of action and reducing adverse effects. It can be taken once or twice a day; it can be stored at room temperature for easy storage and transportation. The price is suitable and the daily treatment cost is lower among similar imported drugs. Side effects may include dry mouth, insomnia, nausea, etc. ②Luvotide (Neurostan, Sait John’s Wort Extracts, SWE, St. John’s Wort Extracts) is an extract of the pure natural plant St. John’s Wort. Each tablet contains 300mg of St. John’s wort extract, including 9mg of hyperforin, 0.36-0.84mg of hypericin and pseudohypericin, and other components such as flavonol glycosides. Lutet has a significant inhibitory effect on 5-HT, NE and DA in the central nervous system, increasing the concentration of the 3 neurotransmitters in the synaptic gap and maintaining a balance of the reuptake inhibition of these 3 systems. In addition, it also down-regulated the density of adrenergic β receptors in the presynaptic membrane, which reduced the opportunity for the 3 neurotransmitters to bind to adrenergic β receptors in the presynaptic membrane and increased the synthesis and release of the 3 neurotransmitters in a feedback manner. It also inhibits MAO-A and MAO-B at high doses. The oral dose for adults is 300 mg three times daily. It is well tolerated by patients and has a low incidence of adverse effects. The main ones are headache, nausea, and lethargy [19]. (3) S-adenosyl-L-methionine (S-adenosyl-L-methioine, SAM, AdoMet, S-Amet) is a sulfonyl compound of the organic tetravalent sulfur form of methionine (Methioine, Met), which is widely found in various organisms and is an important active substance in the body, which is synthesized in living organisms from methionine and ATP via SAM It is synthesized by methionine and ATP via SAM synthetase. It has the function of trans-methyl, trans-sulfur and trans-aminopropyl. It is a precursor of cysteine, taurine, glutathione, coenzyme A and other important substances. Involved in more than 40 biochemical reactions in living organisms. The drug appeared in the European market as early as the 1970s, when it was mainly used for the treatment of arthritis; in 1973, SAM was clinically found to have antidepressant effects; after the 1990s, it gradually turned to the research and treatment of liver diseases. 2000 saw the entry of SAM into our market. It is because SAM has such complex and important biochemical reactions that it has shown multifaceted therapeutic effects in clinical practice. Not only is it effective in arthritis, liver dysfunction and depression, but it is also an advanced health drug for the prevention of cancer, cardiovascular and cerebrovascular diseases as well as anti-aging.The mechanism of SAM antidepressant Most studies agree [20] that SAM, as a methyl donor of neurotransmitters, determines the synthesis and activation of adrenaline, noradrenaline, dopamine, 5-hydroxytryptamine and histamine, which control emotional responses. SAM promotes the metabolism and conversion of epinephrine, norepinephrine, dopamine, 5-hydroxytryptamine and histamine, increasing their concentrations and producing antidepressant effects. The regular oral dose for adults is 200-400 mg three times a day. Clinical observations have shown that SAM is well tolerated by patients, has no significant anticholinergic or hepatotoxic effects, and has a rapid onset of action, with some patients experiencing improvement in symptoms within 1 week and most producing effects within 2 weeks. The only side effects seen were mild dry mouth, nausea, anorexia, constipation, insomnia, sweating and dizziness.