Choosing an antidepressant based on effectiveness and tolerability

Depression is one of the most common diseases. In terms of prevalence, it is second only to cardiovascular diseases. And of all those suffering from depression, only no more than 20% seek qualified help.

In this article we will tell you about all the drugs used to treat depression.

All medications with antidepressant effects can be divided into several groups:

1. Antidepressants.
2. Normotimic drugs.
3. Neuroleptics.
4. Tranquilizers.
5. Nootropics and metabolic agents.
6. Herbal remedies.
7. Amino acids.
8. Psychostimulants.

Normotimic drugs

Medicines in this group have an antidepressant effect only in cases where the depressive state is caused by chronic affective diseases, such as bipolar affective disorder (BD, manic-depressive psychosis), cyclothymia, dysthymia, schizoaffective disorder. Most commonly used medications:

• Carbamazepine (finlepsin)
• Depakine chrono
• Lamotrigine (Lamictal)
• Lithium carbonate

Neuroleptics

Despite the fact that most antipsychotic drugs depress the nervous system, among them there are drugs with antidepressant effects:

• Flupenthixol (fluanxol).

  It has an antidepressant effect only when administered in small doses (less than 2 mg per day).

• Aripiprazole.

  Effective for depression in bipolar affective disorder and schizitypal disorders.

• Levomepromazine (tizercin).

  Prescribed for endogenous depression accompanied by insomnia.

PsyAndNeuro.ru

Major depressive disorder (MDD) is a serious psychiatric syndrome with high prevalence and socioeconomic impact. The most common antidepressants act at the level of blockade of serotonin transporters (5-hydroxytryptamine, 5-HT) and/or norepinephrine. These drugs exhibit slow onset of clinical effect and limited efficacy, in part due to the activation of physiological negative feedback mechanisms operating through autoreceptors (5-HT1A, 5-HT1B, α2-adrenergic receptors) and postsynaptic receptors (eg, 5-HT3) (Figure - 1).

Figure 1 - Schematic representation of the total effect of antidepressants that inhibit SERT (serotonin transporter) (TCAs, SSRIs, SSRIs) on active (extracellular) 5-HT concentrations. Blockade of SERT in forebrain nerve terminals has a beneficial effect that is partially attenuated by a decrease in 5-HT release at axon terminals caused by activation of somatodendritic 5-HT1A autoreceptors in the midbrain raphe following SERT blockade in this region. Activation of terminal 5-HT1B autoreceptors also helps to reduce local 5-HT release. In addition, activation of postsynaptic 5-HT receptors may influence 5-HT release either directly or indirectly through GABA interneurons, or distally at postsynaptic structures projecting to the midbrain raphe nuclei in the prefrontal cortex. Therefore, activation of 5-HT1A receptors in pyramidal neurons and 5-HT3 receptors in GABA interneurons has a distal negative feedback on serotonergic activity, whereas activation of 5-HT2A or 5-HT4 receptors in pyramidal neurons has a positive effect on 5-HT neuron activity. and release of 5-HT. 5-HT3 receptors on GABA interneurons may also locally control 5-HT through activation of GABA-B receptors. The overall balance between positive and negative effects depends on the dose of antidepressant. Consequently, SSRI doses >10 times the clinically recommended dose increase active forebrain 5-HT concentrations, but clinically recommended doses do not result in such an increase and instead reduce 5-HT release below basal levels. Modified from Artigas et al . (2001).

As a result, clinically relevant doses of reuptake inhibitors increase extracellular (active) 5-HT concentrations in the midbrain raphe nuclei, but not in the forebrain, as demonstrated by rodent microdialysis studies and primate/human PET brain scan studies.

The study presents three main strategies for increasing the effectiveness and accelerating the development of antidepressant effects.

Prevention of self-inhibitory mechanisms by antagonists of the above receptors increases the preclinical and clinical effects of antidepressants. Consequently, the mixed β-adreno/5-HT1A antagonist pindolol accelerated and in some cases enhanced the clinical effects of selective serotonin reuptake inhibitors (SSRIs). This strategy was used to create two new multitarget antidepressants, Vilazodone and Vortioxetine , which combine 5-HT reuptake inhibition and partial 5-HT1A receptor agonism (Figure 2 ) .

Figure 2 - Schematic representation of the feedback between the medial prefrontal cortex (MPFC) and the dorsal and medial raphe nuclei of the midbrain (DS and MS, respectively), also indicating the main targets for Vilazodone and Vortioxetine. The axons of pyramidal neurons in the MPFC innervate the DS and MS and generate excitatory impulses mediated by AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) and NMDA on 5-HT neurons and GABAergic interneurons. In anesthetized rats, physiological stimulation of the MPFC primarily results in inhibitory responses of 5-HT neurons due to 1) excitatory effects on GABAergic raphe interneurons 2) self-inhibitory responses in 5-HT neurons mediated by 5-HT1A autoreceptors following excitation of releasing 5-HT ( Celada et al., 2001). In addition to blocking SERT, Vilazodone and Vortioxetine partially prevent activation of the 5-HT1A autoreceptor due to its partial agonistic nature, allowing for increased extracellular 5-HT in the forebrain region following SERT blockade. This action may also contribute to desensitization of 5-HT1A autoreceptors. In addition, Vortioxetine shows high affinity for other 5-HT receptors (5-HT1B, 5-HT1D, 5-HT3 and 5-HT7) with the highest affinity for 5-HT3 receptors. These receptors are expressed by a subpopulation of GABA interneurons located in cortical layers I-III. Blockade of 5-HT3 receptors reduces the level of GABA at the GABA-A and GABA-B receptors, which leads, respectively, to i) an increase in the activity of pyramidal neurons projecting to the monoamine nuclei of the brainstem (DS/MS, ventral tegmental area - VTA and locus coeruleus – GP (locus coeruleus)), which in turn return to the PFC (not shown for the VTA and GP in this figure) and ii) an increase in the release of 5-HT after a decrease in the effect on GABA-B receptors, probably located on the nerve 5-HT endings. In turn, serotonergic DS/MS neurons modulate the activity of MPFC pyramidal neurons through inhibitory 5-HT1A receptors and excitatory 5-HT2A receptors located on pyramidal and GABAergic neurons. Adapted from Artigas, 2015 and Riga et al., 2021.

Vortioxetine also shows high affinity for other 5-HT receptors, including excitatory 5-HT3 receptors located in cortical and hippocampal GABA interneurons. Blockade of 5-HT3 receptors by Vortioxetine increases the activity of pyramidal neurons in the prefrontal cortex, as well as the release of 5-HT from the cortex and hippocampus. It is premature to speculate whether these antidepressants will have a real advantage over currently existing ones. However, their development opened the way to a future of antidepressants based on the prevention of local and distal self-inhibitory mechanisms that attenuate the activity of monoamines.

The development of glutamatergic agents is a promising area of ​​antidepressant development given the antidepressant properties of the noncompetitive NMDA receptor antagonist ketamine. Its unique properties likely result from activation of AMPA receptor metabolite [(2S,6S;2R,6R)-hydroxynorketamine (HNK)] and mTOR (mammalian target of rapamycin) signaling (Figure 3).

Figure 3 - Scheme showing the proposed mechanism of antidepressant action of the non-competitive NMDA receptor antagonist, ketamine. ( BDNF – brain-derived neurotrophic factor, MPFC – medial prefrontal cortex, DS – dorsal raphe nucleus, MS – medial raphe nucleus).

These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and improve serotonergic transmission of nerve impulses along descending pathways to the raphe nuclei. This notion is supported by the reversal of the antidepressant-like effects of ketamine by inhibition of serotonin synthesis.

No method used previously has achieved such success after a single injection as ketamine. These observations have generated enormous interest in the neuropsychopharmacology community in preclinical and clinical settings to identify new directions in antidepressant development to overcome the limitations of monoamine drugs. Indeed, the clinical effects of ketamine challenge the suitability of the pharmacological targets and mechanisms on which current antidepressant development is based and indicate that faster and more effective antidepressants than monoamine reuptake inhibitors may be developed in the future.

Reviews existing evidence supporting the involvement of microRNAs in MDD and the preclinical use of RNA interfering (RNAi) strategies to target genes involved in the antidepressant response. Many microRNAs (miRNAs) have been associated with MDD, some of which, such as the miR-135 target gene, have been implicated in the antidepressant effect. Likewise, SSRI-conjugated small interfering RNA (siRNA) produces faster and/or more effective antidepressant-like responses. Intranasal administration of sertraline-conjugated small interfering RNA targeting 5-HT1A receptors and SERT produced much more rapid changes in pre- and postsynaptic antidepressant markers than did fluoxetine.

The use of interfering RNA strategies offers a series of advantages, such as the ability to target any protein-coding mRNA with short RNAs – such as microRNAs or small interfering RNAs – while avoiding non-specific drug action. This strategy may be particularly useful to modulate protein expression when adequate pharmacological agents are lacking and/or when the observed effects are required. However, the use of these strategies has two significant limitations, such as delivery of short RNAs to the brain and selective targeting of desired neuronal populations. The approach of delivering SSRI-conjugated small interfering RNA to 5-HT neurons via the intranasal route has been successful in addressing these two major problems, producing rapid and sustained antidepressant-like effects in rodents.

Author: Cherapkin E.S.

Sources:

1. Artigas F., Bortolozzi A., Celada P. Can we increase the speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies. Eur Neuropsychopharmacol. 2021 Apr; 28(4): 445-456.
2. Artigas F., Celada P., Bortolozzi A. Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies. Eur Neuropsychopharmacol. 2018 Apr; 28(4): 457-482.

Tranquilizers

• Bromodihydrochlorophenylbenzodiazepine (phenazepam).

  The drug of choice for neurotic conditions with depression and post-stress conditions. That is, in cases where short-term treatment is required.

• Clonazepam.

  Strong anti-anxiety and sedative effect. When taken for a long time it causes dependence.

• Alprazolam.

  Prescribed for anxiety and depression. Recommended for short courses (no more than 10 days) due to the risk of developing addiction and dependence.

Which antidepressant is better to buy?

The presented rating nominees differ in composition, natural or synthetic base, indications, contraindications. Also, each of them has a large list of advantages and minor disadvantages. Based on a comparative analysis of all stated selection criteria, the following conclusions can be drawn:

• Glycine is a cheap means of supporting the brain and central nervous system;
• Afobazole is a mild over-the-counter tranquilizer without addiction or risk;
• Calm formula Tryptophan - dietary supplement for any age, pregnant and lactating;
• Imipramine is a proven remedy with proven effectiveness;
• Fluoxetine is a new generation TCA without addictive effects;
• Spectra (Doxepin) - the most extensive list of therapeutic properties.

What to buy from all the above names - a modern or time-tested medicine for mental disorders - is decided only by the attending doctor. The rating is intended to narrow the search range and identify the strengths and weaknesses of different medications. In addition, most of the nominees are sold strictly according to a doctor's prescription.

Nootropics and Metabolic Aids

The remedies in this group help to get out of a depressive state that has developed against the background of stress, overwork, encephalopathy, the consequences of injuries and poisoning. By improving the blood supply to neurons and energy metabolism within cells, they contribute to the activation of cognitive functions and memory. The most effective drugs in this group:

• Phenibut
• Mexidol
• Aminalon (GABA)
• Piracetam (nootropil)
• Picamilon
• Pyriditol (encephabol)
• B vitamins.

Are there non-drug treatments for depression?

In addition to medications, there are many non-drug treatments for depression. These are psychotherapy, biofeedback therapy, diet therapy, physical therapy, exercise therapy, reflexology, light and color therapy, sleep deprivation, etc. Most often, a combination of several methods is used to treat depression. For example: psychotherapy + drug treatment, biofeedback therapy + psychotherapy, medication + diet therapy, etc.

You cannot prescribe or use medications on your own. If you or your loved one is faced with the problem of depression, you need to see a psychiatrist or psychotherapist! Only according to his recommendations can you use drugs. Self-medication is life-threatening!

Which brand of antidepressant is better to choose?

The first indicator of the quality and effectiveness of any medicine is the reputation of its manufacturer. Therefore, before moving on to the list of top sedatives, experts suggest briefly getting acquainted with the companies that presented the nominees. In 2021, the review included:

• MNPK Biotics LLC (Glycine) is a research and production medical complex that was founded in 1991. For 25 years of work, it is considered a leading manufacturer of original metabolite drugs. Is the first company to produce Glycine.
• Grocam GBL LLC (Stressovit) is a Polish pharmaceutical company that began its activities in 2008. The main goal is to provide the population with affordable but effective medicines to improve the quality of life.
• OJSC Pharmstandard-Leksredstva (Afobazol) is one of the largest pharmaceutical companies in Russia. Participates in the import substitution program, which means it aims to produce vital drugs available to domestic buyers. Founded in 1992.
• LEK dd (Persen) is a pharmaceutical company from Slovenia that has been developing and selling medicines since 1946. Since 2002, it became part of the largest company Sandoz. In addition to medicines, the brand offers cosmetic products, medical products, and veterinary drugs.
• JSC "Evalar" (Formula of Calm Tryptophan) is the largest manufacturer of dietary supplements in Russia. Founded in 1991. Products from Evalar occupy 17% of the dietary supplement market. The basis is taken from natural raw materials extracted in valuable protected areas of Altai.
• CJSC Pharmaceutical (Imipramine) is a drug manufacturer from Hungary that has been in this business for over 100 years. Included in the list of leading suppliers of generics in Central and Eastern Europe. The work is based on a combination of tradition and innovation.
• Federal State Unitary Enterprise "Moscow Endocrine Plant" (Amitriptyline) is a Russian pharmaceutical enterprise that has existed for over 60 years. Most of the medicines produced are widely used in endocrinology, cardiology, psychiatry, ophthalmology, etc. More than 70% of painkillers on the Russian market are produced by this plant.
• L. Pharma GmbH (Fluoxetine) is an Austrian pharmaceutical company engaged in the development, production, and sale of patented innovative drugs since 1988. In recent years, most of the attention has been paid to medications for the nervous and cardiovascular systems, and anesthetics.
• Novartis Farma , S. _ p . a . (Anafranil) is one of the official world leaders in the production of original prescription drugs, services and solutions for doctors and their patients. The main office is located in Switzerland, founded in 1996, the rest are dispersed in more than 140 countries. In terms of market share in Europe, it ranks 2nd.
• Ratiopharm (Spectra) is a pharmaceutical company from Germany, founded in 1974. It became famous for its effective and inexpensive generics, which are distributed in 35 countries around the world. It has been the standard of high quality and affordability for over 40 years.