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Treatment of Depression Magdalena Burat* , Ewa Gibula-Tarlowska , Ewa Kedzierska

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Treatment of Depression Magdalena Burat* , Ewa Gibula-Tarlowska , Ewa Kedzierska DOI: 10.2478/cipms-2020-0036 Curr. Issues Pharm. Med. Sci., Vol. 33, No. 4, Pages 177-183 Current Issues in Pharmacy and Medical Sciences Formerly ANNALES UNIVERSITATIS MARIAE CURIE-SKLODOWSKA, SECTIO DDD, PHARMACIA journal homepage: http://www.curipms.umlub.pl/ Different molecular targets, one purpose – treatment of depression Magdalena Burat* , Ewa Gibula-Tarlowska , Ewa Kedzierska Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Poland ARTICLE INFO ABSTRACT Received 12 January 2020 Although vast scientific progress has been made, the current pharmacotherapy Accepted 04 December 2020 of depression is still not fully effective. In adults, depressive disorders are among the Keywords: most common diseases in industrialized countries, impact upon all aspects of family and depression, working life and significantly disturb social functioning. Moreover, increasingly, they antidepressants, affect children and teenagers. atypical mechanisms, novel strategies. Depressive disorders have a complex etiology. This includes a number of mechanisms that are not yet fully understood. Therefore, the current review concentrates on bringing to the foreground the many molecular areas involved in occurrence of this disease. The work highlights the notion that depression has a complex pharmacology and inevitably requires the adoption of individual pharmacotherapy. This manuscript concentrates on currently used drugs drawn from diverse therapeutic groups and presents new promising targets for the treatment of depression. This is a particularly important issue due to the continuous lack of effective therapy and the constant search for new drugs and molecular targets for its treatment. INTRODUCTION Depression and its accompanying symptoms are a – especially of monoamines, such as serotonin (5-HT), common cause of disability in the world. It is estimated norepinephrine (noradrenaline, NA) and dopamine (DA). that, globally, they strike down almost 350 million people It is emphasized that inappropriate transmission through – a figure that is growing. Indeed, according to WHO, in glutamatergic receptors also leads to depressive symptoms. 2030, depression will affect a higher percentage of patients Additionally, genetic factors may determine the inheritance than heart diseases. Despite the wide access to a large group of this disease from generation to generation. Furthermore, of drugs, not all patients respond to current treatment [1]. previous studies have uncovered a correlation between the A mental illness, depression manifests itself in low mood, decrease of brain-derived neurotrophic factor (BDNF), nerve anhedonia and a decrease in psychomotor drive. Addition- growth factor (NGF) and neurotrophin-3 (NT-3) concentra- ally, it is characterized by gastrointestinal problems (heart- tion and depression. These factors belong to the class of neu- burn, bloating, loss of appetite), fatigue, insomnia and palpi- rotrophins, which may modulate monoamines levels. Several tations. It should be also emphasized that in extreme cases, other theories on the origins of depression include hyperac- the patient’s life may be endangered since most suicide inci- tivity of the hypothalamic–pituitary–adrenal (HPA) axis or dents are thought to be caused by depression. Moreover, an increase in pro-inflammatory cytokines level, especially the initial symptoms of depression – abdominal pain or tumor necrosis factor α (TNF-α) and interleukins (ILs). Each headache – are a source of mistakes in diagnosis, not only theory explains certain pharmacological targetable aspects among patients, but also in the medical community [2,3]. of the mechanisms of depression, and advances the need for There are various theories explaining the causes of new therapeutic substances [5,6]. depression. Apart from personal risk factors (including trau- Research into depression highlights the limitations of matic experiences), many pathological changes in the human currently available antidepressants, including the significant body are observed [4]. The basic concept of depression latency for treatment response and modest rates of efficacy. etiology is based on the dysfunction in neurotransmission Additionally, studies underline the concern that the most commonly used agents require several weeks to months of * Corresponding author administration before a therapeutic response is observed. e-mail: [email protected] Beyond the aforementioned, it is stressed that only one-third © 2020 Author(s). This is an open access article distributed under the Creative Commons Attribution-NonComercial-No Derivs licence (http://creativecommons.org/licenses/by-nc-nd/3.0/) 177 Different molecular targets, one purpose – treatment of depression Magdalena Burat, Ewa Gibula-Tarlowska, Ewa Kedzierska Different molecular targets, one purpose – treatment of depression of patients respond to the first prescribed antidepressant and another one-third will only respond following multiple trials that can take many months to years. Importantly, it should be emphasized that approximately one-third of all individuals diagnosed with depression fail to respond to two or more first line antidepressant treatments and need individual multi drug therapy [1,3]. Frequently, depression also co-occurs with other diseases, Figure 1. Synthesis of serotonin [10] i.e. cardiovascular, diabetes, Alzheimer’s and Parkinson’s, having a disadvantageous effect on their therapeutic process. However, 5-HT is not the only neurotransmitter involved Additionally, along with the deterioration of the patient’s in the mechanisms of depression. Studies have indicated that mental state, he or she will fail to follow therapeutic recom- NA and DA catecholamines also have a significant role in mendations, which may reduce recovery rate [7]. its pathogenesis. Researches demonstrate that noradrenergic Understanding the pathophysiology of depressive and dopaminergic pathways are closely related to the sero- disorder has progressed considerably, but it is well known tonergic, and drugs activating these systems are effective that no single mechanism is involved in this process. in the treatment of depression. Therefore, the objective of Moreover, there is a particular need for novel treatment antidepressant therapy, through monoamine system modula- options. Therefore, we briefly review currently available tion, is to increase the neurotransmitter concentration in the pharmacological treatment strategies and emerging targets synaptic cleft through various mechanisms [11,12]. for antidepressant drug discovery. 1.1 Monoamine reuptake inhibitors MATERIALS AND METHODS The low concentration of amine in the synaptic cleft may be modulated in different ways. Drugs may inhibit A literature search was performed using PubMed, Google specific proteins transporting the neurotransmitters (reuptake Scholar, Scopus and Web of Science databases (the time carriers), i.e. the serotonin transporter (SERT), NA trans- frame of the literature: 1995-2020). Structural formulas were porter (NET) and DA transporter (DAT). As a result, the independently developed on the basis of drugbank sites with monoamines persist longer in the synaptic cleft and have IUPAC names. a therapeutic effect on the human body by enhancing acti- vation of postsynaptic receptors [13]. At first, tricyclic 1. MODULATION OF MONOAMINERGIC antidepressants (TCAs) were the foundation of antidepres- NEUROTRANSMISSION sant therapy. Unfortunately, they possess a non-selective The most common theory focuses on the monoamine mechanism of action, because they inhibit reuptake of both hypothesis of depression. It assumes that monoamine neu- catecholamines and 5-HT, and additionally modulate the rotransmitter deficiency is the cause of this disease [5]. In effects of many receptors, including adrenergic, cholinergic fact, there is a huge amount of data supporting the view and histamine (not involved in depression therapy). Such that 5-HT (in particular) and catecholamines-containing wide receptor activity possesses the risk of inducing many neuronal systems are altered in depressed patients. Pres- adverse effects such as increased body weight, dizziness, dry ently, it is known that at least seven distinct serotonergic mouth, sleepiness or constipation. Newer drugs are charac- receptor classes are distributed throughout the body with terized by higher selectivity against one neurotransmitter. stimulatory (5-HT2, 5-HT3, 5-HT4, 5-HT6, 5-HT7) and inhibi- They may inhibit double NA and serotonin (SNRI), only tory (5-HT1, 5-HT5) effects. Each receptor class has a proper norepinephrine (NARI), only serotonin (SSRI) or only DA subclass, and their large number indicates a great commit- reuptake (Table 1) [14-16]. ment to the body’s regulatory processes [8,9]. 5-HT is responsible for daily rhythm, mood, Table 1. Groups of drugs belonging to specific antidepressants [14-17] memory and psychomotor drive. The synthesis Mechanism Nonselective (TCAs) Selective NA/5-HT NA 5-HT DA/NA Imipramine process consists of two steps. Initially, a hydrox- (SNRI) (NARI) (SSRI) (NDRI) Desipramine Citalopram ylation process occurs, catalysed by tryptophan Nortriptyline Escitalopram Drugs Amitriptyline Venlafaxine Maprotiline Fluoxetine hydroxylase (TPH). A short-lived intermediate Clomipramine Duloxetine Bupropion Reboxetine Fluvoxamine Opipramol Milnacipran product of this reaction is 5-Hydroxytrypto- Paroxetine Dibenzepin phan (5-HTP). Subsequently, a decarboxylation Sertraline reaction with relatively nonspecific aromatic
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