Introduction

All mental problems, including neurodegenerative diseases, occur due to external and internal factors like comorbid diseases (diabetes and angina), old age, societal pressure, loss of loved ones, malnutrition, genetic mutation, and drug use.¹ Globally, 3.8% of people are suffering from depression, as per the World Health Organisation (WHO). Depression is more common in females (43%) as compared to males (33%). An effective pharmacotherapy is available to mitigate this mental illness, which includes drugs like selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin/norepinephrine reuptake inhibitors (SNRIs), and atypical antidepressants like vilazodone.^2,3

Role of neurons and neurotransmitters in depression

Usually, all brain or nervous system disorders either directly or indirectly may influence levels of chemicals called neurotransmitters in or may trigger neuroglial cell activation. Among neuroglia, microglial cells are more commonly implicated in depression.⁴

Which types of neurotransmitters are involved in depression?

Altered levels of monoamines like norepinephrine (NE), serotonin (5-hydroxytryptamine or 5HT), and dopamine are implicated in depression.⁵

For example:

• 5-HT regulates sleep, appetite, and mood, and its imbalance may lead to depression⁵
• Dopamine is involved in reward processes, motivation, and confidence, with dopaminergic loss reducing pleasure and enjoyment⁵
• NE is released in response to stress and causes alertness, improves cognition, and motivation. NE loss leads to cognitive issues, restlessness, fatigue, and demotivation⁵

Where are these neurotransmitters present?

Different types of neurotransmitters are synthesised in multiple neurons.^6,7

For example:

• Dopamine is synthesised from tyrosine within dopaminergic neurons
• NE is released from adrenergic neurons
• 5-HT is formed from AA-tryptophan within serotonergic nerves
• Glutamate from the glutamatergic and GABA from the GABAergic system

All these neurons are highly occupied in the following regions of the brain:^6,7

• Prefrontal cortex(PFC)
• Nucleus accumbens in the lentiform nucleus (basal ganglia of the cerebrum in the forebrain)
• Ventral tegmental area (VTA) in the midbrain
• Hippocampus
• Amygdala

Which factors lead to depression?

Depression results from environmental, psychological, and physical stresses:⁸

• Illness, lethargy—physical
• Rifts in social relations, mental trauma, psychological
• Noise pollution in overcrowded places—environmental

Also, genetic factors like the monoamine oxidase gene mutations can trigger it. Theories which are implicated in the pathogenesis of depression are as follows:⁹

For example:

Monoamine deficiency 

Due to disturbances in the following stages⁹

• Synthesis of NE, 5-HT, and dopamine
• Transport
• Release into the synaptic cleft
• Metabolism of monoamines
• Depleted levels of tryptophan and tyrosine: malnutrition

Neuroinflammation

Stress provokes inflammation by activating multiple inflammatory pathways like nuclear factor kappa B (NFkB) and nucleotide-binding domain, leucine-rich–containing family, and pyrin domain–containing-3 (NLRP-3), thereby producing pro-inflammatory interleukin-6 (IL-6) and tumour necrosis factor alpha (Tnf-α), which consequently impairs monoamine transmission.^9,10

Dysfunction in the hypothalamus-pituitary gland-adrenal gland axis (HPA)

Chronic stress produces glucocorticoid receptor-GR resistance through cortisol, resulting in suppression of the anti-inflammatory pathways and more activation of inflammation through NLRP-3 and NFkB.^9,10,11

Neurotrophic theory

GR resistance downregulates the gene expression of brain-derived neurotrophic factor (BDNF), leading to atrophy of neurons in the hippocampus and PFC and enhanced neuroinflammation.^9,10

Antidepressants in neuropharmacology

Psychological intervention, including cognitive behavioural therapy (CBT) and lifestyle changes like exercise and yoga, can ameliorate depression symptoms like consistent crying over little things, annoyance, mood fluctuations, impaired attention (focus), and suicidal thoughts. Among them, pharmacotherapy is important to restore the normal physiological response.^2,3,12

How is the normal physiological synthesis of monoamines related to depression and intervention?

Normally, in the neurons, dietary amino acids (AAs) like tryptophan and tyrosine are transported from blood into cytosol by solute carrier (SLC) transporter proteins. This is coupled with sodium ion-dependent secondary active transportation.^6,7

• In the case of serotonin, such AA in the cytoplasm acts as a substrate for tryptophan hydroxylase and is converted into serotonin^6,7
• In the dopamine case, Tyrosine is converted into L-3,4-dihydroxyphenylalanine (L-DOPA) with the help of the enzyme tyrosine hydroxylase, and then L-DOPA undergoes decarboxylation to form a dopamine molecule^6,7
• In the case of NE, amine undergoes hydroxylation to form norepinephrine by the dopamine β-hydroxylase^6,7

After the synthesis, dopamine, norepinephrine, and serotonin are stored in synaptic vesicles, and upon action potential generation, these are released into the synaptic cleft. From here, there are three options:^6,7

• The first option is to bind to the receptors of the postsynaptic membrane of neurons, like 5-HT receptors (for serotonin), D1-D2 receptors (for dopamine), and adrenergic receptors (in the case of NEN), thereby performing their biological functions^6,7
• The second option is metabolism by monoamine oxidase (MAO) and catechol-O-methyltransferases (COMT)^6,7
• The last option is to reuptake them by norepinephrine transporter (NET), dopamine transporter (DAT), and serotonin transporter (SERT) present on the presynaptic membranes.^6,7 SSRIs and SNRIs work by inhibiting these reuptake proteins, which will lead to the accumulation of serotonin and norepinephrine in the synaptic space.^2,3,12
  These will then act upon postsynaptic receptors to restore their memory, cognition, motivation, and rewards. However, the rest of the two classes, like TCAs and atypical antidepressants, block different postsynaptic sites like serotonin receptors, adrenergic, muscarinic, and histamine receptors in addition to reuptake inhibition of serotonin and NEN. Consequently, possible side effects are related to their additional antagonistic actions at multiple sites within the limbic system and midbrain^2,3,12

Antidepressants in different drug classes

The following are drugs listed as:^2,3,12

SSRIs

Fluoxetine, escitalopram, paroxetine, and sertraline.^2,3,12

SNRIs

Desvenlafaxine and venlafaxine.^2,3,12

Atypical antidepressants

Mirtazapine, trazodone, and bupropion.^3,12

Tricyclic antidepressants

Imipramine, nortriptyline, amitriptyline, and desipramine.^2,3,12

Possible pharmacokinetic parameters of antidepressants

• All drug classes are administered orally and undergo hepatic and renal excretion. Antidepressants undergo extensive hepatic metabolism through the cytochrome P450 system (CYP450)^2,3,12
• SSRIs have the longest half-life, unlike SNRIs. For example, the half-life of fluoxetine is 2-4 days. As far as the distribution half-life of antidepressants is concerned, imipramine showed 90-96% plasma protein binding, unlike others, thereby possessing the longest distribution half-life. Whereas fluoxetine is converted into the norfluoxetine active metabolite. This slows its elimination from the body, thereby possessing a longer elimination half-life^2,3,12

Potential side effects of antidepressants

• Nausea, emesis, constipation, and diarrheal conditions are very common while treating depression patients^2,3,12,13.
• Cardiotoxicity, xerostomia (dry mouth), weight gain, orthostatic hypotension, and constipation are more evident after the administration of TCAs^2,3,12,13

Examples of antidepressants: pharmacodynamic and pharmacokinetic approach

Mirtazapine

Mirtazapine inhibits serotonin and NE reuptake into the neuron. Also, this drug antagonises presynaptic α2-adrenergic receptors, serotonin receptors (5-HT2 and 5-HT3), and H1 histamine receptors, producing anxiolytic, antiemetic, and sedative effects.^2,3,12,13

Secondary amines: TCAs

Desipramine blocks NEmore potently than amitriptyline. It has weaker actions on 5-HT, H1 receptors, and cholinergic receptors. It treats neuropathy and lethargic effects more effectively than other antidepressants ^2,3,12,13

Imipramine: tertiary amines

It inhibits 5-HT more strongly than desipramine and nortriptyline. Imipramine possesses more anticholinergic effects and antagonises H1 receptors more potently. This leads to sedation and orthostatic hypotension. These drugs are more effective in the treatment of depression, unlike secondary amines.^2,3,12,13

FAQ’s

What are the withdrawal effects of antidepressants?

The most common among them are headache, short temper, intrusive thoughts, and lack of sleep. 

How are antidepressants connected to neuroscience?

Neuroscience explains the structure and functions of the nervous system. This system works by using chemicals called neurotransmitters. Imbalance in the levels of these neurochemicals can lead to mental disorders (psychosis, anxiety, and depression) and neurodegenerative diseases (Alzheimer's disease and Parkinsonism). Antidepressants restore this imbalance of chemicals like serotonin and dopamine, NE, and BDNF.

How are psychology and antidepressant drugs interlinked?

Psychology deals with the mind and behaviour of people, whereas antidepressant drugs are part of the pharmacological treatment that work to modulate the levels of different neurotransmitters like serotonin and dopamine, thereby regulating the mood, emotions, and cognitive capacity.

Summary

Humans are suffering from an increasing number of mental disorders. In this era of digitalisation and globalisation, people have become victims of depression due to financial constraints, lack of resources, drug addiction, pessimism, past mental traumas, loss of jobs, and loss of loved ones. Depression is an imbalance of neurotransmitters in the neuronal network. We take advantage of drugs to treat depression. For this purpose, four classes of drugs have been classified as antidepressants, like SSRIs, SNRIs, TCAs, and atypical antidepressants. These medications restore the levels of neurotransmitters that are lost in depressive disorders. The administration of antidepressants requires extreme care due to sudden withdrawal effects occurring after prompt discontinuation, which can be lethal.