Depression being a state of sadness may be defined as a psychoneurotic disorder characterised by mental and functional activity, sadness, reduction in activity, difficulty in thinking, loss of concentration, perturbations in appetite, sleeping, and feelings of dejection, hopelessness and generation of suicidal tendencies. It is a common and recurrent disorder causing significant morbidity and mortality worldwide. The antidepressant compounds used against depression are reported to be used also for treating pain, anxiety syndromes etc. They have been grouped in five different categories such as

1. Tricyclic antidepressants (TCAs)
2. Selective serotonin-reuptake inhibitors (SSRIs)
3. Monoamine oxidase inhibitors (MAOIs)
4. Serotonin-norepinephrine reuptake inhibitor (SNRI) and
5. Non-TCA antidepressants based on their mode of action.

Most of the antidepressants have been reported to possess adverse effects on the health of users. The present review article focuses on an updated current of antidepressants, their mechanism of actions, pathophysiology of these compounds, their side effects and the strategies to combat the drug induced toxicity. An account of phytochemicals found to be acting as antidepressant is also included.

Keywords: depression, antidepressants, toxicity, neurotransmitters, biomarkers

TCAs, tricyclic antidepressants; SSRIs, selective serotonin-reuptake inhibitors; MAOIs, monoamine oxidase inhibitors; SNRI, serotonin-norepinephrine reuptake inhibitor; PMDD, premenstrual dysphoric disorder; SAD, seasonal affective disorder; PMS, premenstrual syndrome; NE, norepinephrine; 5-HT, 5-hydroxytryptamine; DA, dopamine; CNS, central nervous system; NRI, noradrenalin specific reuptake inhibitor

Depression may be defined in terms of a state of feeling sad. It may also be defined as a psychoneurotic disorder characterised by mental and functional activity, sadness, reduction in activity, difficulty in thinking, loss of concentration, perturbations in appetite, sleeping, and feelings of dejection, hopelessness and generation of suicidal tendencies.¹ It is a common and recurrent disorder causing significant morbidity and mortality worldwide.^2,3 Depression, a kind of mental illness, includes arousal of grief which may affect the overall thinking process, behaviour and feelings.¹ Such persons suffer froman imbalanced sleep and sleeping disorders.^4-6 Several workers.^7,8 have described the causes of depression which include genetic, heterogeneous parental behaviour to the siblings, neglect and sexual abuse. In addition, certain conditions like difficulties in job, relationships, natural disasters, finances, child birth, catastrophic injury, loss of life of loved ones and menopause.^9,10 It is known that different brain regions may mediate the onset of variety of symptoms of depression as they regulate emotions, neural circuitry and mood. There is meagre information available about the underlying mechanisms of their regulations. The malfunctioning of the hypothalamus region of the brain has been found to be associated with very less or too much sleep, disinterest in sex and other activities of enjoyment. Depression in general has three main forms such as

1. Psychotic depression characterised by severe depression,
2. Postpartum depression characterised by perturbations in the levels of hormones and physical features after child birth and
3. Seasonal Affective Disorder (SAD) concerning specially the winter months with less sunlight.¹¹

In the women, the depression arises also due to extra work load, domestic responsibilities, child care, strained relationship, care of aged parents and poverty. In addition to all these indices, the psychological, biological and hormonal factors also significantly contribute in depression. The premenstrual dysphoric disorder (PMDD) or premenstrual syndrome (PMS) and osteoporosis in women can play important role in development of depression. Depression in men may be associated with sufferings from serious diseases such as cancer and cardiac diseases, extreme tiredness, irritation, disinterest in once-pleasurable activities, loss of balance, less sleep and getting aggressive. In older men, arteriosclerotic depression (vascular depression) has been observed. The depression which may lead to suicide in the children may be associated to the emerging sexuality and onset of puberty. The present article is an endeavour to illustrate an updated account and varied aspects of depression such as its pathophysiology, symptoms, diagnosis, treatment with drugs and their mode of actions, toxicity and use of plant products as potential antidepressants.

Pathophysiology of depression

There are no useful biomarkers or imaging abnormalities to determine pathophysiology of depression during life time. The post-mortem study of brain does not reveal any consistent structural or neurochemical abnormality. Majority of the currently available medications were discovered empirically. Most current theories are based on “amine hypothesis”.¹² The most important hypothesis of mood disorder is related to the alterations in the levels of biogenic amines.^13-15 It states that depression is caused by a functional deficiency of catecholamines, particularly norepinephrine (NE), whereas mania is caused by a functional excess of catecholamines at the critical synapses in the brain. The occurrence of depression has been found to be associated with the alterations in the levels of biogenic amines in the brain such as NE, dopamine (DA) and epinephrine, indolamine, serotonin, 5-hydroxytryptamine (5-HT) and two catecholamines.

Antidepressants

Antidepressants are those drugs which help in the reduction in symptoms of depressive disorders by altering chemical imbalances of neurotransmitters in the brain. The change in mood and behaviour is due to chemical imbalance. Neurotransmitters are the communication link between neurons in the brain. Neurotransmitters are located in vesicles found in nerve cells. The neurotransmitters such as serotonin, dopamine and noradrenaline or norepinephrine are released by the exonic end of one nerve and received by the other; the phenomenon called as reuptake. The antidepressants inhibit reuptake of neurotransmitters through selective receptors thereby increasing the concentration of specific neurotransmitter around the nerves in the brain. One of such antidepressant is selective serotonin reuptake inhibitor (SSRI), which affects the brain serotonin level. Antidepressants may recover the signs of depression, but also exert some side-effects. They are used in the medication of a number of symptoms, including not only depression, some anxiety disorder, nervousness, OCD, manic-depressive disorders, bedwetting in childhood, major depressive disorder, diabetic peripheral neuropathic pain, social fretfulness, post-traumatic stress disorder etc. and some conclude, but not perfect in fibromyalgia, chronic hives (allergic reaction), flashes, drug induced hyperhidrosis (sweating in excess), premenstrual symptoms, pruritus (itching), nervosa, tourette, binge eating disorder etc. The medicines achieve their desired function by adversely influencing the concentrations of neurotransmitters in the brain such as NE, serotonin and dopamine and the central nervous system (CNS). Based on the mode of actions, a group of antidepressants contain 17 substances which can be further divided into subgroups. The commonly used medicines against depression are summarised in Table 1.

Antidepressants and their classification

Imipramine was discovered in 1958 as an antidepressant regimen.¹⁷ The antidepressants have been divided into five groups:

1. Tricyclic antidepressants (TCAs),
2. Selective serotonin-reuptake inhibitors (SSRIs),
3. Monoamine oxidase inhibitors (MAOIs),
4. Serotonin-norepinephrine reuptake inhibitor (SNRI) and
5. Non-TCA antidepressants.

The TCAs block the reuptake of both norepinephrine (NE) and serotonin (5HT). This phenomenon being the primary mechanism of actions of antidepressants brings changes in the physiological behaviour of neuro-receptors. TCAs have also been reported to block muscarinic, alpha1 adrenergic and histaminic receptors. However, these molecules may lead to occurrence of different side effects in patients as summarised in Table 2.

Mourilhe²⁰ have reported that the Selective serotonin-reuptake inhibitors (SSRIs) may block the reuptake of 5HT and increase synaptic 5HT transmission. The SSRIs have very little or insignificant effect on the reuptake of other neurotransmitters. It has been observed that SSRIs does not display any activity at the muscarinic and histaminergic receptors which probably results into minute anti-cholinergic (ACH) and sedative effects (Table 3).

The mechanisms of actions of different antidepressants such as monoamine oxidase inhibitors (MAOIs), phenelzine (Nardil) and tranylcypromine (Parnate) associate with the inhibition of the enzymatic conversion of 5HT and NE into their corresponding metabolites. MAOIs are generally prescribed in cases of atypical or drug resistant depression. These compounds contain a certain level of toxicity. On the contrary to it, the moclobemide (manerix) has been reported to be the first reversible inhibitor of monoamine oxidase A (RIMA). This molecule is found relatively more effective and safe.²³ Another antidepressant, nefazodone (serzone) has properties of both: it acts like SSRIs which blocks the reuptake of 5HT and also act as an antagonist of 5HT2 receptor²³ thereby reducing the stimulating effects similar to SSRIs. Nefazodone has structural and pharmacological similarities to another antidepressant, trazodone (desyrel). The only difference is that nefazodone binds with α1 receptors with low affinity. All of these antidepressants do not significantly influence ACH mediated functions (Table 4).

The activity of serotonin nor-epinephrine reuptake inhibitors (SNRIs) does not exert any side effects such as sedation or hypotension but display TCAs like activity²³ Higher doses of SNRIs have been reported to mildly increase blood pressure. The above mentioned antidepressants in adequate dosages exhibit same level of effects for treatment of depression. Some of the SNRIs are duloxetine (Cymbalta), venlafaxine (Effexor XR), desvenlafaxine (Pristiq, Khedezla) and levomilnacipran (Fetzima). The first line of antidepressants is the Non-TCAs (NTCA) which includes SSRIs. These agents are relative safer with better tolerability. Those patients which do not show any response to other drugs or suffering from chronic pain or migraine are given TCAs. However, the existing reports suggest that the secondary amine TCAs (desipramine and nortriptyline) possess more side effects than tertiary amine TCAs (Table 5). A comparative estimate of antidepressants and their therapeutic properties are summarised in Table 6.

Interaction of antidepressants with the cellular receptors

As explained above, the MAOIs block the metabolism of neurotransmitters such as NE, DA and 5-HT and cause increase in the concentration of monoamine transmitters. The traditional MAOIs (tranylcypromine) act in irreversible and non-selective manner whereas the recently investigated MAOIs are reversible in binding and very selective for MAO-A or MAO-B. TCAs is a combo drug.³⁰ containing at least five chemical agents with different activities such as a serotonin reuptake inhibitor activity, a norepinephrine reuptake inhibitor activity, an anti-cholinergic anti-muscarinic activity, an alfa1-adrenergic antagonist activity, and an antihistamine (H1) activity.³¹ When taken in overdose, they cause toxicity in terms of lethal cardiac arrhythmias and seizures. The mechanism of action of TCAs relies on the inhibition of reuptake of serotonin and NE.³¹ The different members of TCAs display differential inhibition activity on 5HT and NE transporters. Clomipramine has been reported to be the most potent at 5-HT reuptake pump whereas desipramine and maprotiline were more potent at NE reuptake pump. The drug toxicity of TCAs has been explained in terms of their effects on certain receptors such as H1, M1, and alfa1.

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs are known to selectively inhibit serotonin transport. Some of the SSRIs are fluoxetine (Prozac, Selfemra), paroxetine (Paxil, Pexeva), sertraline (Zoloft), citalopram (Celexa) and escitalopram (Lexapro). This action of SSRIs results into abrupt increase in serotonin in the somatodendritic area of serotonergic neurons which causes desensitization of the somatodendritic serotonin-1A autoreceptors.^31-33 As a result, the neuronal impulse flow is increased³³ It causes increased release of serotonin from axon terminals, which culminates into desensitization of postsynaptic serotonin receptors. Desensitization of these receptors may contribute to the therapeutic actions of SSRIs or it could account for the development of tolerance to acute side effects of SSRIs. The pharmacological analysis of SSRIs suggests that these agents may cause strong but slow disinhibition of 5-HT neurotransmission in the central nervous system (CNS). In this case, the actions of antidepressants are mediated by a pathway from midbrain raphe to prefrontal cortex^34,35 The side effects generated by SSRIs include anxiety, sleep disturbances, sexual dysfunction (decreased libido, reduced pleasurability and reduction in arousal), and gastrointestinal disturbances.³⁰ It is thought that the toxicity the 5-HT2 and 5-HT3 receptors of certain serotonergic pathways are responsible. A reciprocal relationship exists between serotonin and dopamine viz. serotonin tending to inhibit sexual functioning and dopamine tending to enhance sexual functioning. It is believed that serotonin pathway descending from brain stem down the spinal cord to spinal neurons that mediate various spinal reflexes is responsible for the sexual dysfunction in the form of ejaculation and orgasm problems. It has been reported that the enhanced serotonergic flow through this pathway inhibits sexual functioning. The serotonin’s negative effects on sexual functioning are mediated via 5-HT2 receptors. Therefore 5-HT2 antagonists can reverse SSRIs induced sexual dysfunction.^36,37

The antidepressant acting as serotonin/norepinephrine/dopamine reuptake inhibitor (SNRI)

Stahl³⁰ have demonstrated the pharmacologic effect of venlafaxine and found it to be dose dependent. At low doses, it essentially acts as an SSRI and at medium to high doses, it causes additional NE reuptake inhibition and at very high doses, DA reuptake inhibition occurs.^30,39 Other antidepressants such as nefazodone and trazodone act via serotonin-2 receptor antagonism with serotonin reuptake blockade. It is interesting to mention here that SSRIs stimulate 5-HT2 receptors where as nefazodone and trazodone blocks the receptor.³⁰ This action of nefazodone and trazodone makes it safer antidepressants than the SSRIs.

Depressants as norepinephrine and dopamine reuptake inhibitor (Bupropion)

Bupropion is the only antidepressant that selectively acts on the noradrenergic and dopaminergic systems and not on the serotonin system.⁴⁰ Bupropion exhibits dopaminergic and noradrenergic activity, therefore it may exert positive effect in overcoming the attention deficit disorder⁴¹ and in the treatment of smoking cessation.³⁸ In contrary to the benefits from this drug, bupropion has been shown to induce some side effects such as overstimulation, agitation, insomnia and nausea.^30,39

Antidepressants showing α-2 antagonism plus serotonin-2 and serotonin-3 antagonism

Mirtazapin, a noradrenergic and specific serotonergic antidepressant,⁴³ has both pro-adrenergic and proserotonergic actions. The pro-adrenergic and proserotonergic actions of mirtazapin are due to its alpha2-antagonist properties i.e. disinhibition of both serotonin and norepinephrine neurotransmission. Similar to nefazodone, mirtazapine also does not exert any toxicity of SSRIs due to 5-HT2 stimulation. Since strong antihistamine properties are associated to mirtazapin, it has some side effects such as weight gain and sedation.^30,39

The antidepressants acting as a noradrenalin specific reuptake inhibitor (NRI) (Reboxetine)

Reboxetine, a noradrenaline (norepinephrine) reuptake inhibitor, is exclusively unrelated to TCA or SSRIs. The specific properties of reboxetine includes its high affinity for the noradrenaline transporter, and little affinity for other neuro receptors including serotonin, dopamine, histamine, muscarinergic and alpha adrenergic sites.⁴³

Antidepressants as a serotonin reuptake enhancer (Tianeptine)

Tianeptine being, a tricyclic compound of dibenzothiazepine type increases the presynaptic uptake of serotonin after single as well as repeated administration, but this action is not linked to any effects on the 5-HT post-synaptic systems.^50,89 Tianeptine has no affinity for alfa1 adrenergic and H1 antihistaminic receptors. Tianeptine can be considered as the mid-position antidepressants. Defrance et al.⁴⁵ have shown that tianeptine does not show any affinity for the muscarinic receptors. Tianeptine has been reported to exert little toxicity such as gastralgia, abdominal pain, dry mouth, anorexia, nausea, vomiting, flatulence, insomnia, drowsiness, nightmares, asthenia, and tachycardia in certain patients^44-46

Phytochemicals as antidepressants

Some phytochemicals are reported to act as antidepressants. These chemicals present in the plant extracts are expected to be safer and more cost effective than the existing antidepressants. Different ethno-pharmaceutical properties of various plant extracts and their effects are summarised in Table 7.

Depression is a serious psychological condition but it can be effectively treated with available therapies. The stock of antidepressants available may be selectively used for treating depression safely without any side effects. The right medication to an individual depends on the clinico-physiological conditions of the patient such as symptoms, possible side effects, and interaction with other medications, state of pregnancy or breast feeding and the mental conditions. Different classes of antidepressants are in practice depending on the type and requirement of depression. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), Serotonin and norepinephrine reuptake inhibitors (SNRIs), Norepinephrine and dopamine reuptake inhibitors (NDRIs: Bupropion (Wellbutrin, Aplenzin, Forfivo XL), Atypical antidepressants (trazodone (Oleptro), mirtazapine (Remeron) and vortioxetine (Brintellix)), Tricyclic antidepressants (imipramine (Tofranil), nortriptyline (Pamelor), amitriptyline, doxepin, trimipramine (Surmontil), desipramine (Norpramin) and protriptyline (Vivactil)), Monoamine oxidase inhibitors (MAOIs: tranylcypromine (Parnate), phenelzine (Nardil) and isocarboxazid (Marplan)) and other medications such as such as mood stabilizers or antipsychotics all as well as anti-anxiety and stimulant medications. Many of these medications have their side effects. It could be however worthwhile to investigate the plant based principles to be used as more effective and safe chemotherapeutic compared to the currently used synthetic regimen.

Khushboo is grateful to UGC-New Delhi for financial support in the form of a fellowship.

The author declares no conflict of interest.

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