Antidepressants and Antipsychotics

There are various disorders and diseases that disturb the human mind. Certain individuals are distressed by a wide range of conditions that affect their mood, thoughts, behaviours and emotions. These are referred to as psychiatric disorders, which inhibit a patients normal functioning and have the ability to increase their risk of disability and pain. Psychiatric disorders have been the topic of discussion for centuries now; with researchers constantly looking into how these psychiatric disorders can be treated, what new-generation treatments are currently on market, and what future improvements can be discovered to enhance the current therapeutic targets.

Antidepressant and antipsychotic drugs are medicinal treatments, typically used to treat a wide range of psychiatric disorders; such as depression and schizophrenia, as well as bipolar and anxiety disorders (Fasipe, 2018). Antipsychotics are clinically used for the management of psychosis, which includes delusions, hallucinations and disordered thoughts that are primarily associated with schizophrenia and bipolar disorders. Whilst antidepressants are medications that work to help alleviate symptoms of disorders; such as moderate, severe and chronic depression, as well as anxiety and social anxiety disorders. They also work to help improve mood, restore emotional balance and relieve symptoms of restlessness, sleep disorders and suicidal thoughts (Fasipe, 2018).

Over the years different drug classes of antidepressants have reached the market. These include first generation antidepressants, such as tricyclic antidepressants, which have been on the market the longest. Additionally, newer, second generation antidepressants such as selective serotonin re-uptake inhibitors (SSRIs) and serotonin-noradrenaline re-uptake inhibitors (SNRIs) are also included.

Tricyclic antidepressants (TCAs) include drugs such as Amitriptyline and Imipramine, and are approved for treating multiple types of depression and obsessive compulsive disorders, but they are also able to treat conditions such as panic disorders, chronic pain and bulimia.

Serotonin and noradrenaline are the two neurotransmitters that TCAs operate on. As serotonin has a role in both memory and mood, and noradrenaline plays a part in arousal within the central nervous system, the TCAs work by inhibiting the re-uptake of noradrenaline and serotonin into the presynaptic terminals (Fasipe, 2018). This allows for an improvement of neurotransmission as the synaptic concentration of both serotonin and noradrenaline increases. However, the TCAs have been found to block histamine, cholinergic and α1-adrenergic receptor sites which caused patients to suffer from unwanted side effects such as drowsiness, weight gain, dry mouth, and blurred vision (P. Feighner, 1999).

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As a result, the newest generation of antidepressants known as the SSRIs and the SNRIs have been more frequently prescribed in that they targeted specific brain receptor sites with an absence of affinity for unwanted sites, such as histamine (P. Feighner, 1999). Selective serotonin re-uptake inhibitors, such as Fluoxetine, are typically used for the treatment of depressive disorders, but can also be prescribed for anxiety disorders, panic disorders and obsessive-compulsive disorders. As depression is associated with decreased levels of monoamines in the brain, such as serotonin (5-HT), SSRIs aim to increase the synaptic concentration of serotonin and allow a considerable amount to be available to bind to the postsynaptic receptors by blocking the re-uptake of serotonin into the presynaptic nerve terminal (Nutt, 1999).

SNRIs are also a newer class of antidepressants, acting on the two major neuroamines of depression: noradrenaline and serotonin (Lambert and Bourin, 2002). They perform via a mixed presynaptic inhibition of noradrenaline and serotonin reuptake, which results in an escalation in the concentration of both these neurotransmitters in the synaptic cleft(5). As they are better tolerated, they can be prescribed for long-term use and in elevated doses in refractory depression (Lambert and Bourin, 2002).

Psychiatric disorders also rely on antipsychotics for their treatment, which are typically long lasting with no known cure available. The treatments being utilised are selected for their ability to diminish the possibility that psychotic symptoms will occur, and aim to stabilise the condition.

There are two main drug classes, the first-generation, "typical" antipsychotics and the secondgeneration, "atypical" antipsychotics. They are both prescribed to treat schizophrenia and decrease symptoms linked with psychotic conditions by working to reduce dopaminergic neurotransmission.

Typical antipsychotics, such as Haloperidol, are dopamine D2 antagonists, and are not specifically selective. However, are efficient in lessening only positive symptoms, such as hallucinations and delusions in a relative amount of patients with schizophrenia (Seeman, 2002). They produce a high affinity for dopamine receptors in the brain, blocking approximately 72% of the receptor site, causing unwanted side effects and inducing extrapyramidal symptoms (EPS)(7).

Atypical antipsychotic drugs, such as Clozapine, exert akin effects as typical antipsychotics on the D2 receptors, as well as blocking serotonin receptors, particularly 5-HT2A and 5-HT2C receptors (Seeman, 2002). However, they only briefly occupy D2 receptors long enough to evoke antipsychotics effects whilst promptly dissociating themselves to exert lower affinity for dopamine receptors in order to avoid inducing EPS (Seeman, 2002). Therefore, making them the current treatment method being chosen, as they are better tolerated and exert reduced adverse effects.

Although new-generation antipsychotic and antidepressant medications have displayed enhanced efficacy in the treatment of psychotic disorders and cognitive function, these treatments don't prove to be effective for every individual; leaving substantial room for further improvement. New research has raised potential targets for the development of both antipsychotics and antidepressant drugs. Recent observations into antidepressants have found that N-methyl-Daspartate (NMDA) receptor antagonists have the ability to produce a variety of schizophrenialike symptoms, which has allowed researchers to hypothesis that certain deficiencies in NMDA performance may contribute to the pathophysiology of schizophrenia (Kane and Malhotra, 2003).

The new research looked at how drugs which enhance NMDA function may have a variable degree of therapeutic potential. Clinical trials have taken a deeper look at Glycine, an agonist at the NMDA receptor, as well as D-cycloserine, which exerts it effects as a partial agonist at the glycine recognition site of the glutamatergic NMDA receptor (Kane and Malhotra, 2003). The results have demonstrated a degree of success in treating negative symptoms, both independently or in amalgamation with other antipsychotic medication, however further research is still being conducted.

Physical or emotional stress can expedite or intensify depression in susceptible individuals, and developing research suggest that hypothalamic-pituitary-adrenal (HPA) axis and corticotropinreleasing factor (CRF) have a role in this process (Holtzheimer and Nemeroff, 2008).

Depressed patients display increased HPA axis activity and heightened cerebrospinal fluid CRF concentrations in contrast with healthy individuals (Holtzheimer and Nemeroff, 2008). Antidepressant treatments have been linked with a decline in cerebrospinal fluid CRF concentration in non-depressed controls, along with depressed controls after fluoxetine treatment (Holtzheimer and Nemeroff, 2008). This research proposes that decreased CRFergic function contributes to the mechanism of action of various antidepressant treatments, therefore promoting investigation of modulation of CRF neurotransmission as an antidepressant treatment approach.

Newer research has also looked at the modulation of GABA receptors as a potential target for the development of new antidepressants. There has been an increased interest in the use of GABA receptors as new targets due to the finding that major depressive disorders are associated with the loss of GABAergic transmission within the brain (Pacher and Kecskemeti, 2004). Additionally, antidepressant medication increases GABA levels in depressed individuals, implying that controlling GABA function will be efficient for antidepressant treatment (Pacher and Kecskemeti, 2004). Therefore, a new therapeutic target for the development of newer antidepressants can be established through the modification of GABAA receptors and G proteincoupled GABAB receptors as a result of GABAergic normalisation (Pacher and Kecskemeti, 2004).

Psychiatric disorders, affecting millions of suffering patients, can be grave burdens to live with. Luckily, with various antipsychotics and antidepressant medicinal treatments, such as SNRIs and atypical antipsychotics, sufferers are able to control their symptoms and live fairly normal lifestyles. The future for new potential targets that are more effective are looking promising, with new ongoing studies being operated; looking at treatment options that will enhance antipsychotics treatments through the modulation of GABA receptors and the improvement of NMDA functioning to exert therapeutic potential for antidepressants. With further successful outcomes, development and comprehension of both treatments, the future is looking a little more positive for patients suffering from psychiatric disorders.

References

1. Fasipe, O. (2018). Neuropharmacological classification of antidepressant agents based on their mechanisms of action. Archives of Medicine and Health Sciences, 6(1), p.81.

2. P. Feighner, J. (1999). Mechanism of Action of Antidepressant Medications. THE JOURNAL OF CLINICAL PSYCHIATRY, [online] 60(4), pp.1-8.

3. Nutt, D. (1999). Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. European Neuropsychopharmacology, 9, pp.S81-S86.

4. Lambert, O. and Bourin, M. (2002). SNRIs: mechanism of action and clinical features. Expert Review of Neurotherapeutics, 2(6), pp.849-858.

5. Seeman, P. (2002). Atypical Antipsychotics: Mechanism of Action. The Canadian Journal of Psychiatry, 47(1), pp.29-40.

6. Chokhawala K, Stevens L. Antipsychotic Medications. (2019). In: StatPearls (Internet). Treasure Island (FL): StatPearls Publishing; -. Available from: https://www.ncbi.nlm.nih.gov/ books/NBK519503/

7. Kane, J. M., & Malhotra, A. (2003). The future of pharmacotherapy for schizophrenia. World psychiatry : official journal of the World Psychiatric Association (WPA), 2(2), 81–86.

8. Pacher, P. and Kecskemeti, V. (2004). Trends in the Development of New Antidepressants. Is there a Light at the End of the Tunnel?. Current Medicinal Chemistry, 11(7), pp.925-943.

9. Holtzheimer, P. and Nemeroff, C. (2008). Novel targets for antidepressant therapies. Current Psychiatry Reports, 10(6), pp.465-473.