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Year : 2019  |  Volume : 12  |  Issue : 6  |  Page : 484-489  

The Atypical Antipsychotics as a New Generation Class of Antidepressants in Clinical Practice


Department of Clinical Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, University of Medical Sciences, Ondo City, Ondo State, Nigeria

Date of Submission26-Dec-2018
Date of Acceptance20-Mar-2019
Date of Web Publication17-Oct-2019

Correspondence Address:
Oluwatosin Beatrice Ibiyemi-Fasipe
Department of Clinical Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, University of Medical Sciences, Ondo City, Ondo State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_259_18

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  Abstract 


This study was designed to announce and discuss the atypical antipsychotics as a new generation class of antidepressants that had bring forth significant improvement and positive outcome to the management of patients with depressive disorders in clinical practice. Furthermore, there is opportunity for antidepressant activity to arise through a novel mechanism of action as in the case of atypical antipsychotics. In addition, this article further justifies the current pharmacological standpoint of view with respect to repurposing of the atypical antipsychotics as emerging antidepressant agents for the treatment of depressive disorders in clinical practice. From the psychopharmacological point of view, an atypical antipsychotic is efficacious as a sole monotherapy or adjunct-augmenting pharmacotherapeutic agent for the treatment of patients having anxious depression disorders (that is, either major depressive disorder [MDD] or bipolar depression or schizoaffective/psychotic depression with anxiety disorder component). The atypical antipsychotics appear to be more consistently effective in the treatment of bipolar depression and also do not increase the risk of inducing mania or increasing the frequency of bipolar cycling. In fact, patients with depressive disorders tend to even respond far better and become clinically more stable (undergo remission faster) on an atypical antipsychotic alone as monotherapy compared to the other old conventional antidepressant agents, such as tricyclic antidepressant, selective serotonin reuptake inhibitor (SSRI), or serotonin–norepinephrine reuptake inhibitor (SNRI) alone. This is one of the main reasons behind the Food Drug Administration (FDA) approval of a fixed-dose combination of an SSRI with the atypical antipsychotics such as fluoxetine and olanzapine. A fixed-dose combination of an SSRI with the atypical antipsychotics such as fluoxetine and olanzapine has received the FDA approval for the pharmacotherapy of MDD, acute bipolar depression, and schizoaffective (psychotic) depression. Furthermore, a fixed-dose combination of sertraline and aripiprazole is currently undergoing clinical trial investigation for the same indications.

Keywords: Atypical antipsychotics, depressive disorders, emerging antidepressant, new generation antidepressant class, pharmacological repurposing


How to cite this article:
Fasipe OJ, Ibiyemi-Fasipe OB. The Atypical Antipsychotics as a New Generation Class of Antidepressants in Clinical Practice. Med J DY Patil Vidyapeeth 2019;12:484-9

How to cite this URL:
Fasipe OJ, Ibiyemi-Fasipe OB. The Atypical Antipsychotics as a New Generation Class of Antidepressants in Clinical Practice. Med J DY Patil Vidyapeeth [serial online] 2019 [cited 2019 Nov 19];12:484-9. Available from: http://www.mjdrdypv.org/text.asp?2019/12/6/484/269431




  Introduction Top


This study was designed to announce and discuss the atypical antipsychotics as a new generation class of antidepressants that had bring forth significant improvement and positive outcome to the management of patients with depressive disorders in clinical practice. In addition, this article further justifies the current pharmacological standpoint of view with respect to the repurposing of atypical antipsychotics as emerging antidepressant agents for the treatment of depressive disorders. The atypical antipsychotics class does fit appropriately into the antidepressants classification nomenclature, and its pharmacological properties also deem it worthy and appropriate to be accepted and announced as a new generation class of antidepressants aside still being fully considered, regarded, and accepted as a primary antipsychotic agents class. There is opportunity for antidepressant activity to arise through a novel mechanism of action as in the case of atypical antipsychotics. Furthermore, to buttress this point of view, either of the benzodiazepines class or the barbiturates class is pharmacologically acceptable both as an anticonvulsant class and as an anxiolytic-sedative-hypnotic class. Likewise, the drug amoxapine directly exhibits the dual pharmacological properties of both antidepressant effect and typical antipsychotic action; hence, it is quite acceptable both as an antidepressant agent and as an antipsychotic agent in this medical context. In addition, the class of noradrenergic α2-receptor antagonist with specific serotonergic receptors-2 and-3 antagonism (NASSA) that has mirtazapine and mianserin as members is pharmacologically quite acceptable both as an antidepressant class and as an anxiolytic-sedative-hypnotic class. Finally, the famous drug ketamine also exhibits the dual pharmacological properties of both general anesthetic effect and rapid-onset, novel antidepressant action; hence, it is quite acceptable both as a general anesthetic agent and as a separate, rapid-onset, novel antidepressant agent in this medical context.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10]


  Atypical Antipsychotics as a New Generation Class of Antidepressants in Clinical Practice Top


The atypical antipsychotics exhibit weak D2 receptor antagonism with potently strong 5-HT2A/2C receptor blockade (or inverse agonism). In most cases, they also act as partial agonists at the 5-HT1A autoreceptor, which produces synergistic effects with the 5-HT2A/2C receptor antagonism. Most atypical antipsychotics are either 5-HT6 or 5-HT7 receptor antagonists. The atypical antipsychotics such as olanzapine, quetiapine, clozapine, risperidone, lurasidone, aripiprazole, and brexpiprazole are now being used by clinical psychiatrists as sole or adjunct-augmenting pharmacotherapeutic agents in the management of major depressive disorder (MDD) that has been unresponsive or showed inadequate remission after 4–8 weeks of active treatment with other classes of antidepressants such as selective serotonin reuptake inhibitor (SSRI), serotonin–norepinephrine reuptake inhibitor (SNRI), or tricyclic antidepressant (TCA)-alone monotherapy. Aripiprazole and its new structural congener brexpiprazole exhibit partial agonist activity (that is, weak-mixed agonist-antagonist action) at both the dopaminergic D2 and serotonergic 5-HT1A receptors but still maintain a potently strong 5-HT2A/2C receptor blockade (or inverse agonism). An atypical antipsychotic agent will potently block or antagonize the postsynaptic serotonergic 5-HT2A and 5-HT2C receptors in the prefrontal cortex to mediate its antidepressant effect clinically. While the synergistic influence/combination of the full antagonism of the somatodendritic serotonergic 5-HT7 autoreceptor by an atypical antipsychotic and the partial agonism of the somatodendritic serotonergic 5-HT1A autoreceptor by an atypical antipsychotic in the presence of an SSRI or SNRI or NASSA or TCA will enhance and produce fast disinhibition of the serotonergic neurotransmission signals from the midbrain raphe nucleus toward the prefrontal cortex to mediate moderately quick-onset antidepressant action within 2–4 weeks of administration as the somatodendritic serotonergic 5-HT7 and 5-HT1A autoreceptors, desensitization phenomenon has been bypassed by the full antagonistic and the partial agonistic (weak-mixed agonistic-antagonistic) effects of these two autoreceptors, respectively [Figure 1]. Furthermore, by antagonizing the neocortical postsynaptic serotonergic 5-HT2C receptors on the noradrenergic and dopaminergic neurotransmission pathways in the prefrontal cortex, an atypical antipsychotic disinhibits/increases norepinephrine and dopamine release specifically in the neocortical areas, such as the prefrontal cortex, but neither in the subcortical areas such as the basal ganglia, hippocampus, nor mesolimbic cortex. Therefore, an atypical antipsychotic is a norepinephrine–dopamine disinhibitor. The mesolimbic cortex comprises dopaminergic neuronal projections from the ventral tegmental area toward the nucleus accumbens shell. It is also worth mentioning here that dopaminergic and noradrenergic neurotransmission pathways in neocortical areas such as the prefrontal cortex, entorhinal cortex, cingulate cortex, superior temporal cortex, and orbital cortex are hypofuctionally impaired in depressive disorders. In fact, it has been demonstrated that genetically modified knock-out experimental model mice lacking 5-HT2A and/or 5-HT2C receptors significantly exhibits/manifests reduced and limited anxiety symptoms. Hence, by antagonizing the postsynaptic serotonergic 5-HT2A and 5-HT2C receptors in the subcortical areas such as basal ganglia, mesolimbic cortex, and hippocampus, an atypical antipsychotic will produce anxiolytic effect clinically. The synergistic influence/combination of the full antagonism of the somatodendritic serotonergic 5-HT7 autoreceptor by an atypical antipsychotic and the partial agonism of the somatodendritic serotonergic 5-HT1A autoreceptor by an atypical antipsychotic in the presence of an SSRI or SNRI or NASSA or TCA will also enhance and produce fast disinhibition of the serotonergic neurotransmission signals from the midbrain raphe nucleus toward the hippocampus and mesolimbic cortex, basal ganglia, and hypothalamus to mediate its respective therapeutic actions in panic disorder, obsessive–compulsive disorder, and binge-eating disorder (bulimia nervosa). As clinical findings and evidences support the interference of an atypical antipsychotic with the different serotonergic neurotransmission pathways mediating and controlling different neuropsychiatric disorders. In each case, an atypical antipsychotic induced disinhibition of serotonergic neurotransmission with delivering of serotonin neurotransmitter where it is needed, hypothetically in different neocortical and subcortical areas for different neuropsychiatric disorders [Figure 1]. The clinical observations obviously support the fact that different serotonergic pathways mediate the different therapeutic actions of an atypical antipsychotic, since pharmacological actions on different neocortical and subcortical areas depend on which particular neuropsychiatric disorder is being therapeutically targeted. From the psychopharmacological point of view, an atypical antipsychotic will be efficacious as a sole monotherapy or adjunct-augmenting pharmacotherapeutic agent for the treatment of patients having anxious depression disorders (that is, either MDD or bipolar depression or schizoaffective/psychotic depression with anxiety disorder component). The atypical antipsychotics appear to be more consistently effective in the treatment of bipolar depression and also do not increase the risk of inducing mania or increasing the frequency of bipolar cycling. In fact, patients with depressive disorders tend to even respond far better and become clinically more stable (undergo remission faster) on an atypical antipsychotic alone as monotherapy compared to the other old conventional antidepressant agents, such as TCA, SSRI, or SNRI alone. This is one of the main reasons behind the Food Drug Administration (FDA) approval of a fixed-dose combination of an SSRI with atypical antipsychotics such as fluoxetine and olanzapine. A fixed-dose combination of an SSRI with atypical antipsychotics such as fluoxetine and olanzapine has received the FDA approval for the pharmacotherapy of MDD, acute bipolar depression, and schizoaffective (psychotic) depression. Furthermore, a fixed-dose combination of sertraline and aripiprazole is currently undergoing clinical trial investigation for the same indications. The 5-HT1B/1D and 5-HT1A/5-HT7 autoreceptors play important roles in regulating the terminal presynaptic release of serotonin neurotransmitter and the somatodendritic-onset depolarizing activity of serotonergic neurons, respectively [Figure 2]a. Increase serotonin neurotransmitter at the somatodendritic region and the terminal presynaptic region, which is as a result of an SSRI or SNRI or NASSA or TCA pharmacodynamics effect, activates the combinations of the somatodendritic serotonergic 5-HT1A/5-HT7 autoreceptors and the terminal presynaptic serotonergic 5-HT1B/1D autoreceptors, thereby leading to a decrease in the firing rate at the somatodendritic region and a decrease in serotonin neurotransmitter release from the terminal presynaptic region, respectively, thus reducing the antidepressant and the anxiolytic clinical responses (sensitization or predesensitization phenomenon/effects). Furthermore, it is also worth mentioning here that the addition of a drug, such as a selective 5-HT7 autoreceptor antagonist with 5-HT1A autoreceptor partial agonism (such as an atypical antipsychotic); or alternatively a selective 5-HT1A autoreceptor partial agonist (such as buspirone or tandospirone); or alternatively a selective 5-HT1A and 5-HT1B/1D autoreceptors antagonist (such as pindolol), to an SSRI or SNRI or NASSA or TCA treatment will decouple the negative feedback inhibition mechanism of serotonergic neurotransmission, thereby accelerating and enhancing its antidepressant and anxiolytic response clinically by bypassing the serotonergic autoreceptors desensitization phenomenon/effects [Figure 2]b. This effect is achieved as a fast disinhibition process coupled with increase outflow of different generated serotonergic neurotransmission action potentials from the different somatodendritic regions at the midbrain raphe nucleus toward the different terminal presynaptic membrane regions located at different cortical (prefrontal cortex) and subcortical (hippocampus, mesolimbic cortex, basal ganglia, and hypothalamus) areas of the brain to mediate the observed therapeutic effects in different neuropsychiatric disorders due to increase serotonin neurotransmitter release. The pro-serotonergic neurotransmission enhancing activity of an atypical antipsychotic in the absence or presence of an SSRI or SNRI or NASSA or TCA is completely antagonized and diverted away from the somatodendritic serotonergic 5-HT1A and 5-HT7 autoreceptors and postsynaptic serotonergic 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors toward the other terminal presynaptic- and postsynaptic-serotonergic subtype receptors in the central nervous system. Finally, antidepressant and anxiolytic activities can arise through this novel mechanism of action as in the case of atypical antipsychotics.[1],[2],[3],[4],[11],[12],[13],[14],[15]
Figure 1: The somatodendritic regions containing the serotonergic 5-HT1A and 5-HT7 autoreceptors are located predominantly at the midbrain raphe nucleus which is highly rich in serotonergic neurons. The terminal presynaptic regions of their projected axons synapse with different cortical (prefrontal cortex) and subcortical (hippocampus, mesolimbic cortex, basal ganglia, and hypothalamus) areas of the brain to mediate different serotonergic neurotransmission signals in different neuropsychiatric disorders. The synergistic influence/combination of the full antagonism of the somatodendritic serotonergic 5-HT7 autoreceptor by an atypical antipsychotic and the partial agonism of the somatodendritic serotonergic 5-HT1A autoreceptor by an atypical antipsychotic in the presence of selective serotonin reuptake inhibitor or serotonin–norepinephrine reuptake inhibitor or noradrenergic α2-receptor antagonist with specific serotonergic receptors-2 and -3 antagonism or tricyclic antidepressant will enhance and produce fast disinhibition of the serotonergic neurotransmission signals from the midbrain raphe nucleus toward the prefrontal cortex, hippocampus and mesolimbic cortex, basal ganglia, and hypothalamus to mediate its respective therapeutic actions in depressive disorders, panic disorder, obsessive–compulsive disorder, and binge-eating disorder (bulimia nervosa); as the somatodendritic serotonergic 5-HT7 and 5-HT1A autoreceptors desensitization phenomenon has been bypassed by the full antagonistic and the partial agonistic (weak-mixed agonistic-antagonistic) effects of these two autoreceptors, respectively. That is, an atypical antipsychotic disinhibits different serotonergic neurotransmission signals from the midbrain raphe nucleus in different neuropsychiatric disorders to turn on serotonin neurotransmitter release from the terminal presynaptic regions in different cortical and subcortical areas

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Figure 2: (a) Increase serotonin neurotransmitter at the somatodendritic region and the terminal presynaptic region, which is as a result of selective serotonin reuptake inhibitor or serotonin–norepinephrine reuptake inhibitor or noradrenergic α2-receptor antagonist with specific serotonergic receptors-2 and -3 antagonism or tricyclic antidepressant pharmacodynamics effect activates the combinations of the somatodendritic serotonergic 5-HT1A/5-HT7 autoreceptors and the terminal presynaptic serotonergic 5-HT1B/1D autoreceptors, thereby leading to a decrease in the firing rate at the somatodendritic region and a decrease in serotonin neurotransmitter release from the terminal presynaptic region, respectively, thus reducing the antidepressant and the anxiolytic clinical responses (sensitization or pre-desensitization phenomenon/effects). (b) The addition of a drug such as a selective 5-HT7 autoreceptor antagonist with 5-HT1A autoreceptor partial agonism (such as an atypical antipsychotic); or alternatively a selective 5-HT1A autoreceptor partial agonist (such as buspirone or tandospirone); or alternatively a selective 5-HT1A and 5-HT1B/1D autoreceptors antagonist (such as pindolol) can hasten the antidepressant and the anxiolytic clinical responses to selective serotonin reuptake inhibitor or serotonin–norepinephrine reuptake inhibitor or noradrenergic α2-receptor antagonist with specific serotonergic receptors-2 and -3 antagonism or tricyclic antidepressant by bypassing the serotonergic autoreceptors desensitization phenomenon/effects. Finally, the pro-serotonergic neurotransmission enhancing activity of an atypical antipsychotic in the absence or presence of selective serotonin reuptake inhibitor or serotonin–norepinephrine reuptake inhibitor or noradrenergic α2-receptor antagonist with specific serotonergic receptors-2 and -3 antagonism or tricyclic antidepressant is completely antagonized and diverted away from the somatodendritic serotonergic 5-HT1A and 5-HT7 autoreceptors, and postsynaptic serotonergic 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors toward the other terminal presynaptic- and postsynaptic-serotonergic subtype receptors in the central nervous system

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  Currently Proposed Antidepressants Classification Nomenclature Top


The different classes of clinically available antidepressants are:[16]

  1. TCAs such as amitriptyline, imipramine, desipramine, nortriptyline, clomipramine, trimipramine, protriptyline, and doxepin
  2. Monoamine oxidase inhibitors (MAOIs) such as phenelzine, nialamide, isocarboxazid, hydracarbazine, tranylcypromine, moclobemide, *bifemelane, *pirlindole, *toloxatone, *selegiline, *rasagiline, and *safinamide
  3. SSRIs such as fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine
  4. SNRIs such as venlafaxine, desvenlafaxine, duloxetine, *ansofaxine, *nefopam, and *levomilnacipran
  5. Norepinephrine–dopamine reuptake inhibitor (NDRI) such as bupropion
  6. ++ Selective norepinephrine reuptake inhibitors (NRIs) such as *reboxetine, *viloxazine, *teniloxazine (also known as sulfoxazine or sufoxazine), and *atomoxetine
  7. Serotonin receptors antagonist with serotonin reuptake inhibition (SARI) such as trazodone, nefazodone, and *vortioxetine
  8. ++ Serotonin 5-HT1A autoreceptor partial agonist with serotonin reuptake inhibition (SPARI) such as *vilazodone
  9. NASSA such as mirtazapine and® mianserin
  10. ++ Norepinephrine reuptake inhibitor with serotonin receptors antagonism (NRISA) such as maprotiline
  11. ++ Serotonin-norepinephrine reuptake inhibitor and serotonin receptors antagonism (SNRISA) antidepressant with potent antipsychotic D2 receptor blockade/antagonism such as amoxapine
  12. ++ Atypical antipsychotics that exhibit weak D2 receptor antagonism with potently strong 5-HT2A/2C receptor blockade such as *olanzapine, *quetiapine, *risperidone, *lurasidone, *aripiprazole, and *brexpiprazole
  13. ++ NMDA-glutamatergic ionoceptor blockers that exhibit a direct action on the excitatory glutamatergic neurotransmission system such as *ketamine, *CP-101,606 (traxoprodil), *GLYX-13 (rapastinel), *NRX-1074 (apimostinel), and *Riluzole.


Note: ++ Emerging antidepressant classes using mechanisms of action-based classification; *Novel/emerging antidepressant drug (s) in a particular class;® Drug approval was rejected/denied by the United States FDA due to the submission of fraudulent data regarding its clinical trial by the investigators but had been approved for the treatment of depression disorders long-time ago in the European Union and other countries.


  What This Article Adds to the Body of Knowledge? Top


  • This article remarkably advocates for the incorporation of the atypical antipsychotics as a new member class of the antidepressant agents because of its clinically significant role and impact in the management of depressive disorders. In addition, the atypical antipsychotics class does fit appropriately into the antidepressants classification nomenclature, and its pharmacological properties also deem it worthy and appropriate to be accepted and announced as a new generation class of antidepressants aside still being fully considered, regarded, and accepted as a primary antipsychotic agents class because antidepressant activity can arise through a novel mechanism of action.



  Conclusion Top


This article remarkably advocates for the incorporation of the atypical antipsychotics as a new member class of the antidepressant agents because of its clinically significant role and impact in the management of depressive disorders. In addition, the atypical antipsychotics class do fit appropriately into the antidepressants classification nomenclature, and its pharmacological properties also deem it worthy and appropriate to be accepted and announced as a new generation class of antidepressants aside still being fully considered, regarded, and accepted as a primary antipsychotic agents class because antidepressant activity can arise through a novel echanism of action.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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