Öznur Demirci1, İrem Adar1, Oytun Erbaş1

1ERBAS Institute of Experimental Medicine, Illinois, USA & Gebze, Türkiye

Keywords: Antipsychotics, atypical, extrapyramidal, schizophrenia, typical

Abstract

Antipsychotics are currently used in many disorders, especially schizophrenia and psychotic disorders. Due to extrapyramidal side effects including weight gain, sexual dysfunction, movement disorders, and development of tolerance, the production of new antipsychotic drugs is a subject that is still being studied. This process, which first started with the discovery of typical antipsychotics, has become widespread with the discovery of atypical antipsychotics after the 90s, and at the same time, the use of antipsychotics in diseases has expanded. This review aims to describe the types of antipsychotics, the physiological mechanisms by which antipsychotic drugs act on the brain, the different side effects of antipsychotic drugs on the brain, and the mechanisms of action of these drugs in various brain disorders as much as possible to express it clearly and understandably.

Antipsychotics are currently used in psychiatric psychotic disorders, primarily schizophrenia, but there is also a study showing that their use in bipolar disorder (BD) is effective.[1-3] Although there are many categories of antipsychotics, the common classification can be defined as first (typical) and second (atypical) generation antipsychotics.[1]

MECHANISMS OF ACTION OF ANTIPSYCHOTICS

While typical antipsychotics (TAs) function as dopamine receptor antagonists, atypical antipsychotics (AAs), which started to be produced in the 90s, are differentiated in two different functions: serotonin-dopamine antagonists and partial dopamine agonism.[1,4]

Typical Antipsychotics

Typical antipsychotics are generally known that effective in the positive symptoms of schizophrenia.[5,6] They anatomically stop depolarization in dopamine cells in the mesolimbic, corticolimbic, and nigrostriatal systems of the brain.[7,8] Typical antipsychotics function by binding to the dopaminergic dopamine D2 receptor and there is a relationship between the drug’s therapeutic effect and its D2 receptor binding action. They bind to postsynaptic D2 receptors and keep them.[9] Thus, they prevent the flow of extra dopamine into the brain. Since drug binding to the D2 receptor is associated with therapeutic effects, it can be predicted that this process may play a role in the alleviation of positive symptoms in schizophrenia. A dose range has been determined for the efficacy of TAs and to keep side effects under control. Since 65-70% D2 receptor blockade can provide the desired effect in patients, and there is a risk of increased side effects in the extrapyramidal system in the brain if it is above 80%, the threshold range for use of the drug has been determined as 65-80% D2 blockade. [1,10,11] However, there may be patients for whom this dose is not sufficient.[9] Prolonged suppression of dopamine during the treatment process leads to excessive dopamine sensitivity and an increase in dopamine receptors. In this case, the doses that patients receive after a certain period of time need to be increased further to achieve the same effect. In summary, patients develop tolerance to the drug.[1,9,12-14]

Atypical Antipsychotics

Research on AAs started with clozapine. According to an animal experiment, this drug was found to produce fewer extrapyramidal and other side effects and weaker D2 blockade in its mechanism of action. [15,16] The weaker D2 blockade may reduce the risk of dopamine sensitization and thereby the risk of tolerance. We mentioned that AAs act on the brain as serotonin dopamine antagonists or partially as dopamine agonists. Primarily, AA has a similar affinity for D2 receptors as TA but lower than TA. Atypical antipsychotics have differentially high levels of D3 and D4 receptor affinity.[17] There are several hypotheses regarding the effect of AAs on the dopaminergic system.[1]

The mechanism mentioned above is the hypothesis of a weaker D2 blockade, although there are several imaging studies on this blockade effect.[18-20] Another hypothesis is the rapid uncoupling hypothesis, which is thought to result from the low affinity of D2 partial agonists for D2 receptors in AAs.[1,21,13] The situation here is a rapid detachment of the agonist substance from D2 receptors.[21,13] The last hypothesis is that of partial dopamine agonists. According to this hypothesis, despite a high affinity for D2 receptors, there is also antagonism of the serotonin or 5-hydroxytryptamine (5-HT)2A receptors with limited efficacy. In this hypothesis, D2 partial agonism exists in the mesolimbic pathway.[1,22] In terms of serotonindopamine antagonism, the binding affinity of AAs to the 5HTA2 receptor is higher than the binding affinity to the D receptor. This is one of the conditions that lead to atypical effects, unlike TAs.[1,23,24] The 5HT2A receptors are serotonin receptors found in the brain, predominantly in the cortex.[25] These receptors are also located in brain areas where the terminals and sources of dopamine neurons in the nigrostriatal and mesocorticolimbic areas are located. In this connection, stimulation of 5HT2A receptors inhibits dopamine stimulation. However, suppression of 5HT2A receptors by AAs eliminates dopamine inhibition and increases dopamine excitation in these areas.[26-28] Negative effects in depressive states and psychotic disorders This 5HT2A antagonism may affect symptoms.[28] Similarly, suppression of the 5HT2C serotoninergic receptor, which antagonizes serotonin, can affect depressive states and negative symptoms. In combination with 5HT2A, the potency was increased.[27-29] In addition, there are studies in which increased dopamine activation in the prefrontal region was observed in rat experiments given 5HT2A and 5HT2C antagonists.[30-32] There is one research in which AAs can be evaluated as different from TA. According to the study, it is observed that some AAs cause an increase in acetylcholine in the prefrontal cortex. It has been observed that clozapine, olanzapine, risperidone, and ziprasidone can show this effect. Similar to 5HT2A receptors, it was observed that it can indirectly increase dopamine activation in the prefrontal cortex.[27,28] According to a study on this subject, the combination of 5HT2A and D2 antagonism is thought to be partially involved in dopamine release in the prefrontal cortex.[33,34] A mechanism of action first discovered with clozapine is adrenergic alpha 1 and alpha 2 receptor antagonism, which are epinephrine and norepinephrine receptors.[1] The combination of A1 receptor antagonism with 5HT2A antagonism or with D2 blockade increases the atypical effect of the drug.[35,36] Clozapine, risperidone and quetiapine were given examples of antipsychotics with high A1 affinity and low D2 affinity compared to A1. The difference between A1 and D2 affinity of risperidone is much less than clozapine and quetiapine.[37-40]

Clozapine

Clozapine is an antipsychotic with low D2 receptor affinity and high 5HT2 receptor affinity.[22,37] Low D2 affinity is thought to improve the positive symptoms of schizophrenia and reduce extrapyramidal side effects with high 5HT2 affinity.[38] Clozapine is a substance that acts against low D2 affinity. Its direct and indirect total D1 and D2 receptor occupancy is higher than other AAs. In addition to its antagonistic interference with D4 receptors, clozapine’s metabolite N-desmethylclozapine also has D2 and D3 agonism.[41,42] In addition, this metabolite could indirectly increase glutamate activity by binding to muscarinic M1 receptors, one of the acetylcholine receptors.[43,44]

Risperidone

It is an antipsychotic that was introduced after clozapine and shows a high affinity for both D2 and 5HT2 receptors.[22,45] Thus, it is thought to be effective for both positive and negative schizophrenia symptoms. Additionally, BD is thought to be effective in short-term treatment for mania states and in long-term treatment to prevent relapse in schizophrenia.[38]

Quetiapine

Like clozapine, quetiapine is effective in schizophrenia and acute mania. It has a high affinity for 5HT2A receptors and a low affinity for D2 receptors. Binding time to D2 receptors is short. For this reason, extrapyramidal side effects are also low. It can improve schizophrenia symptoms and manic episodes of BD.[45-47]

In a study on quetiapine, quetiapine in substance and related disorders usability has been reported. A few other studies that could contradict this study suggest that some antipsychotics with high antagonist properties administered to substance addicts may increase substance use in addicts. This risk was explained by the fact that due to the high dopamine antagonism of these antipsychotics, addicts may increase their substance use in order to reach satisfaction.[48-52] Regarding the therapeutic aspect of quetiapine, in a study on its effect on substance addicts, it was observed that addicts given quetiapine during the treatment process could alleviate anxiety, reduce pain and insomnia, and increase appetite.[53] However, quetiapine can also cause sedation in addicts.[54] The sedation effect is thought to be due to the blockade of histamine 1 (H1) receptors, the side of quetiapine that produces antihistamine effects.[48] Research on the abuse of quetiapine suggests that its ability to alleviate symptoms of anxiety and insomnia and its sedative effects lead to abuse.[48,55]

Ziprasidone

Ziprasidone shows high 5HT2 affinity and low D2 affinity in parallel with other AAs. In addition, it has greater 5HT1A agonism than other AAs. Results showed that ziprasidone may increase dopamine activation in the cortical area.[56-59] Another thing about ziprasidone that makes ziprasidone different from other AAs is that the 5HT2 and D2 affinity difference is much greater than other AAs.[59,60] There were found several studies on the clinical effects of ziprasidone on negative symptoms of schizophrenia and schizoaffective disorder. There were found several studies on the clinical effects of ziprasidone on negative symptoms of schizophrenia and schizoaffective disorder.[61-63]

Aripiprazole

Aripiprasole has high affinity partial agonism of D2 and 5HT1A.[63-65] Atypical antipsychotics While the difference in 5HT2 and D2 affinity is significant in others, this difference is quite low in aripiprazole.[27,65,66] In this situation, aripiprazole, interestingly, D2 full agonism and antagonism also to presynaptic D2 receptors. At this point can say that, the agonist effect of aripiprazole on presynaptic D2 receptors while showing antagonist effects on postsynaptic D2 receptors.[65,66]

Olanzapin

Olanzapine antagonizes 5HT2 and D2. The differences in 5HT2 and D2 affinity are greater than one. While D2 affinity is still higher than clozapine, it has an affinity for H1 receptors and 5HT2A, 5HT2C, and 5HT3 receptors.[67] At this point, we have discussed olanzapine’s risk of weight gain and obesity. Since H1 receptors are also associated with the satiety center and there are studies that blockade of H1 may lead to weight gain.[68-70] At the same time, 5HT2C receptors are also associated with the satiety center and may further increase the risk of weight gain with H1 blockade. A second reason for 5HT2C affinity can also be shown according to this information.[71-73]

BIPOLAR DISORDER AND ANTIPSYCHOTICS

Lithium is known to be the most common and accepted treatment in BD, but antipsychotics can also be used.[74,75] Although haloperidol and chlorpromazine from TAs can be stabilizing in BD, there are studies showing that quetiapine, ziprasidone, aripiprazole, risperidone, and olanzapine from AAs can be effective.[76-80] However, two generations of antipsychotics Even though it can be used in BD, a comparative study on the treatment of BD with chlorpromazine and clozapine showed that clozapine was superior to chlorpromazine in the intervention of acute mania in BD.[81] Physiologically, BD has been found to be associated with over-arousal in the ventral limbic pathway and concomitant under-arousal in the cortical pathway in the left hemisphere.[82-86] There are studies showing that BD patients respond well to clozapine as an antipsychotic treatment.[87,88] In a study conducted on groups of BD patients who did not respond to gold-standard treatments or were unable to continue treatment, it was observed that clozapine use could regulate the mood of these patients.[89] Contrary to popular belief, clozapine is not a mood stabilizer It is more effective in patients with BD than in patients with schizophrenia.[87,89,90] Although the mood-regulating effect of clozapine has been established, it is more effective in manic episodes than depressive episodes.[91-93]

Although clozapine has similar effects to other AAs, it is not preferred due to certain side effects. [94] These side effects include sialorrhea leading to increased salivation, sedation and weight gain.[95-97] Sialorrhea, which does not only lead to increased salivation, can indirectly disrupt daily life and patients may have to discontinue treatment.[97] Sedation, on the other hand, is most common with clozapine among AAs, but patients reported that they experienced this side effect only in the early stages of use and that it disappeared later.[98] In addition to habituation, it is also thought that the sedative effect disappears later since the metabolite produced by the action of clozapine has different affinities than clozapine.[99] Weight gain is another side effect, and again clozapine leads the way compared to AAs.[95] There is also a study showing that clozapine has no effect on weight gain in schizophrenia patients.[100]

ANTIPSYCHOTICS AND SEXUAL DYSFUNCTION

The common mechanism of antipsychotic D2 blockade is known to lead to problems with sexual function.[101] However, it is also possible that some diseases for which antipsychotics are used may lead to sexual dysfunction (SD) without drugs.[102] Many D2 affinity and its blockade in antipsychotics may indirectly affect prolactin levels and may alter sexual processes.[101] Increased prolactin, follicle-stimulating hormone, and luteinizing hormone inhibition, which may reduce sexual arousal and orgasm.[103] But this effect may be mediated by mesolimbic and is associated with dopamine blockade in the tuberoinfundibular pathway. Nevertheless, the increase in prolactin is not the only antipsychotic effect. Other than that, the dopamine effects of antipsychotic blockade may also affect sexual functioning by reducing sexual motivation. Similarly, H1 and A1, A2 receptor affinity can also cause SD. H1, for which many antipsychotics have an affinity, may cause sedation and prevent arousal.[101,104]

There is much information that M1, A1, and A2 blockade, which is one of the other mechanisms mentioned about antipsychotics, causes orgasm difficulties.[105,106] Considering the differences according to the drugs, although clozapine causes D2 blockade in the mesolimbic area, its blockade in the tuberoinfundibular pathway is not enough to lead to increased prolactin and SD.[106-108] The low D2 affinity of clozapine also plays a role here.[109] In addition, it can be said that D4 receptor antagonism by clozapine may also disrupt sexual functions, according to a study indicating that D4 receptor activity is associated with sexual functions.[110] Risperidone has a high affinity for D2 and 5HT2 receptors and a moderate affinity for A1 and A2 receptors.[111] The high D2 receptor affinity of risperidone may cause SD due to increased prolactin could be a trigger and this is supported in a comparative study with quetiapine.[104,112] There also appears to be research that risperidone causes erectile dysfunction.[113] Considering the differences according to the drugs, although clozapine causes D2 blockade in the mesolimbic area, its blockade in the tuberoinfundibular pathway is not enough to lead to increased prolactin and SD.[106,107] In addition, it can be said that D4 receptor antagonism by clozapine may also disrupt sexual functions, according to a study indicating that D4 receptor activity is associated with sexual functions.[110] Risperidone has a high affinity for D2 and 5HT2 receptors and a moderate affinity for A1 and A2 receptors.[111] The high D2 receptor affinity of risperidone may trigger SD due to increased prolactin and this is supported in a comparative study with quetiapine.[104,112] There is also research showing that risperidone causes erectile dysfunction.[113] Olanzapine has A1 and A2 affinity similar to risperidone and in addition, has affinity for M1 receptors and H1 receptors.[114] Although it does not cause erection problems as much as risperidone, it may cause sedation problems due to its H1 affinity. Sedation can be said to affect sexual functions. [104,115,116] In addition to what we have mentioned about quetiapine, it has A1 and A2 affinity. Quetiapine binds to D2 receptors with low affinity and does not cause an increase in prolactin.[109] There is even a study showing that it can bring increased prolactin to normal levels.[117] A similar study was done for aripiprazole and it was found that aripiprazole can also stabilize increased prolactin levels.[118]

In conclusion, antipsychotics are shown therapeutic in emotional and psychotic disorders in a variety of ways.The side effects of first-generation antipsychotics, mainly due to high D2 blockade, can be reduced with the development and widespread use of second-generation antipsychotics. In particular, it has been observed that side effects are reduced due to low D2 blockade and rapid dissociation from receptors. Its intense antagonism to 5HT receptors plays a role in the elimination of side effects.Different amounts of affinity according to AAs provide different effects of the drugs. Clozapine, despite its high success in schizophrenia and BD, is associated with SD sialorrhea weight gain and sedation for a certain period of time. Olanzapine differs in that its high affinity for both H1 and 5HT2C carries risks of weight gain. Sedation can be considered a common feature of AAs with H1 affinity. At this point, among the AAs that carry a risk in terms of SD, olanzapine causes sedation due to H1 affinity and risperidone causes prolactin increase due to D2 affinity arousal problems can be mentioned. The difference between aripiprazole and quetiapine, which do not cause SD as much as these two AAs, is their ability to stabilize prolactin levels. An interesting difference that can be added to aripiprazole is that it can both fully agonize and antagonize. The fact that quetiapine relieves anxiety and insomnia in the treatment of addiction and that its sedation effect due to H1 affinity may be a risk factor in its use in addicts is also different from other AAs and should be taken into consideration. Differences such as these may be an opportunity to predict whether the use of AAs for the treatment of various disorders will be effective. In conclusion, Antipsychotics may still have unknown therapeutic effects despite the knowledge about their use and effects. Due to their side effects, their use should be appropriate. In therapeutic use, it is important to take precautions against dosage and tolerance.

Cite this article as: Demirci Ö, Adar İ, Erbaş O. An Overview of Antipsychotics: Mechanisms of Action. JEB Med Sci 2023;4(1):62-70.

Conflict of Interest

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Financial Disclosure

The authors received no financial support for the research and/or authorship of this article.

References

  1. Anil Yağcioğlu AE. Antipsikotik İlaçların Etki Mekanizmaları: Sizofreni Tedavisinde "Atipiklik" Bir Üstünlük mü? [The mechanisms of action of antipsychotic drugs: is atypicality superior in schizophrenia treatment?]. Turk Psikiyatri Derg. 2007 Winter;18:364-74.
  2. Narasimhan M, Bruce TO, Masand P. Review of olanzapine in the management of bipolar disorders. Neuropsychiatr Dis Treat. 2007;3:579-87.
  3. Sasani H, Erbaş O. Microglial Effects on Psychiatric Disorders. JEB Med Sci 2022;3:26-34.
  4. Kayabaşı Y, Güneş B, Erbaş O. Serotonin Receptors and Depression. JEB Med Sci 2021;2:240-6.
  5. Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011 Jan;1:41-7.
  6. Dokuyucu R, Kokacya H, Inanir S, Copoglu US, Erbas O. Antipsychotic-like effect of minocycline in a rat model. Int J Clin Exp Med. 2014 Oct 15;7:3354-61.
  7. Blaha CD, Lane RF. Chronic treatment with classical and atypical antipsychotic drugs differentially decreases dopamine release in striatum and nucleus accumbens in vivo. Neurosci Lett. 1987 Jul 22;78:199-204.
  8. Hand TH, Hu XT, Wang RY. Differential effects of acute clozapine and haloperidol on the activity of ventral tegmental (A10) and nigrostriatal (A9) dopamine neurons. Brain Res. 1987 Jul 14;41:257-69.
  9. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 2005 Jan;10:79-104.
  10. Farde L, Nordström AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992 Jul;49:538-44.
  11. Akı BN, Erbaş O. Schizophrenia Susceptibility Genes. JEB Med Sci 2022;3:191-8.
  12. Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000 Apr;157:514-20.
  13. Kapur S, Seeman P. Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action. J Psychiatry Neurosci. 2000 Mar;25:161-6.
  14. Pala HG, Erbas O, Pala EE, Artunc Ulkumen B, Akman L, Akman T, et al. The effects of sunitinib on endometriosis. J Obstet Gynaecol. 2015 Feb;35:183-7.
  15. Kinon BJ, Lieberman JA. Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology (Berl). 1996 Mar;124:2-34.
  16. Kokacya MH, Inanir S, Copoglu US, Dokuyucu R, Erbas O. The Antipsychotic Effects of Omega-3 Fatty Acids in Rats. Am J Med Sci. 2015 Sep;350:212-7.
  17. Roth BL, Tandra S, Burgess LH, Sibley DR, Meltzer HY. D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs. Psychopharmacology (Berl). 1995 Aug;120:365-8.
  18. Pilowsky LS, Costa DC, Ell PJ, Murray RM, Verhoeff NP, Kerwin RW. Clozapine, single photon emission tomography, and the D2 dopamine receptor blockade hypothesis of schizophrenia. Lancet. 1992 Jul 25;340:199-202.
  19. Xiberas X, Martinot JL, Mallet L, Artiges E, Canal M, Loc'h C, et al. In vivo extrastriatal and striatal D2 dopamine receptor blockade by amisulpride in schizophrenia. J Clin Psychopharmacol. 2001 Apr;21:207-14.
  20. Pilowsky LS, Mulligan RS, Acton PD, Ell PJ, Costa DC, Kerwin RW. Limbic selectivity of clozapine. Lancet. 1997 Aug 16;350:490-1.
  21. Abi-Dargham A, Laruelle M. Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies. Eur Psychiatry. 2005 Jan;20:15-27.
  22. Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003 Aug;28:1400-11.
  23. Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther. 1989 Oct;251:238-46.
  24. Akdemir A, Erbaş O, Ergenoğlu M, Ozgür Yeniel A, Oltulu F, Yavaşoğlu A, et al. Montelukast prevents ischaemia/ reperfusion-induced ovarian damage in rats. Eur J Obstet Gynecol Reprod Biol. 2014 Feb;173:71-6.
  25. Hoyer D, Pazos A, Probst A, Palacios JM. Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites. Brain Res. 1986 Jun 18;376:85-96.
  26. Nocjar C, Roth BL, Pehek EA. Localization of 5-HT(2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group. Neuroscience. 2002;111:163-76.
  27. Meltzer HY, Li Z, Kaneda Y, Ichikawa J. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27:1159-72.
  28. Stahl SM. Symptoms and circuits, part 3: schizophrenia. J Clin Psychiatry. 2004 Jan;65:8-9.
  29. Balkan BC, Tunç KC, Erbaş O. Evidence for Genetic Relationships in Attention-Deficit Hyperactivity Disorder. JEB Med Sci 2022;3:253-8.
  30. Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD, et al. Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology. 2000 Sep;23:250-62.
  31. Millan MJ, Dekeyne A, Gobert A. Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo. Neuropharmacology. 1998 Jul;37:953-5.
  32. Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E. Selective blockade of serotonin2C/2B receptors enhances dopamine release in the rat nucleus accumbens. Neuropharmacology. 1998;37:265-72.
  33. Ichikawa J, Dai J, O'Laughlin IA, Fowler WL, Meltzer HY. Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum. Neuropsychopharmacology. 2002 Mar;26:325-39.
  34. Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O'Laughlin IA, Meltzer HY. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem. 2001 Mar;76:1521-31.
  35. Hertel P, Fagerquist MV, Svensson TH. Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha2 adrenoceptor blockade. Science. 1999 Oct 1;286:105-7.
  36. Svensson TH. Alpha-adrenoceptor modulation hypothesis of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27:1145-58.
  37. Schmidt AW, Lebel LA, Howard HR Jr, Zorn SH. Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Eur J Pharmacol. 2001 Aug 17;425:197-201.
  38. Chopko TC, Lindsley CW. Classics in Chemical Neuroscience: Risperidone. ACS Chem Neurosci. 2018 Jul 18;9:1520-29.
  39. Erbaş O, Akseki HS, Eliküçük B, Taşkıran D. Antipsychotic-like effect of trimetazidine in a rodent model. ScientificWorldJournal. 2013 Oct 22;2013:686304.
  40. Tauscher J, Hussain T, Agid O, Verhoeff NP, Wilson AA, Houle S, et al. Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics. Am J Psychiatry. 2004 Sep;161:1620-5.
  41. Wong AH, Van Tol HH. The dopamine D4 receptors and mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27:1091-9.
  42. Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, et al. Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist. J Pharmacol Exp Ther. 2005 Dec;315:1278-87.
  43. Sur C, Mallorga PJ, Wittmann M, Jacobson MA, Pascarella D, Williams JB, et al. N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci U S A. 2003 Nov 11;100:13674-9.
  44. Koyun D, Sevinç MN, Altuntaş İ, Erbaş O. Glutamat Receptor Activity in Neuropsychiatric Disorders. JEB Med Sci 2022;3:54-61.
  45. Goldstein JM. Quetiapine fumarate (Seroquel): a new atypical antipsychotic. Drugs Today (Barc). 1999 Mar;35:193-210.
  46. Green B. Focus on quetiapine. Curr Med Res Opin. 1999;15:145-51.
  47. Riedel M, Müller N, Strassnig M, Spellmann I, Severus E, Möller HJ. Quetiapine in the treatment of schizophrenia and related disorders. Neuropsychiatr Dis Treat. 2007 Apr;3:219-35.
  48. Reeves RR, Brister JC. Additional evidence of the abuse potential of quetiapine. South Med J. 2007 Aug;100:834-6.
  49. Martinotti G, Andreoli S, Di Nicola M, Di Giannantonio M, Sarchiapone M, Janiri L. Quetiapine decreases alcohol consumption, craving, and psychiatric symptoms in dually diagnosed alcoholics. Hum Psychopharmacol. 2008 Jul;23:417-24.
  50. McEvoy JP, Freudenreich O, Levin ED, Rose JE. Haloperidol increases smoking in patients with schizophrenia. Psychopharmacology (Berl). 1995 May;119:124-6.
  51. Green AI, Zimmet SV, Strous RD, Schildkraut JJ. Clozapine for comorbid substance use disorder and schizophrenia: do patients with schizophrenia have a reward-deficiency syndrome that can be ameliorated by clozapine? Harv Rev Psychiatry. 1999 Mar-Apr;6:287-96.
  52. Sattar SP, Bhatia SC, Petty F. Potential benefits of quetiapine in the treatment of substance dependence disorders. J Psychiatry Neurosci. 2004 Nov;29:452-7.
  53. Pinkofsky HB, Hahn AM, Campbell FA, Rueda J, Daley DC, Douaihy AB. Reduction of opioid-withdrawal symptoms with quetiapine. J Clin Psychiatry. 2005 Oct;66:1285-8.
  54. Kennedy A, Wood AE, Saxon AJ, Malte C, Harvey M, Jurik J, et al. Quetiapine for the treatment of cocaine dependence: an open-label trial. J Clin Psychopharmacol. 2008 Apr;28:221-4.
  55. Pierre JM, Shnayder I, Wirshing DA, Wirshing WC. Intranasal quetiapine abuse. Am J Psychiatry. 2004 Sep;161:1718.
  56. Pinta ER, Taylor RE. Quetiapine addiction? Am J Psychiatry. 2007 Jan;164:174-5.
  57. Rollema H, Lu Y, Schmidt AW, Sprouse JS, Zorn SH. 5-HT(1A) receptor activation contributes to ziprasidoneinduced dopamine release in the rat prefrontal cortex. Biol Psychiatry. 2000 Aug 1;48:229-37.
  58. Bagnall A, Lewis RA, Leitner ML. Ziprasidone for schizophrenia and severe mental illness. Cochrane Database Syst Rev. 2000;:CD001945.
  59. Sprouse JS, Reynolds LS, Braselton JP, Rollema H, Zorn SH. Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation. Neuropsychopharmacology. 1999 Nov;21:622-31.
  60. Seeger TF, Seymour PA, Schmidt AW, Zorn SH, Schulz DW, Lebel LA, et al. Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharmacol Exp Ther. 1995 Oct;275:101-13.
  61. Keck PE Jr, Reeves KR, Harrigan EP; Ziprasidone Study Group. Ziprasidone in the short-term treatment of patients with schizoaffective disorder: results from two double- blind, placebo-controlled, multicenter studies. J Clin Psychopharmacol. 2001 Feb;21:27-35.
  62. Keck P Jr, Buffenstein A, Ferguson J, Feighner J, Jaffe W, Harrigan EP, et al. Ziprasidone 40 and 120 mg/ day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology (Berl). 1998 Nov;140:173-84.
  63. Prommer E. Aripiprazole. Am J Hosp Palliat Care. 2017 Mar;34:180-5.
  64. Kessler RM. Aripiprazole: what is the role of dopamine D(2) receptor partial agonism? Am J Psychiatry. 2007 Sep;164:1310-2.
  65. Davies MA, Sheffler DJ, Roth BL. Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology. CNS Drug Rev. 2004 Winter;10:317-36.
  66. Jordan S, Koprivica V, Dunn R, Tottori K, Kikuchi T, Altar CA. In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function. Eur J Pharmacol. 2004 Jan 1;483:45-53.
  67. Tamminga CA, Lahti AC. The new generation of antipsychotic drugs. Int Clin Psychopharmacol. 1996 May;11 Suppl 2:73-6.
  68. Provensi G, Blandina P, Passani MB. The histaminergic system as a target for the prevention of obesity and metabolic syndrome. Neuropharmacology. 2016 Jul;106:3-12.
  69. Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003 Mar;28:519-26.
  70. Michl J, Scharinger C, Zauner M, Kasper S, Freissmuth M, Sitte HH, et al. A multivariate approach linking reported side effects of clinical antidepressant and antipsychotic trials to in vitro binding affinities. Eur Neuropsychopharmacol. 2014 Sep;24:1463-74.
  71. Sohn JW, Elmquist JK, Williams KW. Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci. 2013 Sep;36:504-12.
  72. Montastruc F, Palmaro A, Bagheri H, Schmitt L, Montastruc JL, Lapeyre-Mestre M. Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: A pharmacoepidemiological-pharmacodynamic study in VigiBase. Eur Neuropsychopharmacol. 2015 Oct;25:1556-65.
  73. Erbaş O, Yılmaz M, Taşkıran D. Levetiracetam attenuates rotenone-induced toxicity: A rat model of Parkinson's disease. Environ Toxicol Pharmacol. 2016 Mar;42:226-30.
  74. Nivoli AM, Murru A, Vieta E. Lithium: still a cornerstone in the long-term treatment in bipolar disorder? Neuropsychobiology. 2010;62:27-35.
  75. Tohen M, Vieta E. Antipsychotic agents in the treatment of bipolar mania. Bipolar Disord. 2009 Jun;11 Suppl 2:45-54.
  76. Fountoulakis KN, Grunze H, Vieta E, Young A, Yatham L, Blier P, et al. The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 3: The Clinical Guidelines. Int J Neuropsychopharmacol. 2017 Feb 1;20:180-195.
  77. Scherk H, Pajonk FG, Leucht S. Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Arch Gen Psychiatry. 2007 Apr;64:442-55.
  78. Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011 Oct 8;378:1306-15.
  79. Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes T, Cipriani A, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016 Jun;30:495-553.
  80. Atagün Mİ, Oral T. Acute and Long Term Treatment of Manic Episodes in Bipolar Disorder. Noro Psikiyatr Ars. 2021 Sep 20;58:S24-S30.
  81. Barbini B, Scherillo P, Benedetti F, Crespi G, Colombo C, Smeraldi E. Response to clozapine in acute mania is more rapid than that of chlorpromazine. Int Clin Psychopharmacol. 1997 Mar;12:109-12.
  82. Fountoulakis KN, Giannakopoulos P, Kövari E, Bouras C. Assessing the role of cingulate cortex in bipolar disorder: neuropathological, structural and functional imaging data. Brain Res Rev. 2008 Nov;59:9-21.
  83. Phillips ML, Ladouceur CD, Drevets WC. A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder. Mol Psychiatry. 2008 Sep;13:829, 833-57.
  84. Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biol Psychiatry. 2003 Sep 1;54:515-28.
  85. Blumberg HP, Charney DS, Krystal JH. Frontotemporal neural systems in bipolar disorder. Semin Clin Neuropsychiatry. 2002 Oct;7:243-54.
  86. Taskin B, Erdoğan MA, Yiğittürk G, Günenç D, Erbaş O. Antifibrotic Effect of Lactulose on a Methotrexate-Induced Liver Injury Model. Gastroenterol Res Pract. 2017;2017:7942531.
  87. McElroy SL, Dessain EC, Pope HG Jr, Cole JO, Keck PE Jr, Frankenberg FR, et al. Clozapine in the treatment of psychotic mood disorders, schizoaffective disorder, and schizophrenia. J Clin Psychiatry. 1991 Oct;52:411-4.
  88. Calabrese JR, Meltzer HY, Markovitz PJ. Clozapine prophylaxis in rapid cycling bipolar disorder. J Clin Psychopharmacol. 1991 Dec;11:396-7.
  89. Kılınçel O, Kılınçel Ş, Gündüz C, Cangür Ş, Akkaya C. The Role of Clozapine as a Mood Regulator in the Treatment of Rapid Cycling Bipolar Affective Disorder. Turk Psikiyatri Derg. 2019 Winter;30:268-71.
  90. Tanrıkulu A, Erbaş O. Genetic basis of schizophrenia: Basic hypothesis pathways and gene functions. D J Tx Sci 2020;5:13-21.
  91. Banov MD, Zarate CA Jr, Tohen M, Scialabba D, Wines JD Jr, Kolbrener M, et al. Clozapine therapy in refractory affective disorders: polarity predicts response in long-term follow-up. J Clin Psychiatry. 1994 Jul;55:295- 300.
  92. Frye MA, Ketter TA, Altshuler LL, Denicoff K, Dunn RT, Kimbrell TA, et al. Clozapine in bipolar disorder: treatment implications for other atypical antipsychotics. J Affect Disord. 1998 Mar;48:91-104.
  93. Zarate CA Jr, Tohen M, Banov MD, Weiss MK, Cole JO. Is clozapine a mood stabilizer? J Clin Psychiatry. 1995 Mar;56:108-12.
  94. Solmi M, Murru A, Pacchiarotti I, Undurraga J, Veronese N, Fornaro M, et al. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag. 2017 Jun 29;13:757-77.
  95. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013 Sep 14;382:951-62.
  96. Asenjo Lobos C, Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, et al. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010 Nov 10;:CD006633.
  97. Sockalingam S, Shammi C, Remington G. Clozapine-induced hypersalivation: a review of treatment strategies. Can J Psychiatry. 2007 Jun;52:377-84.
  98. Miller DD. Review and management of clozapine side effects. J Clin Psychiatry. 2000;61 Suppl 8:14-7; discussion 18-9.
  99. Ramos Perdigués S, Sauras Quecuti R, Mané A, Mann L, Mundell C, Fernandez-Egea E. An observational study of clozapine induced sedation and its pharmacological management. Eur Neuropsychopharmacol. 2016 Jan;26:156-61.
  100. Gürcan G, Hun Şenol Ş, Anıl Yağcıoğlu AE, Karahan S, Ertuğrul A. Common Side Effects and Metabolic Syndrome due to Clozapine: Relationship with the Clinical Variables and Disability. Turk Psikiyatri Derg. 2021 Summer;32:87-99.
  101. Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs. 2004;64:2291-314.
  102. Howes OD, Wheeler MJ, Pilowsky LS, Landau S, Murray RM, Smith S. Sexual function and gonadal hormones in patients taking antipsychotic treatment for schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2007 Mar;68:361-7.
  103. Smith S, Wheeler MJ, Murray R, O'Keane V. The effects of antipsychotic-induced hyperprolactinaemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol. 2002 Apr;22:109-14.
  104. Knegtering H, van der Moolen AE, Castelein S, Kluiter H, van den Bosch RJ. What are the effects of antipsychotics on sexual dysfunctions and endocrine functioning? Psychoneuroendocrinology. 2003 Apr;28 Suppl 2:109-23.
  105. Meston CM, Gorzalka BB. Psychoactive drugs and human sexual behavior: the role of serotonergic activity. J Psychoactive Drugs. 1992 Jan-Mar;24:1-40.
  106. Turrone P, Kapur S, Seeman MV, Flint AJ. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry. 2002 Jan;159:133-5.
  107. Aizenberg D, Modai I, Landa A, Gil-Ad I, Weizman A. Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. J Clin Psychiatry. 2001 Jul;62:541-4.
  108. Erdogan MA, Erdogan A, Erbas O. The Anti-Seizure Effect of Liraglutide on Ptz-Induced Convulsions Through its Anti-Oxidant and Anti-Inflammatory Properties. Neurochem Res. 2023 Jan;48:188-95.
  109. Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis. Am J Psychiatry. 2001 Mar;158:360-9.
  110. Bitner RS, Nikkel AL, Otte S, Martino B, Barlow EH, Bhatia P, et al. Dopamine D4 receptor signaling in the rat paraventricular hypothalamic nucleus: Evidence of natural coupling involving immediate early gene induction and mitogen activated protein kinase phosphorylation. Neuropharmacology. 2006 Apr;50:521-31.
  111. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996 Mar;124:57-73.
  112. Nakonezny PA, Byerly MJ, Rush AJ. The relationship between serum prolactin level and sexual functioning among male outpatients with schizophrenia or schizoaffective disorder: a randomized double-blind trial of risperidone vs. quetiapine. J Sex Marital Ther. 2007 May-Jun;33:203-16.
  113. Spollen JJ 3rd, Wooten RG, Cargile C, Bartztokis G. Prolactin levels and erectile function in patients treated with risperidone. J Clin Psychopharmacol. 2004 Apr;24:161-6.
  114. Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology. 1996 Feb;14:87-96.
  115. Kinon BJ, Ahl J, Liu-Seifert H, Maguire GA. Improvement in hyperprolactinemia and reproductive comorbidities in patients with schizophrenia switched from conventional antipsychotics or risperidone to olanzapine. Psychoneuroendocrinology. 2006 Jun;31:577-88.
  116. Compton MT, Miller AH. Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry. 2001 May;62:362-6.
  117. Brunelleschi S, Zeppegno P, Risso F, Cattaneo CI, Torre E. Risperidone-associated hyperprolactinemia: evaluation in twenty psychiatric outpatients. Pharmacol Res. 2003 Oct;48:405-9.
  118. Mir A, Shivakumar K, Williamson RJ, McAllister V, O'Keane V, Aitchison KJ. Change in sexual dysfunction with aripiprazole: a switching or add-on study. J Psychopharmacol. 2008 May;22:244-53.