Use of antipsychotics in the treatment of depressive disorders

Ping WANG, Tianmei SI*

·Review·

Use of antipsychotics in the treatment of depressive disorders

Ping WANG1, Tianmei SI2*

1. Introduction

Depressive disorders cause substantial disability,often exceeding that resulting from other chronic conditions such as heart disease and diabetes.[1]Many antidepressant medications have been developed over the last couple of decades but the mechanism of action of these drugs remains unclear and the proportion of patients who are not helped by these medications remains high. The complete resolution of all the symptoms of depression may require the use of multiple medications that have different mechanisms of action.[2]Some authors believe that concurrent treatment with antidepressants and antipsychotics (including traditional antipsychotics, such as sulpiride, or atypical antipsychotics, such as clozapine, olanzapine, quetiapine,aripiprazole, risperidone, and ziprasidone) are more effective than monotherapy with antidepressants because this approach acts on multiple receptor systems.[2]Based on this rationale, the use of atypical(second generation) antipsychotics has become one of the main strategies to boost the efficacy of treatment for depression.[3]This review will discuss the current use of antipsychotics in the treatment of depressive disorders,consider the pharmacological mechanisms involved in this combined treatment approach, highlight the warning signs to watch for during this type of treatment,and consider future trends of this therapeutic practice.

2. The history of the use of antipsychotics in the treatment of depressive disorders

Antipsychotics have long been used in the treatment of depressive disorders. The treatment effect of phenothiazines was found to be similar to that of tricyclic antidepressants[4]but the side effects of using antipsychotics (extrapyramidal symptoms [EPS], tardive dyskinesia [TD], neuroleptic malignant syndrome[NMS], etc.) decreased interest in using monotherapy antipsychotics to treat depression. Nevertheless,combined treatment with antidepressants and antipsychotics became the treatment of choice for depressed patients who had psychotic symptoms as part of their depressive disorder.[5]The range of patients given combined treatment with antidepressants and typical(first generation) high-potency antipsychotics gradually increased to include those whose depressive disorders were severe, intense, or accompanied with psychotic symptoms.[6]Over time typical antipsychotics were replaced by atypical (second generation) antipsychotics because of their lower rates of EPS and TD, and their less severe cognitive impairment. At present, atypical antipsychotics are used in combination with antidepressants to treat psychotic depression,[4,5]to improve the efficacy of antidepressants for treatment-resistant depression,[7-9]and as monotherapy antidepressants.[3]

3. Antipsychotics are effective for the treatment of certain depressive disorders

There is abundant evidence of the antidepressant effect of some of the atypical antipsychotics.[3]The United States Food and Drug Administration (USFDA)has approved the use of aripiprazole (5-10 mg/d,maximum dosage 15 mg/d) as an adjunctive medication in the treatment of depressive disorders. Combined treatment with olanzapine and fluoxetine has been approved by the USFDA for the treatment of treatmentresistant depression (olanzapine 5-20 mg/d, fluoxetine 20-50 mg/d).[10]Slow-release quetiapine (150-300 mg/d) has also been approved by the USFDA as an adjunctive treatment for depressive disorders; this is the only atypical antipsychotic approved in Europe as an adjunctive treatment for depression and in Australia it has been approved both as an auxiliary treatment and as a primary treatment for depression.

Meta-analyses have assessed the effectiveness and side effects associated with the use of various atypical antipsychotics as adjunctive or primary treatment for depressive disorders and dysthymia.[11]Slow-release quetiapine: pooled results from seven double-blind RCTs(n=3414) found improved depressive symptoms when used alone or when used jointly with antidepressants,but it also had a clear sedative effect. Olanzapine: pooled results from seven double-blind RCTs (n=1754) found that adjunctive treatment with olanzapine improved patient adherence to treatment but it was not associated with improved treatment effects and it was associated with weight gain and increased prolactin levels. Aripiprazole(3 studies, n=1092) and risperidone (4 studies, n=637):when used as adjunctive treatment to antidepressants both medications improved the outcomes, but they were associated with weight gain and increased prolactin levels.[11]No significant differences have been found in the antidepressant effects of the different atypical antipsychotic medications assessed.[3]

Some studies have also shown benefits of antipsychotic treatment during the maintenance phase of treatment for depression. A 52-week follow-up study reported that relapses were fewer among individuals with depressive disorders who received monotherapy with slow-release quetiapine (50-300 mg/d) during the maintenance phase of treatment than in those given placebos.[12]Another study found that the relapses were delayed among those who received adjunctive treatment with risperidone or amisulpride compared to those who received placebos as adjunctive treatment.[3]

There is also evidence suggesting an augmentation of antidepressant treatment effects in treatmentresistant patients who receive adjunctive ziprasidone.An open-label randomized trial of individuals with treatment-resistant depression on high-dosage sertraline found that the patients had better scores on the Clinical Global Impression-Severity (CGI-S) scale after receiving adjunctive treatment with ziprasidone 160 mg/d compared with those who received adjunctive treatment with ziprasidone 80 mg/d. But this was a small-sample study so these results need to be verified.[13]A retrospective study also found that ziprasidone was effective for treatment-resistant depression, though there was no difference in effectiveness between ziprasidone and other atypical antipsychotics.[14]

No RCTs about the usefulness of clozapine or paliperidone as adjunctive treatments in the management of depressed patients have been identified.

4. Pharmacological mechanisms of antipsychotics in the treatment of depressive disorders

The antidepressant effect of typical antipsychotics is presumed to be related to the inhibition of D2/D3 receptors on the dopamine (DA) pathway in the prefrontal cortex, which increases the DA level in the prefrontal cortex. The antidepressant effects of atypical antipsychotics include rapid disengagement of DA receptors, reduced activation of DA receptors,reduced activation of 5-hydroxytryptamine 1A (5-HT1A)receptors, inhibition of 5-HT2A/2C receptors, inhibition of α2 receptors, the blockage of the norepinephrine transporter (NET), the regulation of the glutamate or the gamma-aminobutyric acid (GABA) system, a decrease in cortisol levels, and an increase in Brain-derived neurotrophic factor (BDNF) levels.

4.1 Dopamine （DA）

The effect of atypical antipsychotics on mood is related to the rapid release of DA from the receptor and the consequent reduced activation of DA receptors. In untreated schizophrenia, the occurrence of positive symptoms is a result of increased output of DA in the midbrain limbic system; the occurrence of cognitive impairment and negative symptoms is a result of decreased output of DA in the cerebral cortical pathways to the dorsal prefrontal cortex; and the occurrence of mood and negative symptoms is a result of decreased output of DA in the cerebral cortical pathways to the ventral prefrontal cortex. In theory, the D2 receptors need to be blocked in order to reduce the DA function in the cerebral cortical pathways and to prevent the exacerbation of mood, cognition, and negative symptoms following rapid release of DA from the receptor. Rapid release translates into low potency. Low potency medications (i.e., those that require a high dosage to achieve a treatment effect such as clozapine and quetiapine) can be released faster from the D2 receptors compared to high-potency medications (i.e., those for which a low dosage achieves a treatment effect such as risperidone), and medium-potency medications (such as olanzapine) which have an intermediate disengagement speed.[2]

Partial activation of DA receptors reduces DA output in the midbrain limbic system, which leads to fewer positive symptoms but is not enough to influence senses of pleasure and satisfaction. Since the DA output in the cerebral cortical pathways may be too low, partial DA activists actually increases DA release in this area which leads to improved cognition, mood, and negative symptoms.[2]Partial DA activists include aripiprazole,amisulpride and sulpiride (for amisulpride and sulpride,the clinical indicators of partial DA activation are more evident at low dosages).[2]

There is a wide variation in the treatment effects of antipsychotics. At low dosages many non-dopaminergic antipsychotics have the same mechanism of action as antidepressants: increasing DA transmission in the prefrontal cortex. Lavergne and colleagues[16]hypothesized that depressive disorders are a result of ‘synaptic depression’ caused by decreased DA transmission and elevated D1 receptor functioning in the prefrontal cortex, changes that can be corrected by increasing DA transmission.[16]Increased functioning of DA can improve synaptic plasticity and neuroregeneration, but there is a U-shaped dose-response relationship between DA activity and synaptic plasticity.[16]The interaction between DA and glutamate is via the D1 receptor subtype and the N-methyl-D-aspartate(NMDA) receptor, so BDNF may play a regulatory role in this process.[16]

4.2 5-hydroxytryptamine （5-HT）

Different atypical antipsychotic medications have very different binding affinity for different types of 5-HT receptors.[17]These differences in binding capacity are often more apparent when combined with antidepressants.[17]

The activation of the 5-HT1A receptor leads to the closure of the 5-HT neuron impulse, decreased electroactivities and release of 5-HT, decreased postsynaptic concentration of NE and 5-HT, and reduced inhibition of NE and DA.[2]Postsynaptic 5-HT1A receptors inhibit the release of glutamate from neurons in the cortical pyramid and regulate the metabolism of hormones that influences mood, anxiety, and cognition. When 5-HT1A is activated by 5-HT, signals are delivered by the second messenger cyclic adenosine monophosphate (cAMP)and promote gene expression. This increase in gene expression can help the regulation of neurotransmitters and neurotrophic factors which, in turn, help the alleviation of depressive symptoms.[2]In support of this explanation for the role of 5-HT1A receptors, a study of 5-HT1A receptor gene knockout mice reported increased anxiety-related behaviors, an anti-depression-like phenotype, and impaired cognition.[18]Moreover, the effect of the partial 5-HT1A receptor activators (such as buspirone ) is delayed, similar to antidepressants, which suggests that the treatment effect is related to upstream or downstream adaptation rather than to acute changes in these receptors.[2]

The isoreceptor function of the 5-HT2A receptor is through the expression at DA, GABA, GA, and Ach neurons on the dendrite of the cell. In vivo microdialysis found that activation of the 5-HT2A receptor may boost the release of GA and GABA and inhibit the release of DA and NE.[18]Contrary to the 5-HT1A receptor, when 5-HT2A is activated the delivery is blocked at the second messenger system cAMP and, thus, inhibits gene expression. In mice, the destruction of the entire 5-HT2A receptor messenger system reduced the inhibition of conflict anxiety and did not influence behaviors related to fear and depression; selective recovery of the cortex 5-HT2A receptor signals restored the conflict anxiety behavior.[18]

5-HT2C receptors are located in GABA, GA, and DA neurons. They function as cellular dendrite isoreceptors.[18]In vivo neurochemical studies found that the activation of 5-HT2C receptors can inhibit the release of DA and NE in the cortex.[18]A study found that 5-HT2C receptormutated mice did not show obvious anxiety induced by 5-HT2C receptor stimulants,[18]which suggests that these receptors influence emotions and behavior.

The inhibition of 5-HT2C receptors is also related to extended slow-wave sleep and the increase of sleep efficiency - which are associated with the core symptoms of depression. Among individuals with depressive disorders, there is less slow-wave sleep, a shorter latency period of REM sleep, shorter sustained sleep time, a longer latency period for sleep initiation,longer awake time, more frequent REM sleep, and more θ and δ waves in the sleep EEG.[19]Selective serotonin reuptake inhibitors (SSRIs) usually lead to increased 5-HT levels between synapses inducing both treatment effects and unintended side effects,[18]including sleep disorders related to the stimulation of 5-HT2C receptors. Low dosages of atypical antipsychotics can inhibit 5-HT2C receptors and, thus, decrease the occurrence and severity of these anti-depressant induced sleep problems,enhancing the treatment effects of SSRI antidepressants.[2]A single 5 mg dose of olanzapine can extend slow-wave sleep, total sleep time, sleep efficiency, and reduce time awake;[20]a single 1 mg dose risperidone can reduce REM sleep.[20]Ziprasidone, 40 mg qd, can extend slowwave sleep and increase sleep efficiency.[20]The effect of extended slow-wave sleep of olanzapine and ziprasidone is related to 5-HT2C receptor inhibition.[21]The binding ability of quetiapine to 5-HT2C receptors is low so it does not influence slow-wave sleep,[22]but daily treatment with 155 mg quetiapine for two to four days has been shown to decrease REM sleep, possibly due to it’s high binding ability with H1 receptors.[23]

Experimental data suggests that the 5-HT7 receptor is the key mediator for the antidepressant effect of aripiprazole.[24]The combination of SSRIs and 5-HT7 receptor antagonists can increase the treatment effects of SSRIs.[25]Animal studies have also found that 5-HT6 receptor antagonists can enhance the effects of antidepressants.[26]

4.3 Norepinephrine （NE）

NE is located in many brain areas. It is the main monoamine neurotransmitter that regulates arousal and stress reactions. Reduced activities in the prefrontal cortex regulated by NE may be related to decline in cognitive functioning (e.g., attention) and motivation.Since noradrenergic descending fibers from the nucleus ceruleus also go to brain areas that regulate motor functioning (i.e., the striatum and cerebellum), NE may also be related to the regulation of physical fatigue.N-desalkylquetiapine, the metabolite of quetiapine, can block the NE transporter and promote the delivery of NE;the binding of quetiapine to the NE transporter is almost negligible.[12]

NE and NE neurons as well as the α2 receptor on the presynaptic membrane of the 5-HT neuron can block the release of NE and 5-HT. Antagonists of the α2 receptor can relieve this inhibition and increase the release of 5-HT and NE, producing an antidepressant effect. Additionally, the α1 receptor on the postsynaptic membrane of the NE and 5-HT neurons can enhance the release of 5-HT. Thus, when NE inhibition is blocked,the α1 receptor is activated, which leads to a magnified release of 5-HT.[2]Preclinical neurological data show that the antidepressant mechanism of risperidone is due to the inhibition of the α2 receptor;[27]some researchers believe the antidepressant effect of quetiapine is also moderated by the inhibition of the α2 receptor.

Unlike other second-generation antipsychotics,ziprasidone can block the reuptake of 5-HT, dopamine,and NE. But the binding of ziprasidone to 5-HT transporters is weaker than that of SSRIs or duloxetine,so it is not clear if this moderate binding is enough to influence the transmission of monoamine in humans.[12]

SSRIs increase the transmission of 5-HT in the cerebrum and nucleus ceruleus, and thus, decrease the discharge of NE neurons. Atypical antipsychotics increase the discharge of NE neurons via the inhibition of 5-HT2A,α2, or NE transporters. This may be the reason that second-generation antipsychotics are effective among depressed patients who get limited benefit from SSRI treatment.[28]

4.4 Glutamate （GA）

GA is the main neurotransmitter stimulant in the central nervous system. The physiological functions of GA are usually moderated via nonionic mechanisms such as N-methyl-D-aspartate (NMDA), A-amino-hydroxy methyl oxazole propionic acid, kainic acid receptor and metabolic GA receptor.[29]Several reports have suggested the key role of GA in the neurobiology and treatment of depressive disorders. Abnormal GA functioning has been found in patients with depressive disorders and some GA-related medications have shown some antidepressant effects.[30]Several metabolic GA receptors(e.g., 9-aminomethyl-9, 10-dihydroanthracene [AMDA]and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor [AMPA]) and the GA transporter have been associated with the development and treatment of depressive disorders.[30]

Studies have found that quetiapine can decrease mRNA expression of the NR-1 and NR-2C subtypes of the NMDA receptor in the septal nuclei.[31]Quetiapine can also increase the expression of the G luR-B and G luR-C subtypes of the AMPA receptor in the hippocampus.[31]Some researchers hypothesize that quetiapine can normalize GA neurotransmission and decrease the risk of overstimulation by changing the activities of the GA receptors.[28]

4.5 gamma-aminobutyric acid （GABA）

Preclinical and clinical studies found that inhibition of the γ-GABA system is related to the pathophysiology of depression. The regulation of extra-cellular concentrations of NE and DA in the prefrontal cortex by the administration of quetiapine is regulated by NMDA which is moderated by AMPA and GABA.[29]Joint use of fluvoxamine and haloperidol led to changes in GABA receptors and signal delivery systems in some brain regions in rats; this change was not observed when fluvoxamine or haloperidol were used alone.[32]Similar observations have been reported among patients with schizophrenia; some studies suggest that combined treatment may lead to a better improvement of negative symptoms.[32]There has been no study on this topic among patients with depressive disorders.

4.6 Hypothalamic-Pituitary-Adrenal （HPA） axis

Mood disorders are related to changes in the stress response system. Convincing evidence has been found for increased cortisol levels among patients with depressive disorders.[33]Unlike haloperidol, low-dose quetiapine and olanzapine can decrease cortisol levels among healthy volunteers.[34]However, there has been no study about changes in cortisol levels after the use of antipsychotics among patients with depressive disorders,[12]so its unclear whether or not the HPA axis plays a role in the antidepressant effect of antipsychotic medications.[12]

4.7 Brain-derived neurotrophic factor （BDNF）

Pre-clinical and clinical studies have found that the increase of neurotrophic factors, especially BDNF,is a common characteristic in the mechanisms of action of antidepressant medications. A meta-analysis summarizing 11 studies found decreased BDNF levels in untreated depression and a return of BDNF levels to the normal after antidepressant treatment.[35]These findings have led some researchers to propose using BDNF concentration as a biomarker for disease severity and treatment effects.[35]After the use of second-generation antipsychotics such as olanzapine, plasma BDNF levels increase.[36]Moreover, one relatively small study found that the increase in BDNF levels of depressed patients treated with a variety of antipsychotics and antidepressants was greater in patients considered responsive to the combined treatment;[37]this suggestive study needs to be repeated with a larger sample that would allow differentiation of the results for different combinations of medications.

5. Adverse reactions when using antipsychotics in the treatment of depressive disorders

Due attention should be paid to the potential side effects of antipsychotic medications when considering adjunctive treatment in patients with depressive disorders. These side effects include the metabolic syndrome (e.g., poor regulation of the metabolism of sugar and fats), EPS, high prolactin, sedation, abnormal liver function, and cardiac irregularities.[12]The doses of antipsychotic medications used as adjunctive treatment in depression are usually lower than when used as the primary treatment in schizophrenia and bipolar disorder,so the prevalence and severity of these side-effects is usually lower,[3,15]but clinicians must be vigilant about these adverse reactions, particularly in elderly patients.

In the mid-1980s, two studies observed a high prevalence of tardive dyskinesia after long-term use of typical antipsychotics in individuals with mood disorders.[38,39]Subsequent studies[40,41]reported that the prevalence of tardive dyskinesia in patients with mood disorders who were treated with antipsychotic medication ranged from 9 to 64%. Among these studies,only one study included patients with schizophrenia;[40]this study reported that the occurrence of tardive dyskinesia was higher among mood disorder patients(42%) than in patients with schizophrenia (25%).

In general, the occurrence of EPS is lower for atypical antipsychotics compared to typical antipsychotics (except for aripiprazole). With the exceptions of risperidone and paliperidone, the influence of atypical antipsychotics on the level of prolactin is also smaller than that of typical antipsychotics.

For patients with treatment-resistant depression who require long-term medication, the advantage of adjunctive treatment with antipsychotics can be considerable, but chronic use of these medications, even at relatively low doses, can lead to increases in blood lipids, triglycerides, and glucose resulting in weight gain and an increased risk of Type II diabetes. These risks are greatest with clozapine and olanzapine; moderate with paliperidone, risperidone, and quetiapine; and small with aripiprazole and ziprasidone. Except for clozapine,the antidepressant treatment effects of different atypical antipsychotics are similar, so the side-effect profile should be the deciding factor in the choice of antipsychotic medication.[42]Clinicians need to consider the patient’s age, weight, body mass index, medical history and family history of diabetes and cardiovascular diseases when weighing the potential risks of different antipsychotics.[43]When using atypical antipsychotics as adjunctive treatment for depressed patients, clinicians should follow the guidance about monitoring and screening of the American Diabetes Association[44]and should counsel patients about diet, exercise and a healthy life style.When life style interventions fail to prevent weight gain in young patients using low-dose atypical antipsychotics,metformin can be considered if other second-generation antipsychotics are not suitable.[42]

In older patients side effects of second-generation antipsychotics include increased mortality (number needed to harm [NNH]=87), stroke (risperidone NNH=53), EPS (olanzapine NNH=10, risperidone NNH=20) and urinary system symptoms (NNH=16-36).[10]Clinicians need to carefully weigh the potential benefits and potential risks of long-term adjunctive treatment of elderly depressed patients with antipsychotic medications.

6. Future directions

Currently, side-effects are more predicable than treatment efficacy, so the relative risk of different types of side-effects is the most important factor to consider when choosing an adjunctive antipsychotic medication for the treatment of depressed patients who are currently receiving antidepressants. Future studies need to identify subgroups of depressive patients - categorized by genetics, neurophysiological markers, or family history- who would benefit from specific types of antipsychotic medications or specific combinations of antidepressant and antipsychotic medications. And more detailed studies on the appropriate dosages and duration of treatment with adjunctive antipsychotic medication will help increase the effectiveness of combined treatment while decreasing the adverse reactions associated with combined treatment, thus enhancing the cost-benefit for this important form of treatment for persons with depressive disorders.

Conflict of interest

The author reports no conflict of interest related to this manuscript. The authors did not receive any financial support for the preparation of this review.

1. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health:results from the World Health Surveys. Lancet 2007;370(9590): 851-858.

2. Si T, Huang J, Yu X (translated edition). Essentials of psychopharmacology: basics and clinical application of neuroscience. 3rdEditied by Stephen M. Stahl. Beijing: Peking University Medical Press, 2011. (in Chinese)

3. Chen J, Gao K, Kemp D E. Second-generation antipsychotics in major depressive disorder: update and clinical perspective.Curr Opin Psychiatry 2011; 24(1): 10-17.

4. Robertson MM, Trimble MR. Major tranquillisers used as antidepressants. A review. J Affect Disord 1982; 4(3): 173-193.

5. Schatzberg AF, Rothschild AJ. Psychotic (delusional) major depression: should it be included as a distinct syndrome in DSM-IV? Am J Psychiatry 1992; 149(6): 733-745.

6. Jc N. The Use of Antipsychotic Drugs in the Treatment of Depression. New York: PMA Publishing Corp., 1987.

7. Kennedy SH, Lam RW, Cohen NL, Ravindran AV, CANMAT Depression Work Group. Clinical guidelines for the treatment of depressive disorders. IV. Medications and other biological treatments. Can J Psychiatry 2001; 46 (Suppl 1): 38S-58S.

8. Goodwin G, Fleischhacker W, Arango C, Baumann P, Davidson M, de Hert M, et al. Advantages and disadvantages of combination treatment with antipsychotics ECNP Consensus Meeting, March 2008, Nice. Eur Neuropsychopharmacol 2009; 19(7): 520-532.

9. Konstantinidis A, Papageorgiou K, Grohmann R, Horvath A, Engel R, Kasper S. Increase of antipsychotic medication in depressive inpatients from 2000 to 2007: results from the AMSP International Pharmacovigilance Program. Int J Neuropsychopharmacol 2012; 15(4): 449-457.

10. Maher AR, Theodore G. Summary of the comparative effectiveness review on of f-label use of atypical antipsychotics.J Manag Care Pharm 2012; 18(5 Suppl B): S1-S20.

11. Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S. Second-generation antipsychotics for major depressive disorder and dysthymia. Cochrane Database Syst Rev 2010;(12): D8121.

12. Sagud M, Mihaljevic-Peles A, Begic D, Vuksan-Cusa B, Kramaric M, Zivkovic M, et al. Antipsychotics as antidepressants: what is the mechanism? Psychiatr Danub 2011; 23(3): 302-307.

13. Dunner DL, Amsterdam JD, Shelton RC, Loebel A, Romano SJ. Efficacy and tolerability of adjunctive ziprasidone in treatment-resistant depression: a randomized, open-label,pilot study. J Clin Psychiatry 2007; 68(7): 1071-1077.

14. Barbee JG, Conrad EJ, Jamhour NJ. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry 2004; 65(7): 975-981.

15. Schwartz TL, Stahl SM. Treatment strategies for dosing the second generation antipsychotics. CNS Neurosci Ther 2011;17(2): 110-117.

16. Lavergne F, Jay TM. A new strategy for antidepressant prescription. Front Neurosci 2010; 4: 192.

17. De Sousa A, Kurvey A. An evidence based clinical review on the role of atypical antipsychotics in depression. Journal of Mental Health and Human Behaviour 2012; 1(17): 38-45.

18. Filip M, Bader M. Overview on 5-HT receptors and their role in physiology and pathology of the central nervous system.Pharmacol Rep 2009; 61(5): 761-777.

19. Begić D, Mahnik-Milos M, Grubisin J. EEG characteristics in depression, “negative” and “positive” schizophrena.Psychiatr Danub 2009; 21(4): 579-584.

20. Gimenez S, Clos S, Romero S, Grasa E, Morte A, Barbanoj MJ. Effects of olanzapine, risperidone and haloperidol on sleep after a single oral morning dose in healthy volunteers.Psychopharmacology (Berl) 2007; 190(4): 507-516.

21. Sharpley AL, Elliott JM, Attenburrow MJ, Cowen PJ. Slow wave sleep in humans: role of 5-HT2A and 5-HT2C receptors.Neuropharmacology 1994; 33(3-4): 467-471.

22. Gedge L, Lazowski L, Murray D, Jokic R, Milev R. Effects of quetiapine on sleep architecture in patients with unipolar or bipolar depression. Neuropsychiatr Dis Treat 2010; 6: 501-508.

23. Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL. N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine’s antidepressant activity.Neuropsychopharmacology 2008; 33(10): 2303-2312.

24. Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL. Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo. Psychopharmacology (Berl)2009; 205(1): 119-128.

25. Hedlund PB. The 5-HT7 receptor and disorders of the nervous system: an overview. Psychopharmacology (Berl) 2009;206(3): 345-354.

26. Wesolowska A. Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data.Pharmacol Rep 2010; 62(4): 564-577.

27. Dhir A, Kulkarni SK. Risperidone, an atypical antipsychotic enhances the antidepressant-like effect of venlafaxine or fluoxetine: possible involvement of alpha-2 adrenergic receptors. Neurosci Lett 2008; 445(1): 83-88.

28. Blier P, Szabo ST. Potential mechanisms of action of atypical antipsychotic medications in treatment-resistant depression and anxiety. J Clin Psychiatry 2005; 66 (Suppl 8): 30-40.

29. Garakani A, Martinez JM, Yehuda R, Gorman JM. Cerebrospinal fluid levels of glutamate and corticotropin releasing hormone in major depression before and after treatment. J Affect Disord 2013; 146(2): 262-265.

30. Tokita K, Yamaji T, Hashimoto K. Roles of glutamate signaling in preclinical and/or mechanistic models of depression.Pharmacol Biochem Behav 2012; 100(4): 688-704.

31. Porcelli S, Drago A, Fabbri C, Serretti A. Mechanisms of antidepressant action: an integrated dopaminergic perspective. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35(7): 1532-1543.

32. Silver H, Susser E, Danovich L, Bilker W, Youdim M, Goldin V,et al. SSRI augmentation of antipsychotic alters expression of GABAA receptor and related genes in PMC of schizophrenia patients. Int J Neuropsychopharmacol 2011; 14(5): 573-584.

33. Stetler C, Miller GE. Depression and hypothalamic-pituitaryadrenal activation: a quantitative summary of four decades of research. Psychosom Med 2011; 73(2): 114-126.

34. Cohrs S, Roher C, Jordan W, Meier A, Huether G, Wuttke W,et al. The atypical antipsychotics olanzapine and quetiapine,but not haloperidol, reduce ACTH and cortisol secretion in healthy subjects. Psychopharmacology (Berl) 2006; 185(1):11-18.

35. Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 2008; 64(6): 527-532.

36. González-Pinto A, Mosquera F, Palomino A, Alberich S,Gutiérrez A, Haidar K, et al. Increase in brain-derived neurotrophic factor in first episode psychotic patients after treatment with atypical antipsychotics. Int Clin Psychopharmacol 2010; 25(4): 241-245.

37. Yoshimura R, Ikenouchi-Sugita A, Hori H, Umene-Nakano W, Katsuki A, Hayashi K, et al. Adding a low dose atypical antipsychotic drug to an antidepressant induced a rapid increase of plasma brain-derived neurotrophic factor levels in patients with treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34(2): 308-312.

38. Baldessarini RJ. A summary of current knowledge of tardive dyskinesia. Encephale 1988; 14(9): 263-268.

39. Casey DE. Affective disorders and tardive dyskinesia.Encephale 1988; 14(9): 221-226.

40. Keck PE Jr, McElroy SL, Strakowski SM, Soutullo CA.Antipsychotics in the treatment of mood disorders and risk of tardive dyskinesia. J Clin Psychiatry 2000; 61(suppl 4): 33-38.

41. Vacheron-Trystram MN, Braitman A, Cheref S, Auffray L.Antipsychotics in bipolar disorders. Encephale 2004; 30(5):417-424.

42. Hasnain M, Vieweg WV, Hollett B. Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians.Postgrad Med 2012; 124(4): 154-167.

43. Zuddas A, Zanni R, Usala T. Second generation antipsychotics(SGAs) for non-psychotic disorders in children and adolescents: a review of the randomized controlled studies.Eur Neuropsychopharmacol 2011; 21(8): 600-620.

44. Morrato EH, Newcomer JW, Kamat S, Harnett J, Cuf f el B. Metabolic screening after the American Diabetes Association’s Consensus Statement on Antipsychotic Drugs and Diabetes. Diabetes Care 2009; 32(6): 1037-1042.

There is a long history of using antipsychotic medications in the treatment of depressive disorders.Atypical antipsychotics, which have fewer side effects than traditional antipsychotics, have been used as monotherapy or adjunctively with antidepressants to treat depressive disorders with or without psychotic symptoms. The antidepressant effect of atypical antipsychotics involves regulation of monoamine, glutamate,gamma-aminobutyric acid (GABA), cortisol, and neurotrophic factors. To date, the United States Food and Drug Administration (USFDA) has approved aripiprazole and quetiapine slow-release tablets as adjunctive treatment for depressive disorders, and the combination of olanzapine and fluoxetine for the treatment of treatmentresistant depression. When using atypical antipsychotics in the treatment of depressed patients, clinicians need to monitor patients for the emergence of adverse effects including extrapyramidal symptoms (EPS), weight gain,and hyperglycemia.

10.3969/j.issn.1002-0829.2013.03.002

1Beijing Shijitan Hospital, Capital University of Medical Sciences, Beijing, China

2Peking University Institute of Mental Health, National Key Laboratory of China, Beijing, China

*correspondence: si.tian-mei@163.com

Dr. Ping Wang graduated with an MD from the Beijing University Medical School in 2010. After graduation she worked as a psychiatric resident in the psychiatry department of the Shougang Hospital of Beijing University and subsequently in the neurology and psychiatry department at the Shijitan Hospital of Capital University of medical Sciences in Beijing. Her research interests are in clinical psychopharmacology.