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RESEARCH

Treatment Strategies for Dosing the Second Generation
Antipsychotics
Thomas L. Schwartz1 & Stephen M. Stahl2,3
1 Department of Psychiatry State, University of New York Upstate Medical University, NY, USA
2 Department of Psychiatry, University of California, San Diego, San Diego, CA, USA
3 Department of Psychiatry, Cambridge University, UK

Keywords SUMMARY
Atypical antipsychotics; Bipolar disorder;
Depression; Schizophrenia; Second generation Background: The second generation antipsychotics now have clinical approvals for the
Antipsychotics. treatment of schizophrenia, bipolar depression, bipolar mania, autism, major depressive
disorder and are used furthermore off-label to treat other mental disorders. Each agent is
Correspondence unique in its pharmacodynamic profile and allows for unique dosing strategies to be em-
Thomas L. Schwartz, M.D., Department of ployed when treating these different disorders. Aims: To review relevant data regarding the
Psychiatry State University of New York Upstate second generation antipsychotics and their empirical dosing strategies. To further review
Medical University, 713 Harrison Street and comment theoretically in these areas where substantial, definitive data are lacking.
Syracuse, NY, USA. Materials and Methods: A MEDLINE and recent textbook review was conducted re-
Tel.: 315 464-3166 garding each second generation antipsychotic and cross-referenced with searches for major
Fax: 315 464-3163 mental disorders. The findings are compiled in the review below. Discussion: The second
E-mail: schwartt@upstate.edu generation antipsychotics are clearly delineated in the treatment of psychosis and mania
and share similar mechanisms of action to achieve these results: dopamine-2 receptor an-
tagonism for efficacy and serotonin-2a receptor antagonism for EPS tolerability. From here,
each agent has a unique pharmacodynamic and pharmacokinetic profile where some agents
carry more, or less antidepressant, anxiolyic, or hypnotic profiles. Choosing an agent, and
dosing it in low, middle, or high ranges may result in differential effectiveness and tolerabil-
ity. Conclusion: The second generation antipsychotics have many clinical applications in
doi: 10.1111/j.1755-5949.2011.00234.x
psychiatric practice. This article serves to review this and also suggests ways clinicians may
optimize treatment based upon patient diagnosis and utilizing appropriate dosing of each
individual second generation antipsychotic.

reach a high dose, often as quickly as possible to help ameliorate
Introduction the patient’s symptoms. This simplistic, unidirectional dosing strat-
Clinicians have been using and dosing the antipsychotics since egy has become more complicated as newer, second generation
the 1950s. These initial, first generation antipsychotics (FGA) antipsychotic agents (SGA) became available. This article seeks to
were uni-dimensional in certain ways. First of all, these drugs review and discuss clinical dosing strategies and patient care issues
were approved to treat one major illness, schizophrenia. Sec- in regard to the eight currently available SGA.
ond, clinicians and researchers were aware that they were
dopamine-2 (D2) receptor antagonists in regards to pharmaco-
logical actions. The high potency FGA agents were very clean Clinical Dosing of Second Generation
drugs in regard to promoting antipsychotic effects and the low po-
Antipsychotics
tency FGA added additional pharmacodynamic components that
essentially dictated side effects, especially sedation and orthosta- With the advent of the second generation, or atypical, antipsy-
sis, more so than effectiveness in reducing psychosis associated chotics in the mid-1990’s clinicians noticed that these agents were
with schizophrenia. Finally, clinical management dealt solely with certainly safer in regard to inducing less extrapyramidal symp-
increasing the FGA dose, to increase D2 blockade, to dampen toms (EPS) and tardive dyskinesia (TD), but also more challeng-
dopaminergic hyperactivity in limbic neurocircuits in hopes of al- ing in regard to dosing. For example, the first modern atypical
leviating psychosis. In other words, clinicians increased the dose antipsychotic, risperidone, was studied and approved at a dos-
unilaterally until symptoms of psychosis abated. The goal was to ing strategy of rapid escalation within 3 days to a 6 mg divided

110 CNS Neuroscience & Therapeutics 17 (2011) 110–117 
c 2011 Blackwell Publishing Ltd

system to avoid iatrogenically induced negative symptoms. some in vivo. pine was initiated at 15 mg. This common. but a tried and true tool in psychopharmacologic practice. sparing other dopamine pathways. The former agent is initially dosed at 2–5 mg in. dopaminergic activity where it is critical for the treatment of posi- wards accordingly until efficacy or intolerable side effects occur. risperidone. with more complexity. if a patient has schizoaffective disorder or major depression fol. and unipolar major de. Despite package insert data regarding low EPS rates. L. of unique dosing strategies that may not be found in each drug’s eration agents was relatively easy as clinicians could use a table official FDA package insert. and per the FDA. ries will use differing assessment protocols. M. ziprasidone at Overall SGA potency values are difficult to truly assess as all 120 mg. had equal fates and were ideally to be dosed in prac- tice to 600 mg. quetiapine at 600 mg. clinicians often dosed olan. nally in the tuberoinfundibular pathway to help avoid prolactine- ther 150 mg or 300 mg in depression. These two dosing strategies mia and its sequelae. This is not a new mechanism of action Dosing the SGAs became more difficult as pharmaceutical com. ziprasidone. As noted above. tive schizophrenia symptoms while remarkably lowering potential The problem is that patients tend to have comorbid illnesses. lower rate of TD and EPS. and fi- and mania. What EPS. Good clinical sense dictated a slower titration cross titration approach. Stahl Second Generation Antipsychotic Dosing Strategies dose. The FDA package insert and suggested dosing affinity) as follows: aripiprazole. FDA regulatory trials suggest a clear dosing and lowing the resolution of a psychotic break? What dosing strategy titration schedule. and aripiprazole. iloperidone. Switching among the original first gen. asenapine. in the mesocortical disorder [6. The latter agent is dosed from 50 mg initially to ei. cated and there are often conflicts between the evidence base for and it was suggested to dose this drug at 10 mg per day initially. principles behind the clinical use of each SGA in day to day clin- mation. cases. bipolar depression. but did not have initial and in a bit more detail the pharmacodynamic and pharmacokinetic readily apparent efficacy compared to the package insert infor. tion of psychosis or mania. respectively. Olanzapine was approved next. there are Amongst the SGAs very few data or clinical experiences at the date of this writing Common Features regarding the ideal clinical doses for newest agents. It does seem apparent that clinicians All second-generation agents act as D2 receptor antagonists have become more comfortable with the aforementioned agents’ [10]. and iloperidone. and oftentimes different laborato- tal days. paliperidone. Schwartz and S. may stead of the usual 10–30 mg noted previously for schizophrenia allow subtle improvement in negative symptoms [14. The final and most recent complication in re. The next three approved SGAs. this agent had less EPS issues. Finally. Clinicians now have to few important functions. of potency values [8] and switch drugs almost over night in many cians quickly learned that EPS were very frequent with this dos. The next part of this manuscript will deal with specific dosing is- zapine more slowly and at lower ineffective doses initially. this antagonism makes these agents make an accurate diagnosis. clini. studies are in vitro. The following section will take the CNS Neuroscience & Therapeutics 17 (2011) 110–117  c 2011 Blackwell Publishing Ltd 111 . This is similar to first generation drugs. dose agents more fairly selective for antagonizing the limbic dopamine system while or less aggressively.15]. clinicians often under dosed these in fear of adverse effects but likely at the Specific Dosing Strategies and Issues expense of solid efficacy in some patients [1]. ziprasi- strategies appear to be ‘loading’ strategies in regards to treating done. or develop side effects that require a netic and pharmacodynamic profile which lends each SGA to a set change of antipsychotics. and aripiprazole at 30 mg. Consequently. 5HT-2a receptor antagonism gard to clinical dose is the approval and use of aripiprazole and tends to allow more dopamine activity and neurotransmission to quetiapine XR for the adjunctive treatment of major depressive occur in the nigrostriatal system to avoid EPS. olanzapine. First. As a sues and strategies regarding each individual SGA and will discuss result. This common pharmacodynamic property serves a when used to treat schizophrenia [3–5]. Again. Clinicians drugs actually makes them selective agents in that they dampen should start at the low FDA recommended dose but titrate up. Dosing again has become more compli- rate to spare side effect burden. asenapine. 5HT-2a receptor antagonism al- bring clinicians back to low and slow dosing in this new patient lows the SGA to be named “atypical” in that they have a much population. the dose of olanzapine was raised to over ical practice. more simple pharmacological properties and move towards those tipsychotic efficacy. the onism pharmacodynamic profile amongst the second generation dosing strategy for efficacy is still similar to the FGA.T. Risperidone again was dosed from 4 to 6 mg. Clinicians were asked to dose the agents very high The exact positioning on this pathway is difficult to assess as some and very quickly to achieve antimanic efficacy within a few hospi. dual receptor antag- In order to bring this back to the schizophrenia population. 160 mg. SGAs antagonize serotonin-2a (5HT-2a) receptors as well as D2 sive initial doses compared to initial doses of these same agents receptors [10]. The authors will begin discussion about SGAs with 10 mg as clinical experience showed that this created more an. paliperidone. which were considered aggres. Timid from risperidone experiences. which in theory gives clinicians reproducible should then be used? Patients also can become resistant clinically results in their patients. and 30 mg. dosing in these situations versus dosing in clinical practice [9]. This ultimate full dosing range over the years in regard to treating schizophrenia dampening of presumed limbic dopaminergic hyperactivity in and perhaps the full dosing range of the newest SGAs will follow schizophrenia or mania leads to clinical effectiveness and reduc- suit [2]. quetiapine. Each SGA has a very unique pharmacoki- to the drug that they are on. Some panies began to investigate treating other psychiatric disorders agents have higher affinity for this action and can loosely be as- such as bipolar mania.7]. signed a potency (affinity) level in rank order (high to low D2 pressive disorder. Ultimately. and quetiapine [11–13]. acute mania. The newer antipsychotics really do not have a potency chart ing strategy and in many cases hurt patient compliance and thus to guide instant cross-titrations and often require a more gradual overall effectiveness. but olanza.

trial results and those sometimes used in clinical practice for each At higher doses.33].5 mg/d with greater than 50% re- that can function on multiple levels to treat different symptoms ceiving above FDA regulatory dose limits. It possesses 5HT-2a receptor blockade and may promote efficacy in these areas nonetheless [32.24]. macodynamic profile suggest to clinicians? Risperidone has affin. clinical intuition. Without an evidence slightly higher doses are needed to stop bipolar mania in adults. At lower doses.28]. but did reveal a clear side effect. 112 CNS Neuroscience & Therapeutics 17 (2011) 110–117  c 2011 Blackwell Publishing Ltd . even at low doses. This study was limited by small antidepressant effect come from? One study suggests that BDNF sample size and lack of a placebo group however [30]. Citrome and Kantrowitz (2009) mentary that will run throughout this article. erentially to the higher. in the persistently mentally ill. but some evidence exists for its erties. but some parent drug according to its receptor pharmacology and available evidence exists for its efficacy in these areas nonetheless. Olanzapine is not ap- seen in the absence of antipsychotic effects. antimanic potential. Schwartz and S. likely for a dose–response curve where antipsychotic and antimanic effects occur. and executive functioning. This dosing makes dy- certain anxiety disorders.25]. An average dose in is approved for treating psychosis from schizophrenia at doses of schizophrenia or bipolar mania might be 3–4 mg/d [16. L. A larger. remission and improved quality Olanzapine of life when used as an augmentation strategy [19]. Olanzapine appears to be absorbed con- neurotrophic levels (BDNF) [20]. 3 mg/d and above. If this occurs in cortical pathways. so where does the weight gain and prolactinemia. A follow-up prospective study regarding 10. M. off-label dosing above regulatory guidelines is needed more DA activates the frontal lobe. however. In re- data [24. This effect ical sense in that as a clinician increases an SGA’s dose. A MEDLINE search suggests no findings for ing in autism in children to adolescents is 1–3 mg/d [18]. In regard to ultimate dosing strategies brings the authors to a very important point and likely a com. or psychotic. antidepressant effects may be chotic and antimanic effects likely occur. Olanzapine. allowing for faster response. full informed consent and increased drug monitoring should symptoms are often noted and are diagnostic for depression and proceed and follow super dosing practices. The authors also com- and syndromes.26]. Once this antagonism reaches 60% or more. there is tends to maintain or even increase dopaminergic activity in se. dose–response curve for of D2 receptor blockade at these low doses.17]. Similar to other off-label prac- tention. 40 mg/d dose [31]. A small. The SGA are drugs suggest an average dose of 22. It follows that there is a relative lack dose. 20. what does risperidone’s phar. sistant depression. an increase D2 receptor occupancy and antagonism. that of clozapine which is sometimes noted to be the most effica- pressed patients to improve and promoted elevated brain derived cious antipsychotic [3. antipsy- tain brain areas at these low doses. These data reinforce Outside of the BDNF hypothesis. Risperidone is a fairly proved for dosing in autism. Risperidone here makes the case that moderate to ment on anecdotal case reports of patients taking 60 mg/d with high doses. to antagonize 5-HT2a receptors. open-label study suggested that low dose risperidone also helped Olanzapine is the SGA with the molecular structure most similar to Selective Serotonin Reuptake Inhibitor (SSRI) non-responsive de.5–3 mg/d) were found to be effective in a 4 week study by Keitner et al. occupancy. It has a high affinity for D2 receptor antagonism. lower doses of paliperidone would be antipsychotic effects likely occur. are needed for antipsychotic and good effect [29]. randomized. Perhaps consistent with other 20 versus 40 mg/d study suggested no difference in doses except literature.5–2 mg/d) risperidone less than risperidone and paliperidone) for D2 receptor antago- was effective in treating depression and suicidality symptoms in nism. This series of risperidone for depression findings be 10–15 mg/d [27. there is less risk for EPS. allows. When this occurs in the nigrostriatal dopamine blockade at greater doses lowers psychotic symptoms. An average dose in schizophrenia or bipolar mania might particular [21]. the higher the dose of antipsychotic needed. Sometimes.Second Generation Antipsychotic Dosing Strategies T. a patient is. lower than ‘antipsychotic’ doses (0. As the active metabolite appears to be state dependent dosing in that lower doses may of risperidone it offers a very similar DA-2/5HT-2a receptor an- better treat younger patients with autism and agitation where tagonism to the risperidone parent product. for ultimate symptom reduction. cross-over sistently after ingestion and has a relatively high affinity (though study suggested that even lower dosed (0. The more severely ill. system. lite seems to have less orthostasis and metabolic risks than the Risperidone is not indicated for depression or anxiety. concentration. increases at low risperidone doses. base. Increasing lect dopamine pathways [10]. A smaller. All SGAs possess this property to some namic sense as higher doses will allow for better DA-2 receptor degree. founded as yet. If they can promote selective dopaminergic activity in cer. There its use in the treatment of depression. This metabo- has little antipsychotic effect. This makes theoret- ity. this drug likely more effective in depression than in schizophrenia. Three milligrams per day and less seem to 40 mg/d doses did not reveal statistical improvement at the higher help depressive symptoms. it could be suggested that palidperidone might have the same This makes dynamic sense as higher doses will allow for better D2 ability as risperidone to treat depression symptoms but this is un- receptor occupancy. Dos- 6–12 mg/d [23. These cognitive tices. dicated for depression or anxiety. Olanzapine monotherapy is not in- Spartan drug in terms of additional pharmacologic binding prop. Risperidone Paliperidone This drug appears to be absorbed consistently after ingestion and This drug is the active metabolite of risperidone noted above. the D2 receptor antagonism becomes stronger and SGA. which may allow for better at. Stahl reader through the similarities and discrepancies between clinical BDNF at low doses affording treatment of depressive symptoms. Similarly. this neurotrophic factor allows for healthier neuronal patients with more significant baseline symptoms responded pref- connectivity and neurotransmission to alleviate depression [22]. Once this antagonism reaches 60% or more.

FDA approved anxiolytic buspirone works through This drug similarly started out indicated for schizophrenia and this purported mechanism in the treatment of generalized anxiety bipolar mania comparable to risperidone and olanzapine. tential as such and observing its unique pharmacodynamic pro- tivity through this 5-HT2c receptor antagonism. Similar to the lower dose effectiveness potential in the fluoxetine ratios: 3–18 mg/d plus 25– 75 mg/d [34. hypercholesterolemia should be screened prior to hypnotic agent [55]. Un- than the FDA norm. olanzapine as 5HT2C blockade may allow better norepinephrine Quetiapine is the only SGA approved as a monotherapy for and dopamine cortical activity through enhancing mesocortical bipolar depression. and executive func. weight gain. and anxiety as a result. Anti. Treating is more potent than for the previous two SGAs (risperidone and depression or anxiety at these lower doses likely does not inhibit paliperidone) and could contribute to the clinical effectiveness of dopamine transmission compared to higher doses. Olanzapine. milligrams to maintain at least 60% receptor occupancy to stop energy. multiple. the serotonergic and noradrenergic pharmacodynamic properties proved which may improve compliance.58]. it allows for 5HT-1a receptor agonism. L. Absorption of the imme. H-1 receptor antagonism is the theoretical mech- fects are likely to occur. Its D2 recep. but clini- a lower EPS side effect profile as a benefit [46]. hydrox- The SGA class carries FDA warnings now about increasing the yzine [46]. Dosing in these to SSRI or SNRI antidepressants. To complicate matters. This low affinity may allow for quetiapine to maintain an inability to treat psychosis and mania at low doses. H-1 receptor blockade can produce fatigue as a side risk of metabolic disorders. psychosis or mania. concentration. Queti- ments that the use of quetiapine at doses greater than 800 mg/d apine XR has now been studied from 50 to 600 mg/d in a myr- up to 2400 mg/d has been noted in anecdotal reports [48]. lease product achieves peak plasma levels. has a slightly more complicated pharmaco. once daily version of quetiapine has been ap. disorder onset. Second. or hyperglucosemia. (2007) reported that in a New til recently. For example. cally has the potential to treat depression at low doses based on A slow release.45]. 4 mg of risperidone or 15 mg of it is likely that at lower doses of quetiapine. Sometimes these side effects cause patients use of olanzapine and throughout its longitudinal use. The norquetiapine metabolite has two in- teresting features. confirmative. NRI properties possessed by FDA approved unipolar antidepres- tor antagonism is quite weak compared to all other SGA and may sants such as venlafaxine. Quetiapine has 5HT-2a and 2c antago- nism. iad of psychiatric disorders and regulatory data would suggest that CNS Neuroscience & Therapeutics 17 (2011) 110–117  c 2011 Blackwell Publishing Ltd 113 . an active metabolite. Enhancing dorsolateral prefrontal cortex DA ac. This does not and desipramine [46]. ample. Simi. disorder [46. effect but also somnolence as a bona fide clinical hypnotic effect. bly with other psychotropics known to promote weight gain and Quetiapine is quite low in anticholinergic activity so these side metabolic clinical syndromes [37–43]. Olanzapine also has higher affinities to antagonize cholin. Patients with a strong family or personal history of diabetes. regulatory studies have consistently shown that lower doses of dynamic profile when compared to risperidone and paliperidone. In regards to dosing quetiapine higher favorable EPS rates. For ex- Olanzapine certainly binds to D2 receptors to dampen dopaminer. Olanzapine approach [49. this drug has enhance cognition. In theory it has very good antidepressant po- pathways [10]. First. which lowers EPS rates and improves cognition likely as dis- cussed for other SGAs. in theory. off-label use of risperidone in depression. 3–4 h post dose. one might expect improvements in cognition. Quetiapine also has some limited data in the blocks 5-HT-2c receptors as well. attention. be considered as a low potency or low affinity drug. and between the parent drug tioning.T. risk for weight gain. anism of anxiolysis utilized by the FDA approved agent. added sion or treatment resistant unipolar depression.50]. the drug is less effec- olanzapine may prove effective where 400–800 mg of quetiapine tive at antagonizing and lowering dopamine activity resulting in is needed. and memory and similar to olanzapine may promote sedation and metabolic problems. Again. quetiapine are quite effective in treating depressive states. noted above and per confirmatory regulatory trials showing clini- diate and slow release products is predictable. Schwartz and S. depression and also as an augmentation strategy that is. effects are largely avoided.35]. A review paper com. ing insomnia as is the recently FDA approved low dose doxepin hypertension. it was unclear if metabolic symptoms emerged in a York State hospital system 40% or more of persistently ill patients dose-dependent fashion or if any exposure to quetiapine created were receiving greater that 750 mg/d [47]. est risks based upon the full evidence base available regarding the Over the counter diphenydramine products are approved for treat- SGAs. This action at 5HT2C receptors treatment of anxiety at doses of 50–300 mg/d [51–53]. is This drug also is now approved as a monotherapy for bipolar FDA approved as a combined therapy for either bipolar depres. fluoxetine. effects. It also has the ability to antagonize 5-HT2a receptors 150–300 mg will treat unipolar depression as an augmentation thus keeping EPS rates low when compared to FGAs. Similar to these FDA approved agents in suggest it has low effectiveness. and likely sedating side Quetiapine’s adverse effect profile shows remarkable sedation. depression. this to stop taking this medication and sometimes these clinical effects practice should likely be implemented for all SGA use and possi. in unipolar major depressive two types of depression is as follows in regard to olanzapine to disorder. The Quetiapine serotonergic. respectively [36]. sedation. bupropion. Olanzapine itself. higher doses (400–800 mg/d) are required to control the pinephrine reuptake inhibitor (NRI) property which is similar to symptoms associated with these disorders [44. norquetiapine. might file is worthy of discussion. carries one of the high. hyperlipidemia. and metabolic disorder side ef. M. concentration. and its metabolite many antidepressant and anxiolytic properties ergic muscarinic receptors and histamine-1 (H-1) receptors. In fact. Citrome et al. duloxetine.56]. emerge [54]. this metabolite has a very potent nore- larly. nortryptiline. cal efficacy [57. but rather requires more dosing clinical application. though the slow re. improve sleep or agitation similar to other antihistamine products. constipation. 300 mg will treat bipolar depression as a monotherapy and gic activity. and a fair risk for metabolic disorders. blurred vision. This drug has remarkable H-1 receptor antagonism cholinergic dry mouth. Stahl Second Generation Antipsychotic Dosing Strategies when combined with the unipolar antidepressant.

This SSRI mechanism is commonly used to treat unipolar neurotransmission. M. Similar In regard to treating anxiety disorders. lower doses of aripiprazole seem to be effective to adverse effects. Aripiprazole was the first FDA approved drug Stahl and Cutler et al. This drug has a relatively tion. using may occur in the dopamine mesolimbic system where dopamine the maximal FDA dose in the schizophrenia and bipolar popu- hyperactivity is felt to cause psychosis and mania. but smaller studies and those that focus lower than doses used in schizophrenia or mania [77]. lower doses of ziprasi- bust activity partially agonizing 5HT-1a receptors similar to the done may be effective in the treatment of anxiety or depression. In regards ously noted SGAs. Stahl doses around 150 mg/d may be safer than those at 300 mg/d. One open-label study for a unipolar depres- stead. but has dosing in a New York State hospital system [47].65]. mechanism of action for the FDA approved anxiolytic buspirone where higher doses are needed for mania or psychosis. doses starting from 15 mg up to 30 mg/d. whereas 300 mg nearly doubled these two side effects’ prevalence in acute studies. may be unique in its ability to This higher dosing strategy uses aripiprazole’s high D2 receptor also act as an SSRI and inhibit the serotonin transporter system affinity. is indicated for schizophre. Again. ziprasidone is unique in that it clearly re- open-label studies exist for generalized anxiety disorder (GAD) or quires it to be taken with food to allow for adequate absorp- panic disorder (PD) with suggested effectiveness in these patients tion and bioavailability [61] and is clearly a drug that should be at doses on average of 13. More recently. In fact. a reduction in dopamine transmission is not required. however. despite partial D2 receptor agonism to lower dopamine [64. but a follow-up study in depres- dren in low doses of 2– 15 mg/d [78]. It is actually a partial D2 receptor agonist. In- results [66. Patients remain on their ziprasi- fact. which is much show consistent results. done longer due to improved clinical effectiveness [62]. Ziprasidone may be effective in treating anxi. 114 CNS Neuroscience & Therapeutics 17 (2011) 110–117  c 2011 Blackwell Publishing Ltd . tory. and given its partial agonist properties. Ziprasidone possesses the common D2 and 5-HT2a receptor dual Originally approved for treating psychosis from schizophrenia at antagonism properties well documented for other SGA. almost 50% of pa- which again diminishes EPS. lations has been found to promote longer. Small Pharmacokinetically. this agent is clinically known to avoid remark- in treating depression and anxiety where higher doses are required able weight gain and metabolic disorders when compared to other for mania and schizophrenia.69]. similar to many other SGAs. in ter due to D2 receptor blockade. aripiprazole shows a difference depend- dotal evidence for dosing above the usual FDA approved limits. weight gain and hyperglycemia nearly comparable [73]. The same This may have pro-cognitive and antidepressant effects in clini- author observed that dosing typically rose above 180 mg/d to an cal practice [10]. sion was less conclusive.68. promotes cognition. (mentioned in regards to norquetiapine and ziprasidone). this drug contains ro- to lower dosed risperidone and quetiapine. tidepressant dosing. Interestingly. which is a Ziprasidone unique pharmacodynamic property amongst the SGAs [10]. SGAs and was the first SGA noted to prolong QTc cardiac intervals For example. This suggests a dopamine balancing property where aripiprazole can This drug. apine above. It stands alone with a unique SGA mechanism for dampening dopamine transmission.74. both at a low 80 mg/d dose. were effective drug was approved for treating irritability due to autism in chil- in reducing symptoms[70. unlike queti- ing super dosing above the approved limit of 30 mg/d. Large-scale studies in bipolar depression have failed to the average dose being approximately 10 mg/d. promoting dopamine. where quetiapineXR was approved later [5.76]. ziprasidone is et al. and antidepres- tients were treated at doses greater than the approved maximum sant potential. In theory this is due to clear dose–response a dopamine-3 (DA-3) receptor partial agonist.’s (2007) review again would offer about a 10% above label not approved for the treatment of depression or anxiety. This property likely effects at the higher doses where symptoms are controlled bet- does not add to antipsychotic or antimanic activity but might. Aripiprazole carries previously mentioned 5HT- average of 206 mg/d in theory for the treatment of more refrac- 2a receptor antagonism and 5HT-1a receptor agonism properties. This drug. Citrome apine and the olanzapine–fluoxetine combination. fewer published data showing some potential antidepressant ef- More recently. Dosing in major ety and depression at low doses where DA-2 antagonism is not depressive disorder is again low and ranges from 2 to 15 mg/d with needed. This data was obtained when quetiapineXR was being studied for antidepressant augmentation Aripiprazole in unipolar depression [4]. especially at higher doses [72].9 mg/d [79.this agent was also approved for treating unipo- fects compared to the limited data of risperidone in depression or lar depression in those patients who failed to respond to initial an- anxiety [66]. Currently. this drug was sec- tagonizes 5-HT1a receptors and inhibits NRI similar to norqueti- ondarily approved to treat mania starting at 30 mg/d [5. It also an. of 160 mg/d [47]. At these on dysphoric symptoms of mania have concluded with positive doses.80]. Schwartz and S. sim- for use as an augmentation strategy in major depressive disorder. sustained ziprasidone Aripiprazole is fairly unique in another property where it is also use amongst patients. ing upon which illness is being treated similar to other SGAs. This mania with average doses of 120–180 mg/d. similar to previ- taken twice a day per regulatory agencies and studies.71]. Aripiprazole might be considered an atypical atypical.Second Generation Antipsychotic Dosing Strategies T. state-hospitalized patients [63]. L. this generalized anxiety. lend to promoting dopamine transmission in cortical areas. [67] suggest that in clinical practice. Ziprasidone appears to have the greatest anec- In regard to dosing. to placebo rates. ilar to quetiapine.75]. norepinephrine and serotonin likely sion augmentation approach and another for treatment resistant occurs as the principal mechanism of action. partially stimulate dopamine in areas of low dopamine concentra- nia and bipolar mania treatment [59–61]. There is very little literature evidence show- depression and many anxiety disorders. actually blocks the full high affinity for D2 receptor antagonism and treats psychosis and agonist dopamine in areas of high dopamine concentration.

This drug’s molecular struc- In this article. and Selective Serotonin- Acknowledgments Norepinephrine Reuptake Inhibitor (SNRI) potential allows for a pharmacodynamic profile more similar to that of risperidone. this drug is known to be a p450 12 mg twice daily on days 2. depression. carry side effects. They have FDA approvals in areas of done oral tablets which require food to be absorbed. With the advent of studying depressive disorders at lower doses. from the most simplistic ture is similar to the antidepressant mirtazapine [81] and may SGA. mania. 4. Similar to other SGAs. and more recently however. disorders. pharmacodynamically speaking. iloperidone may which symptoms the clinician aims to treat. and metabolic yet for using it in the treatment of depression or anxiety. Side effects are likely less at lower erature exist for use of this agent outside the dose range of 10– doses. These daily be confused with more traditional akathisa. This and the authors conclude briefly with the two most recently ap- drug is new and a MEDLINE search suggests no evidence for using proved SGAs. This is the exact opposite of ziprasi- multifunctional drugs [91]. 20 mg/day. Canfield at SUNY Upstate Medical University for their time in lo- or asenapine [10. is felt to be more metabolically friendly in regards to daily. These agents may be flexibly used as monotherapies and appear to be antidepressant/anxiolytic at one dose and anti- Iloperidone manic/antipsychotic at the next higher dose. Similar to other SGAs. This drug adult or child schizophrenia and bipolar disorder. or bipolar for its higher probability of inducing akathisia (sometimes greater disorder. which vary to some degree but all patients on 2a receptor blockade. respectively. and 7. 8 mg twice daily. M. This agent. The sec- taken sublingually and without food or drink 15 min thereafter ond principle suggests that some of the SGA are now well-defined to ensure absorption [81]. L. but also may be due to its over. It has a complicated titration schedule and requires increases all monoaminergic activity where restlessness and agitation may to reach the target dose range of 6–12 mg twice daily. gistical support and preparation of this manuscript. multaneously taking a strong 2D6 inhibitor such as fluoxetine or This drug is a known substrate for the p450 2D6 liver enzyme paroxetine [5]. ziprasidone. to the most complicated. all of the SGAs possess the pharmaco- it in the treatment of depression or anxiety. In general. CNS Neuroscience & Therapeutics 17 (2011) 110–117  c 2011 Blackwell Publishing Ltd 115 . 5. As add-on or aug- Iloperidone is the most recently approved SGA for the treatment mentation therapies.87]. Iloperidone also has been noted to increase cardiac QTc intervals by 9 msec and carries precautions Asenapine similar to that of ziprasidone [86]. Its 5HT-1a. Its pharmacodynamic logic actions needed to ameliorate psychosis. autism. the SGAs are discussed. 3. asenapine may treat these symptoms with a lower risk of EPS due Summary to its D2/5HT-2a receptor blockade. some if not all of profile suggests some treatment possibilities in these clinical areas the SGAs have properties to ameliorate mania. aripiprazole is known ing iloperidone in regard to treating depression. promote cortical serotonin and norepinephrine activity [85]. similar to dosage adjustments proceed from 2 mg twice daily. and minimizing weight gain. Finally. Unique to this SGA is that it must be blockade. it is a clear principle that each SGA must be used Dosing typically is 5 mg twice daily with a maximum daily dose near the peak of its daily dose range. This is also where EPS will most likely occur. macodynamic profile [88] suggests some treatment possibilities in these clinical areas however. It’s phar. system and iloperidone blood levels may increase when adminis- tered with 2D6 inhibitors such as paroxetine or fluoxetine similar to precautions with aripiprazole. anxiety. 6.T. schizophrenia [89. 6 mg twice daily. Very little experience and no lit- pressive disorders in particular. it has a structure similar to mirtazapine themselves to treating psychosis. regulatory data are starting to reveal this fact in a more strin- gent manner. and antidepressant potentials are similar to SGAs mentioned ear- The authors have attempted to describe how these properties lend lier and as noted above. Schwartz and S. 5HT-2a. In order to stop mania cortex. A MEDLINE search reveals no papers study. daily. and some- with documented serotonin and norepinephrine activation in the times anxiety in clinical practice as well. Umar A. The authors would like to thank Dr. or psychosis.90]. This drug is new so there is also no evidence SGAs should be routinely monitored for TD. Siddiqui and Kelly iloperidone. and olanzapine than that of quetiapine. 10 mg twice daily. Asenapine was simultaneously approved for treating schizophre- nia or bipolar mania very recently [81–84]. This optimizes D2 receptor allowed up to 20 mg [81]. Its daily dosing should be halved with was demonstrated at a dose range of 6 to 12 mg twice daily for a maximum daily dose of only 15 mg/d in patients who are si. Stahl Second Generation Antipsychotic Dosing Strategies From an adverse effect point of view. than 20%) [5] compared to other SGAs. Efficacy 2D6 liver enzyme substrate. 4 mg twice ziprasidone. Its relative lack of 5HT-1a receptor agonism. and de- is a known substrate for the p450 1A2 liver enzyme system and pressive disorders. Many of the non-dopaminergic properties of asenapine blood levels may increase when administered with 1A2 these drugs occur at lower doses and lend themselves to treat de- inhibitors such as fluvoxamine. 5HT-2c receptor antagonism. EPS. the dose range is also varied depending upon of schizophrenia [86. and 5HT-2c receptor pro-cognitive some SGAs have shown ability to treat depression and autism. This may be due to The recommended starting dose for iloperidone is 1 mg twice its high D2 receptor affinity. which is common amongst most classes of medications.86]. These drugs certainly treat these symptoms with a lower risk of EPS due to its D2/5HT.

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