Keywords

1 Introduction

Schizophrenia (SZ) and schizoaffective (SA) disorder are pervasive and debilitating conditions. The biological mechanisms underlying these disorders are not fully understood.

The dopamine hypothesis states that there is over activity in the dopamine systems. The hypothesis stems from the finding that all effective anti-psychotic medications block dopamine brain receptors, and that their potency correlates with the strength of binding to dopamine D2 receptors in the brain. However, the idea that the symptoms of psychosis are caused by the overactivity of dopamine is not supported by currently available evidence [1].

Dopamine (DA) D2 receptor antagonism is a unifying property of all antipsychotic drugs, while often effective at ameliorating psychosis, these drugs are largely ineffective in the treatment of negative and cognitive symptoms. In recent years, a variety of new experimental pharmacological approaches have emerged, including compounds that act on targets other than the dopamine D2 receptor. However, there is still an ongoing debate as to whether drugs selective for singe molecular targets (that is, ‘magic bullets’) or drugs selectively non-selective for several molecular targets (that is, ‘magic shotguns’) will lead to more effective new medications for schizophrenia [2]. This has prompted multifactorial approaches to the development of new therapeutics, such as polypharmacy and an augmentative strategy known as “intramolecular polypharmacy”, in which a single drug has the capacity to affect multiple receptor types [3]. These multi-target agents (also called ‘multifunctional drugs’ [4]) with more than one putative therapeutic mechanism of action may lead to the development of selective drugs for the treatment of SZ/SA disorder.

The concurrent use of more than one drug to treat syndromes and diseases is common in internal medicine [5, 6]. Wald and Law [7] postulated that using a combination of well known, inexpensive medications in one pill (the “polypill”) would be a particularly effective treatment against cardiovascular disease. They presented a statistical model which suggested that widespread use of the polypill could reduce mortality due to heart disease and strokes by up to 80%. The treatment is potentially inexpensive, with few side effects (in perhaps 10–15% of recipients) and the research was based on data from many trials relating to the individual components. Increasingly, combined antihypertensive agents are being used in practice to enhance control and improve compliance. In some cases, a combination of relatively low doses has resulted in superior efficacy not only to the components administered alone but to higher doses of the individual components [8 ]. Systematic reviews and meta-analyses have confirmed that there is evidence that low-dose combination products could provide equal or enhanced efficacy with a potentially reduced adverse effect burden [9]. Mahmud and Feely [10] report a prospective study using a capsule containing four different antihypertensive drug classes, each given in a dose one quarter of the usual dose of the preparation: patients received amlodipine (5 mg), atenolol (50 mg), bendroflumethiazide (2.5 mg), and captopril (50 mg twice daily) or a capsule containing each of the four above at one-quarter dosage in a parallel group design for 4 weeks. This randomized trial indicates that the capsule containing four agents of different classes at a quarter of the usual dose was more effective at lowering blood pressure than any of the individual drugs alone in the usual dose. There is clearly a lot of work to be done before any product could be registered for use in hypertension, but this preliminary report confirms the theoretical basis of the polypill concept and suggests that other multiple drug therapy approaches using low doses may be able to realize benefits at least as great as those predicted from the controlled trials [5]. Thus, a range of combination therapies utilizing medications with differing mechanisms of action have been shown to provide superior blood pressure-lowering efficacy than monotherapy with individual components.

Although the international guidelines recommend antipsychotic monotherapy as the treatment of choice, many of SZ/SA patients receive two or more antipsychotics in clinical practice (antipsychotic polypharmacy). The term “combination” includes virtually all the ways in which one medication may be added to another. The other commonly used terms are “augmentation” which implies an additive effect of a second medicine added to the initial prescribed drug, an “add on” which implies adding on to an existing, possibly effective treatment which, for one reason or another, cannot or should not be stopped [11]. Experts recommend polypharmacy in a few special clinical situations [12]:

  • For augmentation when a patient fails to respond to adequate antipsychotic trials,

  • In some instances of failed cross-taper of antipsychotics, and

  • Adding an FGA to a SGA for agitation during acute treatment of psychosis.

Interestingly, a myelin-centered model of human brain function suggests that widely used psychotropic treatments share complex signaling pathways such as Akt and glycogen synthase kinase-3 (GSK3) that affect myelination, its plasticity, and repair [13, 14]. Independent lines of research involving biochemical and behavioral approaches in normal and/or genetically modified mice provide converging evidence for an involvement of the signaling molecules Akt and GSK3 in the regulation of behavior by DA and 5-HT (5-hydroxytryptamine, serotonin) neurotransmissions [15]. It may also provide a link between the action of these neurotransmitters and gene products, such as those disrupted in schizophrenia one (DISC1) and neuregulin (NRG), that are associated with increased risk for mental disorders [16]. These signaling pathways respond to neurotransmitters, neurotrophins, hormones, and nutrition, underlie intricate neuroglial communications, and may substantially contribute to the mechanisms of action and wide spectra of efficacy of current therapeutics by promoting myelination [17].

The trend of antipsychotic polypharmacy has increased considerably, especially since the introduction of second generation antipsychotics (SGAs) [11, 12]. Pickar and associates [18] reported that only 25% of 200 schizophrenia patients are treated with antipsychotics alone. Nielsen and co-authors [19] using a cohort study of newly diagnosed patients with schizophrenia in Denmark (n  =  13,600) reported that between 1996 and 2005 there was increased use and dosing of antipsychotics and antidepressants, as well as more antipsychotic polypharmacy. In contrast, antipsychotic monotherapy of Japanese inpatients with schizophrenia increased from 31.6% in 2007 to 33.8% in 2009 [20].

There are current updates and critical reviews of the pharmacology and clinical profiles of current antipsychotic drugs and preparations that act on novel targets and have the potential to be therapeutic agents in the future [2, 21–26]. This chapter is an overview the current state of evidence of the augmentation of antipsychotics with antidepressants, lithium, antiepileptic agents, benzodiazepines, and new molecules and compounds for the treatment of SZ/SA disorder (Fig. 8.1).

Fig. 8.1
figure 00081

Adjunctive pharmacological drugs and supplements (© M.S. Ritsner (2012) and used by permission)

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2 A Multi-Target Drug Treatment

The aim of augmenting antipsychotics, multi-target drug treatment approach, is to combine two or more drugs/agents with different mechanisms of action on the central nervous system in an attempt to enhance efficacy and/or tolerability. There are several possible rationales for a multi-target drug treatment approach that is more likely to alleviate core and comorbid symptoms.

  • The multifactorial genesis, genetic heterogeneity and pathogenesis of schizophrenia and other functional psychoses/disorders cannot be attributed to any single cause, see, e.g. [27, 28], and Fig. 8.2 [40].

    Fig. 8.2
    figure 00082

    Multidimensional continuum model of functional psychoses for research purposes (Version 1.1) (© M.S. Ritsner [26] and used by permission)

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  • In light of the clinical polymorphism of these conditions, it is unlikely that any antipsychotic drug would work equally well against positive, negative, and mood symptoms, cognitive, functional and quality of life deficits, and against behavioral disturbances in all patients. Indeed, although clinical guidelines recommend the routine use of a single antipsychotic drug in a standard dose [41, 42], prescriptions for high-dose and combined antipsychotics are common in clinical practice [43].

  • Poor treatment response of patients with SZ/SA is a compelling clinical problem. In addition to the poor response of about one-third of SZ/SA patients [44], antipsychotic monotherapy is often inadequate in the management of particularly challenging symptoms such as negative and cognitive disturbances, affective instability, anxiety or insomnia, persistent aggression, functional and quality of life impairments.

  • In addition to dopaminergic, serotonergic, noradrenergic, and glutamatergic pathways, γ-amino-butyric acid (GABA) and acetylcholine dysregulation have also been implicated in the pathogenesis of SZ/SA disorder [45–48].

  • Multiple lines of evidence have linked degenerative abnormalities in both post-mortem and brain imaging studies to the pathophysiology of SZ/SA disorder [49]. These changes include ventricle enlargement, volumetric reduction, and atrophy or loss of neurons and glial cells in selective cortical and limbic brain regions [25, 26, 50, 51].

  • Neurotrophic effects can be considered a therapeutic strategy intended to augment proliferation, differentiation, growth, and regeneration, whereas neuroprotective effects slow or halt the progression of neuronal atrophy or cell death following the onset of disease or clinical decline [52]. Available data suggest that psychotropic treatment needs to target brain protective mechanisms [14, 29].

  • Antipsychotic agents might be enhanced by co-administration with antidepressants, mood stabilizers, benzodiazepines, and others compounds that act via other, non-dopaminergic mechanisms (e.g., serotonergic, glutamatergic, adrenergic receptors, and others) [23–26].

Thus, elucidation of the contribution of multiple signaling pathways to the action of psychotropic drugs might lead to more efficient multi-target drug therapeutics for SZ/SA disorder, especially for the associated cognitive impairments, negative and mood symptoms.

3 Augmentation in the “Real World”

Adjunctive pharmacological agents are extensively used in the treatment of patients with schizophrenia. There are two types of adjunctive agents:

  • Off-label prescription of adjunctive agents, such as antidepressants, lithium, antiepileptic drugs, and benzodiazepines that are already in use; and

  • Newer molecules or compounds based on several non-dopaminergic hypotheses that are currently being examined.

There are established practices in “real world” pharmacotherapy. Pickar et al. [18] reported that 70% of 200 schizophrenia patients received an antipsychotic together with medication from another drug class: the most common drug class combinations were antipsychotics and mood stabilizers. A total of 42.5% of patients received more than one antipsychotic drug.

Cascade et al. [53] found that 43% of patients receive one additional class to supplement their antipsychotic medication, and 10% of patients are prescribed two or more classes of drugs in addition to an antipsychotic agent. The most common classes used to supplement antipsychotic medications in the management of schizophrenia include antidepressants (28%), mood stabilizers (18%), sleep aids (5%), and agents to treat extrapyramidal symptoms (7%), according to Dussias et al. [54]—20%, 15%, 7%, and 6%, respectively.

Längle et al. [55] evaluated the effects of different types of psychotropic polypharmacy on clinical outcomes and quality of life in 374 patients with SZ/SA disorder in routine care before discharge and after 6, 12, 18, and 24 months. At baseline 22% of the participants received antipsychotic monotherapy (quetiapine, olanzapine, or risperidone), 20% received more than one antipsychotic drug, 16% received antipsychotics combined with antidepressants, 16% antipsychotics plus benzodiazepines, 11.5% had antipsychotics and mood stabilizers, and 16% received psychotropic drugs from three or more subclasses.

Shinfuku et al. [56] based on a systematic chart review of 300 patients (100 of whom were psychotropic-free prior to their first visit) during a 2-year period, reported that polypharmacy occurred in 79% of the patients, with 2-year rates of the use of hypnotics (56.7%), benzodiazepine derivative anxiolytics (49.7%), anticholinergic drugs (38.3%), antidepressants (21.3%), and mood stabilizers (14.0%). Once polypharmacy had started, it was continued until their final visit in >70% of the patients. Himelhoch et al. [57] estimated the receipt of prevalent and incident antidepressant medications in the fiscal year 2007 among 2,412 veterans who received treatment for schizophrenia. They found that 37.4% also received an antidepressant prescription.

In order to determine the frequency of off-label prescriptions for mood stabilizers a cross-sectional survey of inpatients aged 18–65 years at St Andrew’s Hospital (Northampton, UK) was carried out [58]. Thirty percent (75/249) patients were administered one or more mood stabilizers, of which 71 were off-label. Sim et al. [59] examined the frequency of mood-stabilizer use and its clinical correlates among hospitalized patients diagnosed with schizophrenia in 2001–2008 in nine Asian regions (China, Hong Kong, India, Korea, Japan, Malaysia, Taiwan, Thailand, and Singapore). Overall, mood stabilizers were given to 20.4% (n  =  1,377/6,761) of hospitalized schizophrenia patients, with increased usage over time. Xiang et al. [60] surveyed the use of adjunctive mood stabilizers in older Asian schizophrenia patients aged 55 years or more that were extracted from a database that included 1,452 patients from nine Asian countries and territories. The frequency of prescription of mood stabilizers was 26.7% in the pooled sample, with 25.5% in 2001, 26.9% in 2004 and 27.7% in 2009. Multiple logistic regression analysis of the whole sample revealed that patients on mood stabilizers were younger and more likely to be men and to have extrapyramidal side effects (EPS) and a longer duration of illness.

Guidelines for the prescription of benzodiazepines (BZD) recommend that their use be limited to the short-term relief of severe anxiety or insomnia. However, clinical experience suggests that in psychiatry these drugs might be more broadly prescribed. Haw and Stubbs [61] investigated benzodiazepine prescribing in a specialist UK psychiatric hospital using a structured interview with consultant psychiatrists. Of 412 inpatients, 77 (18.7%) received 90 BZD prescriptions for psychiatric indications. Most prescriptions were for anxiety (45/90; 50.0%), aggression (23/90; 25.6%) and agitation (13/90; 14.4%). Use was commonest for acquired brain injury, schizophrenia (26/77; 33.8%) and personality disorders. Much usage was chronic (only 4.4% prescriptions had been initiated within the previous 4 weeks) and off-label (94.4%). In psychiatry BZD are quite frequently used in the management of a number of groups of difficult-to-treat patients.

The frequency of BZD prescription in nine Asian countries and territories was 20.7% in the pooled sample, with 20.2% in 2001, 18.4% in 2004 and 23.1% in 2009 (the sample included 1,452 hospitalized schizophrenia patients aged 55 years or more). Compared to patients in China, their Korean and Singaporean counterparts were more likely to be on BZD [60]. Use of psychotropic medications (antidepressant, anxiolytic, and sedative/hypnotics) by 1,449 participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was documented at each study visit: initiation of new adjunctive agents post baseline period was moderately frequent, 14.6% of patients received antidepressants, 13.7% received anxiolytics, and 11.2% received sedative/hypnotics [62].

Thus, substantial proportions of patients with SZ/SA disorder do not achieve acceptable levels of response with antipsychotic therapy alone, which commonly leads clinical psychiatrists to use augmentive agents. Differences in the use of adjunctive medications may be due to true differences in the frequency of ancillary symptom complexes. For instance, among patients with recognized ancillary symptom complexes, black patients may also be less likely than white patients to receive treatment. This may be due to racial differences in accessibility of mental health care, physician perceptions of patients, and patient beliefs and preferences [63]. Further research is needed to clarify the underlying biases and behaviors that affect use of adjunctive medications among patients with schizophrenia.

4 Antidepressants

Depressive symptoms in patients with schizophrenia may be secondary to negative symptoms [64], medications, or neuroleptic-induced movement disorders [65], or a core component of various stages of SZ/SA disorder [66, 67]. At the same time, depressive symptoms are common in older patients with schizophrenia [68]. The most prevalent symptoms cut across several domains of the depressive syndrome: psychological (e.g., depressed mood, depressed appearance, psychic anxiety); cognitive (e.g., guilt, hopelessness, self depreciation, loss of insight); somatic (insomnia, anorexia, loss of libido, somatic anxiety); psychomotor (e.g., retardation and agitation) and functional (diminished work and activities) [69].

Lako et al. [70] investigated the prescribing patterns of antidepressants in relation to the course of depressive symptoms in a cohort of 214 Dutch patients with psychotic disorder patients. Depressive symptoms were prevalent among 43% of the patients. Antidepressants were prescribed for 40% of the patients and the majority (83%) continued this therapy after 1 year.

4.1 Mechanism of Action

A common mechanism of action of antidepressant drugs has not been found. Antidepressants are usually classified according to structure (e.g., tricyclic antidepressants, TCAs) or function (e.g., monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, SSRIs). However, it may be more useful to classify them according to the acute pharmacologic effects that are presumed to trigger behavioral improvement. If this is done, the antidepressants can be grouped in four categories [71]:

  • Selective blockade of norepinephrine reuptake: desipramine, nortriptyline, amoxapine, maprotiline reboxetine

  • Selective blockade of serotonin reuptake (SSRIs): citalopram, fluoxetine, paroxetine, sertraline

  • Nonselective enhancement of norepinephrine and 5-HT transmission: imipramine, amitriptyline, phenelzine, tranylcypromine, venlafaxine, mirtazapine

  • Unknown potent stimulatory effects on norepinephrine and 5-HT: trimipramine, bupropion, nefazodone, trazodone

The molecular mechanisms underlying the augmentation are unclear. There is increasing evidence suggesting that symptoms of depression and anxiety may be associated with serotonergic dysfunction in schizophrenic patients; significant progress has been made, pointing to some candidate systems which may be involved in SSRI-antipsychotic synergism. While as yet limited in scope, the evidence suggests definable molecular targets which may be implicated in drug development based on SSRI-antipsychotic synergistic actions [72]. Laboratory investigations into the mechanism of this synergism showed that co-administration of SSRIs and antipsychotics produces changes in the GABAA receptor and related systems, which differ from the effects of each drug alone. SSRI augmentation of antipsychotics alters the expression of the GABAA receptor and related genes in peripheral mononuclear cells of schizophrenia patients [73].

4.2 Clinical Studies

The antidepressants that are most frequently assessed in clinical trials are those that are specifically targeted to treat persistent negative symptoms [30, 74–78].

4.2.1 Fluvoxamine

Published reports of clinical trials revealed that fluvoxamine improved negative symptoms and cognitive deficits in treated chronic schizophrenia [79–81]. Fluvoxamine at dosages up to 100 mg/day is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of fluvoxamine may elevate plasma levels. Fluvoxamine increases plasma haloperidol and risperidone concentrations in a dose-dependent manner [82, 83].

4.2.2 Fluoxetine

Current evidence indicates that fluoxetine can ameliorate primary negative symptoms in chronic schizophrenic patients treated with first-generation antipsychotics [84]. The combination is well-tolerated, although as antipsychotic drug concentrations may rise, close monitoring of drug doses and possibly drug concentrations is needed.

4.2.3 Citalopram

There is contradictory evidence that add-on citalopram to antipsychotic drugs may improve the psychopathological and/or cognitive symptoms in schizophrenia [85–87]. Kasckow et al. [86] conducted a 10-week single-blind trial of citalopram (20–40 mg/day) vs no citalopram augmentation in 19 middle-aged and elderly patients with schizophrenia hospitalized for more than six of the past 12 months. Patients in both groups improved on positive and negative symptoms, but the citalopram group revealed significantly greater improvement in the Hamilton Depression Rating (HAM-D) scale and Clinical Global Impression Scale scores than the control group. Citalopram (40 mg/d) adjunctive treatment to atypical antipsychotics produced no significant cognitive improvement in patients with schizophrenia after 12 weeks of treatment [87]. Citalopram augmentation of antipsychotic treatment in middle aged and older patients with schizophrenia and subsyndromal depression appears to improve social and mental health functioning as well as quality of life. Among 55 participants with schizophrenia or schizoaffective disorder and baseline suicidal ideation, citalopram reduced suicidal ideation, especially in those whose depressive symptoms responded to treatment [88]. Iancu et al. [75] evaluated the efficacy of escitalopram for the treatment of negative symptoms in patients with schizophrenia. Under double-blind conditions, 40 patients with chronic schizophrenia were randomized to add-on treatment with escitalopram (up to 20 mg) or placebo for 10 weeks. Escitalopram was well tolerated, but was not more effective than placebo in the treatment of negative symptoms in patients with chronic schizophrenia. A double-blind, crossover study demonstrated anti-aggressive effects of adjunctive citalopram in chronic schizophrenia [89].

4.2.4 Mirtazapine

Evidence that the combination of mirtazapine (remeron), and antipsychotic drugs may improve negative and/or cognitive symptoms in schizophrenia is contradictory [90–98]. Berk et al. [92] using a 6 week, double-blind design, recruited schizophrenia patients that were treated with SGAs plus mirtazapine (30 mg/day) or placebo, and did not find significant differences between mirtazapine and placebo treated participants in Positive and Negative Syndrome Scale (PANSS) scores or any of the secondary outcome measures. Abbasi et al. [93] investigated the effect of mirtazapine (30 mg/day) added to risperidone (6 mg/day) as augmentation therapy in 40 inpatients during the active phase of chronic schizophrenia and prominent negative symptoms in a double-blind randomized clinical trial. The mirtazapine group showed significantly greater improvement in negative symptoms and PANSS total scores over the 8-week trial. Mirtazapine was well tolerated and no clinically important side effects were observed. Other clinical trials suggest that augmentation with mirtazapine can effectively improve both negative and/or cognitive symptoms of schizophrenia [96, 97].

Overall, six randomized, double-blind, placebo-controlled trials assessed add-on mirtazapine to SGAs (four trials), and to first generation antipsychotics (FGAs, two trials). Five of the six trials supported the use of mirtazapine for negative symptoms of schizophrenia [98]. An open-label extension phase to a randomized controlled trial showed that mirtazapine continued to produce significant improvement in negative symptoms over a longer duration of time, when added to FGAs [95]. Mirtazapine appears to be well tolerated and associated with few drug interactions. Although adjunct mirtazapine to antipsychotics has been shown to be effective at doses of 30 mg/day in most of the trials, limitations of these studies include short study duration and small sample sizes.

4.2.5 Trazodone

Trazodone used in conjunction with neuroleptics, mildly reduced the severity of negative symptoms in residual schizophrenia (47 patients with an average age of 60 years) and did not exacerbate florid psychosis during a 6-week trial [99]. This conclusion was confirmed by Hayashi et al. [100] in double-blind, placebo-controlled small study (n  =  12) with the dose gradually increased from trazodone 50 mg/day to 200 mg/day. Results also indicated a possible beneficial effect of trazodone in the treatment of tardive dyskinesia.

4.2.6 Bupropion

Bupropion affects the uptake of the neurotransmitters norepinephrine and dopamine. Englisch et al. [101] reported on a consecutive series of depressed patients with psychotic spectrum lifetime diagnoses who received bupropion extended release for a period of 6 weeks in addition to stable doses of antipsychotic agents. All patients experienced significant improvements of their major depressive episodes. Psychotic positive symptoms remained stably absent, and both negative symptoms and global psychopathology considerably improved. The treatment was generally well tolerated; however, subtle electroencephalographic deteriorations were observed. This case series suggests safe and effective antidepressive treatment with bupropion in SZ patients, if stable antipsychotic medication and electroencephalographic-monitoring are provided. Further randomized studies involving a control group are necessary.

4.2.7 Buspirone

Buspirone is a partial agonist at 5-HT1A receptors, and is approved by the US Food and Drug Administration as an anxiolytic. It was tested for use in depression, panic disorder, obsessive-compulsive disorder, and schizophrenia as well [102]. Randomized controlled trials produced mixed results concerning the efficacy of buspirone in the augmentation of antipsychotic drugs [103–105]. For instance, 73 patients with schizophrenia, who had been treated with SGAs for at least 3 months, were randomly assigned to receive either buspirone (30 mg/day), or matching placebo. Attention, verbal fluency, verbal learning and memory, verbal working memory, and executive function, as well as psychopathology, were assessed at baseline, 6 weeks, and 3 and 6 months after baseline. A significant time by group interaction effect was noted on the Digit Symbol Substitution Test, a measure of attention/speed motor performance, with better performance of the buspirone group compared to the placebo group at 3 months [103]. On the contrary, in a 6-week, double-blind, placebo-controlled, independent group study, 18 subjects (14 males, four females) received in random order either placebo or buspirone (15–30 mg/day). There were no statistically significant differences between placebo and buspirone treatments on either of the cognitive function measures or symptom ratings [104]. Another small trial with 23 schizophrenia patients [risperidone (6 mg/day) plus buspirone (60 mg/day)] and 20 patients treated with risperidone plus placebo showed that the buspirone group had significantly greater improvement in the negative symptom and positive general psychopathology subscales and PANSS total scores over the 8-week trial. Therapy with 60 mg of buspirone per day was well tolerated, and no clinically important adverse effects were observed [105].

4.2.8 Meta-analysis

Sepehry et al. [31] performed a meta-analysis of 11 studies that assessed SSRI add-on therapy for the negative symptoms of schizophrenia. Studies were retained if

  • SSRI add-on therapy was compared with antipsychotic monotherapy among schizophrenia spectrum disorder patients;

  • The clinical trial was randomized, double-blind, placebo-controlled with a parallel-arm design;

  • Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms or the PANSS-Negative subscale.

When studies were divided according to severity of illness, a moderate and significant effect size emerged for the studies involving so-called “chronic patients” (n  =  274). This meta-analysis provides support for augmentation with antidepressants for the treatment of negative and affective symptoms in schizophrenia.

Singh et al. [32] published a systematic review and meta-analysis of 23 randomised controlled trials of antidepressant augmentation that included 819 patients with chronic schizophrenia treated with SSRIs (mirtazapine, reboxetine, mianserin, trazodone, and ritanserin). Across the included studies there was a moderate pooled standardized mean difference with an effect size of 0.48. In specific subgroup analyses fluoxetine, trazodone, and ritanserin led to significantly greater response rates than placebo.

Watanabe [106] also concluded that fluoxetine, trazodone and ritanserin are more effective than placebo when used as add-on therapies for negative symptoms of schizophrenia. There was no evidence that antidepressant treatment induced a deterioration of psychotic symptoms. Further research is required to address the potential benefits and risks of chronic administration of antidepressants to patients with schizophrenia. Predictors of antidepressant initiation (14.6% of group) in the CATIE study were female gender or white skin color, and a prior diagnosis of depression or symptoms of depression at baseline. Patients with higher positive symptom scores and younger patients were started on antidepressants sooner. Duration of antidepressant treatment was longer in patients with less education and in those with a history of alcohol abuse/dependence [62].

Recently, Tiihonen et al. [107] showed that antidepressant use is associated with decreased suicide deaths among patients with schizophrenia in Finland.

Thus, clinical studies have shown that negative symptoms of schizophrenia unresponsive to antipsychotic monotherapy can improve after augmentation with some antidepressants. Possible explanations for inconsistencies in study findings include small sample sizes, variable duration of treatment, a range of concomitant antipsychotic regimens, and the nature of the inclusion criteria and outcome measures used [108].

5 Mood Stabilizers

The term “mood stabilizer” does not describe a mechanism, but rather an effect. Lithium, carbamazepine, valproate, and lamotrigine are recognized mood stabilizers.

5.1 Lithium

Lithium, the first mood-stabilizing medication approved by the U.S. Food and Drug Administration for treatment of mania, is often very effective in controlling mania and preventing the recurrence of both manic and depressive episodes.

5.1.1 Mechanism of Action

Lithium, affecting each neurotransmitter system within complex interactive neuronal networks, is suggested to restore the balance among aberrant signaling pathways in critical regions of the brain. Evidence from both in vitro and in vivo studies has demonstrated that lithium exerts multiple effects on neurotransmitter/receptor-mediated signaling, ion transport, signal transduction cascades, hormonal and circadian regulation, and profoundly alters gene expression patterns (see, e.g., reviews [109, 110]). Recent molecular studies have revealed the action of lithium on signal transduction mechanisms, such as phosphoinositide hydrolysis, adenylyl cyclase, G protein, glycogen synthase kinase-3beta, protein kinase C, and its substrate myristoylated alanine-rich C kinase substrate [111]. Lithium’s main mechanisms of action appear to stem from its ability to inhibit glycogen synthase kinase-3 activity and also to induce signaling mediated by brain-derived neurotrophic factor. Lithium has emerged as a neuroprotective agent efficacious in preventing apoptosis-dependent cellular death. Lithium neuroprotection is provided through multiple, intersecting mechanisms; for instance, lithium increases cell survival by inducing brain-derived neurotrophic factor and thereby stimulating activity in anti-apoptotic pathways, including the phosphatidylinositol 3-kinase/Akt and the mitogen-activated protein kinase pathways [112]. Furthermore, there is evidence that demonstrates the action of lithium on cyclic adenosine monophosphate (cAMP)-mediated signal transduction, cAMP response element binding activation, increased expression of brain-derived neurotrophic factor, the phosphatidylinositide cascade, protein kinase C inhibition, glycogen synthase kinase 3 inhibition, and B-cell lymphoma 2 expression [113].

5.1.2 Clinical Studies

Lithium has been the subject of more double-blind studies than any other adjunctive treatment. Patients originally treated with placebo added to neuroleptics did not have significantly greater improvement when they received open-label adjunctive lithium [114]. Findings from another research suggests that lithium might benefit only schizoaffective patients. However, the methodological shortcomings of the trials analyzed limit the impact of the evidence provided [115]. Based on a review of 20 studies with 611 participants, Leucht, Kissling, and McGrath [116] found:

  • Three studies that compared lithium with placebo as the sole treatment showed no difference in any of the outcomes;

  • In eight studies comparing lithium with antipsychotic drugs as the sole treatment, more participants in the lithium group left the studies early (n  =  270);

  • Eleven studies examined whether the augmentation of antipsychotic drugs with lithium salts is more effective than antipsychotic drugs alone. More participants who received lithium augmentation had a clinically significant response (n  =  244). However, statistical significance became borderline when participants with schizoaffective disorders were excluded in a sensitivity analysis (n  =  120, p  =  0.07);

  • No superior efficacy of lithium augmentation in any specific aspect of the mental state was found; and

  • There were no differences between groups for adverse events.

Authors concluded that despite some evidence in favor of lithium augmentation, the overall results are inconclusive. A large trial of lithium augmentation of antipsychotic medications is required in order to detect a benefit of small effect size in patients with schizophrenia but with no affective symptoms.

5.2 Anticonvulsants

Anticonvulsant drugs are widely used for psychiatric indications. This includes alcohol and benzodiazepine withdrawal symptoms, panic and anxiety disorders, dementia, schizophrenia, and to some extent personality disorders. Besides pain syndromes, their main domain aside from epilepsy, however, is bipolar disorder [117].

5.2.1 Mechanism of Action

When hyper-function of glutamatergic pathways in the frontal cortex of schizophrenic patients was proposed [45], clinical studies provided evidence for glutamate abnormalities in schizophrenia. The majority of antiepileptic drugs have more than one mechanism of action [71]. Antiepileptic drugs are divided by mechanisms of action into the following groups [118]:

  • Antiepileptics which block sustained repetitive firing in individual neurons, this effect is mainly due to the blockade of voltage-dependent sodium or calcium channels: carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproate;

  • Drugs that enhance inhibitory events mediated by gama-aminobutyric acid (GABA): gabapentin, phenobarbital, topiramate, and valproate;

  • The third group practically consists of one drug which blocks T-type calcium channels and is active against absences (ethosuximide); and

  • Antiepileptic drugs that reduce events that are mediated by excitatory amino acids: glutamate, phenobarbital, and topiramate [119].

Lamotrigine’s anticonvulsant action has been attributed to the increase in GABA release and also antagonism of voltage-gated sodium channels leading to a reduction in glutamate release [120–122]. There is also a glutamatergic hypo-function hypothesis of schizophrenia based on the ability of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine, to induce psycho-mimetic effects in healthy human volunteers indistinguishable from schizophrenia. Phencyclidine mimics the positive and negative symptoms and cognitive dysfunction as well as formal thought disorders and even auditory hallucinations. It could exacerbate psychosis in schizophrenic patients [123, 124]. The two opposing glutamatergic hypo-function and hyper-function theories have been reconciled by the fact that phencyclidine has a glutamate release increasing potential beside its NMDA associated channels blocking properties [46]. Therefore, the psychotic symptoms of phencyclidine could be due to glutamate release potentiation and not due to the reduction of glutamate activity.

Topiramate is an anticonvulsant drug with alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist properties and a GABA potentiating action [123, 124]. Because of these properties, topiramate could be chosen as a novel medication to address downstream consequences of NMDA receptor hypo-function, which are potentiation of GABAergic neurotransmission and antagonism of the excitotoxic actions of glutamate at the AMPA classes of glutamate-gated channels [125, 126].

Thus, conventional antiepileptics generally inhibit sodium currents (carbamazepine, phenobarbital, phenytoin, and valproate) or enhance GABA-ergic inhibition (valproate). Novel antiepileptic drugs mainly associated with an inhibition of voltage-dependent sodium channels are lamotrigine and oxcarbazepine [127].

5.2.2 Clinical Studies

Add-on carbamazepine, valproate, lamotrigine and several other antiepileptic drugs to antipsychotic agents have been prescribed with diverging or inconclusive results in SZ/SA disorder [128].

5.2.2.1 Carbamazepine (Tegretol)

Although the findings of the various clinical trials are very difficult to compare, the results generally indicate beneficial effects particularly if carbamazepine is used as an adjunct to antipsychotic medication [129]. Recently conducted clinical trials indicated that carbamazepine augmentation may be effective for patients with schizophrenia treated with aripiprazole, although carbamazepine dramatically decreases plasma concentrations of aripiprazole [130].

Leucht and associates [131] evaluated the effects of carbamazepine and its derivatives for the treatment of schizophrenia and related psychoses (ten studies, 258 participants). A favorable effect of carbamazepine was found when those who received the antipsychotic (perphenazine) had Parkinsonism. There were no between group differences between the add-on carbamazepine and the add-on placebo groups, regarding acceptability or early termination of study. Carbamazepine augmentation was superior compared with antipsychotics alone in terms of overall global improvement. No data were available for the effects of carbamazepine on subgroups of people with schizophrenia and aggressive behavior, negative symptoms or EEG abnormalities or with schizoaffective disorder. Based on currently available randomized trial-derived evidence, carbamazepine cannot be recommended for routine clinical use for treatment or augmentation of antipsychotic treatment of schizophrenia.

5.2.2.2 Valproate

There is only limited evidence to support the use of augmentation therapy with valproate (divalproex sodium), including a single small study that revealed less agitation in the valproate augmentation group versus the antipsychotic monotherapy group. A Cochrane review and meta-analysis of only seven randomized studies with 519 participants found no significant benefit of valproate augmentation [132]. A clinical trial with 249 patients hospitalized for acute exacerbation of schizophrenia, in which valproate (a maximum dosage of 30 mg/kg/day) or placebo was added to risperidone (6 mg/day) or olanzapine (15 mg/day), showed improvement from baseline throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups. There were statistically significant treatment differences favoring combination therapy as soon as day 3 for PANSS total score, derived Brief Psychiatric Rating Scale (BPRS) total score, as well as PANSS and BPRS subscales. Treatment with divalproex in combination with an atypical antipsychotic agent resulted in earlier improvement in a range of psychotic symptoms among hospitalized patients with acute schizophrenia [133]. A recent 12-week, randomized, double-blind, parallel-group, multi-center trial with 402 patients failed to show an advantage of valproate augmentation at any of the time points [134].

Citrome et al. [135] compared the specific anti hostility effects of SGAs monotherapy (olanzapine or risperidone) with that of combination treatment with divalproex sodium among 249 inpatients with schizophrenia in a double-blind, 28-day multicenter trial. Combination treatment with risperidone or olanzapine plus divalproex had a significantly greater anti hostility effect at days 3 and 7 than monotherapy. The effect on hostility appears to be statistically independent of antipsychotic effect on other PANSS items reflecting delusional thinking, a formal thought disorder, or hallucinations. Thus, divalproex sodium may be useful as an adjunctive agent in specifically reducing hostility in the first week of treatment with risperidone or olanzapine among schizophrenia patients who are experiencing an acute psychotic episode.

5.2.2.3 Lamotrigine

A double-blind, placebo-controlled 14 week trial with a cross-over design, assessed the addition of lamotrigine to ongoing clozapine treatment in 34 treatment resistant patients. Lamotrigine was shown to be more effective than placebo in reducing positive symptoms and ‘general psychopathological symptoms’ measured by the PANSS, but had no significant benefit on negative symptoms [136]. Two multicenter, randomized, double-blind, 12-week, parallel-group trials were conducted to compare flexibly dosed lamotrigine (100–400 mg/d) with placebo as add-on treatment in 429 schizophrenia patients with stable, residual psychotic symptoms. The primary end point was the change in PANSS total score at week 12 [137]. Results from these two studies do not support the use of lamotrigine as an adjunct to atypical antipsychotics in patients with refractory psychosis. It is unclear why positive results from previous lamotrigine trials were not replicated. The positive effect of lamotrigine on cognition in one trial, while of uncertain significance, may merit further study.

Fifty-one treatment-resistant schizophrenic patients treated with clozapine received, either up to 200 mg/day of lamotrigine or placebo in a double-blind design for 24 weeks, [138]. Lamotrigine added to stable clozapine treatment showed a beneficial effect on negative, positive and general psychopathological symptomatology. Regarding cognitive functions, improvement was observed in attentional resistance to interference, verbal fluency and executive functioning. The findings provide evidence that lamotrigine augmentation of clozapine treatment is well tolerated and may be proposed as an effective therapeutic strategy to improve outcome in treatment-resistant schizophrenia.

Glick et al. [139] compared the efficacy of mood stabilizer augmentation of an antipsychotic for patients with schizophrenia who are both stabilized and partially responsive. Adult patients with SZ/SA disorder were enrolled in a 12-week, double-blind randomized trial. They were randomly assigned to one of three adjunctive treatments: (1) lamotrigine, (2) divalproex sodium, or (3) placebo. There were no differences in global outcomes, positive, negative and depressive symptoms, quality of life, or demoralization among the three groups.

A Cochrane review and meta-analysis of five lamotrigine augmentation studies and 537 participants revealed some efficacy on positive and negative symptoms, though results were mixed and not robust [140]. However, in another more recent meta-analysis data were restricted to lamotrigine add-on therapy to clozapine, with clozapine as a proxy for highly likely treatment resistance. In this meta-analysis of five trials and 161 participants a significant effect in favor of lamotrigine was observed [33]. This meta-analysis drew between two and 30 patients for the clozapine and placebo groups from individual trials in which a mixture of baseline antipsychotics was allowed and in which clozapine treatment was not used as a stratification factor. This means that the included patients were not truly randomly assigned to clozapine or placebo, rendering a suggestive analysis. Nevertheless, overall lamotrigine still seems to hold some promise but more studies are needed.

5.2.2.4 Topiramate

Clinical results suggest that treatment with topiramate may improve negative symptoms and cognitive dysfunction in schizophrenia when added to a stable dose of antipsychotic medication [141–143]; however much of this information is based on open-label studies, case reports and case series [144]. In a randomized, double-blind, placebo-controlled study of SZ patients, the addition of topiramate resulted in a reduction of both positive and negative symptoms compared with patients on antipsychotic monotherapy [143]. A 12-week naturalistic, open study was carried out to examine the potential benefits of topiramate in clozapine-treated schizophrenia patients who exhibited a suboptimal clinical response (20 subjects were enrolled, and 16 completed the study). Topiramate augmentation led to a 14% improvement in total Brief Psychiatric Rating Scale scores (p  =  0.0003), a 2.5% decrease in body weight (p  =  0.015), and was generally well tolerated; paraesthesia was the most common side effect [145]. These findings support topiramate as a viable augmentation strategy in clozapine partial responders.

5.2.3 Aggressive Behavior

Antiepileptic drugs may reduce aggression by acting on the CNS to reduce neuronal hyper-excitability associated with aggression. Huband et al. [146] reviewed 14 studies of five different antiepileptic drugs with data from 672 participants. Four antiepileptics (carbamazepine, valproate/divalproex, oxcarbazepine and phenytoin) were effective, compared to placebo, in reducing aggression in at least one study, although for three drugs (valproate, carbamazepine and phenytoin) at least one other study showed no statistically significant difference between treatment and control conditions. The authors considered that the body of evidence summarized in this review was insufficient to allow any firm conclusion to be drawn about the use of antiepileptic medication in the treatment of aggression and associated impulsivity.

Mood-stabilizer use was significantly and independently associated in multivariate logistic modelling with: aggressive behavior, disorganized speech, multiple hospitalizations, less negative symptoms, younger age, and revealed regional variation [59]. Further research is warranted.

6 Benzodiazepines

The use of benzodiazepines (BZDs) in schizophrenia was mainly for symptoms such as insomnia, anxiety, agitation, aggression, and psychotic excitement in general and control of florid psychotic symptoms such as hallucinations and delusions in particular [147, 148]. BZDs were further found to be useful in the reduction of neuroleptic-induced side effects such as akathisia or tardive dyskinesia [149].

6.1 Mechanism of Action

Benzodiazepines bind to the GABAA receptor, reducing the quantity of GABA required to open the chloride channel, hyperpolarize the neuron and inhibit neurotransmission [150]. Benzodiazepines also have an effect on the mesoprefrontocortical regions where neuroleptics may be less efficient [151].

6.2 Clinical Studies

The use of various types of BZDs as adjunct therapy to neuroleptics in the treatment of symptoms such as agitation and psychotic excitement in general and control of florid psychotic symptoms such as hallucinations and delusions in particular is well known [152–155]. For instance, about half of the 48 alprazolam-treated patients with schizophrenia demonstrated clinically significant improvement in both positive and negative symptoms [154]. The positive symptoms appear to be significantly reduced by BZDs in some but not all studies [156]. These suggest that there could be a group of patients who respond to BZDs. Diazepam was reported to be effective in treating prodromal and early signs of schizophrenia [155].

Multivariate logistic regression and multivariate linear regression analyses were performed to assess predictors of benzodiazepine use and dose, respectively, in Asian patients with schizophrenia [157]. Overall, 54% of the patients received adjunctive BZDs at an average daily dose equivalent to 30.3 mg diazepam, with minor changes over the years sampled. Benzodiazepine use was highest in Taiwan and Japan, lowest in Thailand and China, and was associated with shorter duration of illness, presence of delusions, hallucinations, disorganized speech, social or occupational dysfunction, and use of mood stabilizers, anti-parkinsonian or antidepressant drugs, and lower doses of antipsychotics.

As reviewed by Volz et al. [158], a meta-analysis of 31 randomized studies with 2,454 participants did not reveal significant superiority for BZDs compared with placebo. Nevertheless, a number of methodological problems such as insufficient data or the use of different outcome criteria hampered the meta-analytic process. The sedative effects of benzodiazepines in schizophrenia could be shown, but there is much room for randomized studies on the decisive question whether BZDs improve or at least hasten the amelioration of positive symptoms.

Tiihonen et al. [107] using national databases of mortality and medication prescriptions among a complete nationwide cohort of 2,588 patients hospitalized in Finland investigated if the use of benzodiazepines, antidepressants, or multiple concomitant antipsychotics is associated with increased mortality among patients with schizophrenia. Authors concluded that BZD use was associated with a marked increase in mortality among patients with schizophrenia, whereas the use of an antidepressant or several concomitant antipsychotics was not.

Predictors of anxiolytic initiation (13.7% of group) in the CATIE study were not being African-American, younger age, higher body mass index, and akathisia. Time to anxiolytic initiation was shorter in patients who were separated or divorced and in patients with better neurocognitive functioning. Duration of anxiolytic treatment was shorter for African Americans and longer in patients with better instrumental role functioning. Predictors of sedative/hypnotic use (11.2% of group) were depressive symptoms and prior diagnosis of an anxiety disorder. Time to initiation of sedative/hypnotics was longer for those with depressive symptoms and shorter for those with a history of alcohol abuse or dependence [62].

Thus, BZDs, in conventional doses, can enhance the antipsychotic effect of neuroleptics in schizophrenics who did not respond satisfactorily to neuroleptics alone. This effect is more conspicuous regarding hallucinations, and improvement has also been observed for delusions, thought disturbances, some negative symptoms, anxiety and tension. Some BZDs may be more effective than others in schizophrenia, but this has not been clearly determined. Benzodiazepines combined with clozapine clearly increases the frequency of cardiovascular and respiratory accidents [151].

7 Glutamatergic Drugs

7.1 Mechanism of Action

NMDA receptors are a major subtype of glutamate receptors and mediate slow excitatory postsynaptic potentials. The glutamate hypothesis of schizophrenia is based on the ability of NMDA receptor antagonists to induce schizophrenia-like symptoms. There are strong lines of evidence indicating that dysfunction of NMDA receptors may explain the pathophysiology of schizophrenia [107, 159, 160]. Research over the past two decades has highlighted promising new targets for drug development based on potential pre- and postsynaptic, and glial mechanisms leading to NMDA receptor dysfunction. Reduced NMDA receptor activity on inhibitory neurons leads to disinhibition of glutamate neurons increasing synaptic activity of glutamate, especially in the prefrontal cortex [161].

7.2 Clinical Studies

Presently, glutamatergic drugs are not available for clinical use [162].

Much interest has surrounded the use of agonists at the NMDA-glycine site (D-serine, glycine, D-alanine and D-cycloserine) and glycine transporter-1 (GlyT-1) inhibitor (sarcosine) in order to improve the symptoms of stable chronic schizophrenia patients receiving concurrent antipsychotics.

7.2.1 Glycine

This therapeutic approach for the treatment of schizophrenia aimed to increase synaptic glycine levels with add-on oral glycine to antipsychotic agents. Clinical trials provided clinical support for this approach. For instance, in a double-blind, placebo-controlled fashion 14 medicated patients with chronic schizophrenia were treated with glycine. Significant improvement in negative symptoms occurred in the group given glycine but not in the group given placebo, suggesting that potentiation of NMDA-receptor-mediated neurotransmission may represent an effective treatment for neuroleptic-resistant negative symptoms in schizophrenia [163]. High glycine dose studies replicated and extended initial findings by demonstrating improvements in positive, negative, and cognitive symptoms of the disorder [164–166]. High variability of clinical efficacy of glycine adjuvant therapy (ranging from 20 to 70%) should be noted.

7.2.2 D-cycloserine

Thirty eight stable adult schizophrenia outpatients (87% completed the trial) treated with any antipsychotic except clozapine were randomized to a double-blind, 8-week add-on trial of d-cycloserine 50 mg or placebo. Once-weekly dosing with d-cycloserine for 8 weeks produced persistent improvement of negative symptoms compared to placebo, although statistical significance was, in part, the result of worsening of negative symptoms with placebo [167]. These results must be considered preliminary since a number of outcomes were examined without correction for multiple tests. Preliminary studies with once-weekly administration of D-cycloserine supported its benefit on negative symptoms, memory consolidation, and facilitation of cognitive behavioral therapy for delusions [168].

7.2.3 D-serine

The mammalian brain contains unusually high levels of D-serine. In the last few years, studies from several groups have demonstrated that D-serine is a physiological co-agonist of the NMDA type of glutamate receptor—a key excitatory neurotransmitter receptor in the brain [169, 170]. Heresco-Levy et al. [171] assessed the efficacy and safety of D-serine adjuvant treatment for 39 schizophrenia patients treated with SGAs (risperidone- or olanzapine) using a double-blind, placebo-controlled, 6-week crossover trial with 30 mg/kg/day D-serine. D-serine administration induced increased serine serum levels (p  <  0.001) and resulted in significant (p  <  0.001) improvement in negative, positive, cognitive, and depression symptoms, as measured by the PANSS. D-serine was well tolerated, and no detrimental changes in clinical laboratory parameters were noted. These findings indicate that risperidone and olanzapine efficacy might be augmented with D-serine adjuvant treatment, and confirm D-serine efficacy against main schizophrenia symptom domains.

Kantrowitz et al. [172] performed a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day) with 42 antipsychotic-stabilized patients with SZ/SA disorder. On the PANSS, improvement was observed for positive (p  =  0.006; d  =  0.46), negative (p  <  0.001; d  =  0.68), general psychopathology (p  =  0.001; d  =  0.53), and total (p  <  0.0001; d  =  0.74) symptoms. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function. Thus, findings support a double-blind investigation of D-serine at doses ≥60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction. However, when Lane et al. [173] compared D-serine, and sarcosine with placebo in the treatment of 60 patients using a double-blind, placebo-controlled design, D-serine did not differ significantly from placebo on any measure (symptoms, functioning, and quality of life).

7.2.4 Sarcosine

A glycine transporter-I inhibitor is a small molecule that enhances the NMDA neurotransmission and has been shown to be beneficial as adjuvant therapy for schizophrenia. In one study, 65 risperidone-treated in-patients with acute exacerbations of schizophrenia were given adjuvant sarcosine (a glycine transporter inhibitor) 2 g/day, DSR 2 g/day, or placebo in a 6-week, randomized, double-blind trial. The sarcosine group showed significantly more symptom improvement than the other two groups [174]. In a 6-week, controlled trial with chronic schizophrenia patients, sarcosine 2 g/day adjuvant treatment led to 17% (P  <  0.0001), 14% (P  <  0.0001), and 13% (P  <  0.0001) reductions in positive, negative, and cognitive symptoms, respectively, without inducing any significant side effects [174]

Lane, Huang, Wu et al. [175] examined the effects of sarcosine adjuvant therapy for schizophrenic patients among 20 schizophrenic inpatients enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/day) which was added to their stable doses of clozapine. Sarcosine produced no greater improvement when co-administered with clozapine than placebo plus clozapine at weeks 2, 4, and 6. Sarcosine was well tolerated and no significant side-effects were noted. Thus, unlike patients treated with other antipsychotics, patients who received clozapine exhibited no improvement with the addition of sarcosine or agonists at the NMDA-glycine site. In a replication study sarcosine was shown to be superior to placebo on all four outcome measures of PANSS total score (p  =  0.005), Scale for the Assessment of Negative Symptoms (SANS) (p  =  0.021), Quality of Life (QOL) (p  =  0.025), and Global Assessment of Functioning (GAF) (p  =  0.042) [173].

7.2.5 Meta-analysis

Tiihonen and Wahlbeck [176] analysed 18 short-term trials with 358 randomised participants. All trials were short-term trials with a maximum duration of 12 weeks. In all of these trials, glycine, D-serine, and D-cycloserine was used to augment the effect of antipsychotic drugs. D-cycloserine, a partial agonist of NMDA receptors’ glycine site, seemed ineffective towards the symptoms of schizophrenia. NMDA receptor co-agonists glycine and D-serine showed some effects in reducing the negative symptoms of schizophrenia (n  =  132, p  =  0.0004), but the magnitude of the effect was moderate. In general, all glutamatergic drugs appeared to be ineffective in further reducing positive symptoms of the disease when added to the ongoing antipsychotic treatment. Glycine and D-serine may somewhat improve negative symptoms when added to regular antipsychotic medication, but the results were not fully consistent and data are too few to allow any firm conclusions. Many participants in the included trials were treatment-resistant which may have reduced treatment response. Additional research on glutamatergic mechanisms of schizophrenia is needed.

In a meta-analysis Tsai and Lin [34] included about 800 subjects from 26 studies. Overall, the NMDA-enhancing molecules were effective in most schizophrenic symptom domains with an effect size of total psychopathology of 0.40. Glycine, D-serine, and sarcosine treatments significantly improved multiple symptom domains, whereas D-cycloserine did not improve any symptom domain. Moderator analysis revealed that glycine, D-serine and sarcosine were better than D-cycloserine in improving overall psychopathology. Patients that received risperidone or olanzapine, but not clozapine, improved. No significant side effect or safety concern was noted.

Another meta-analysis was based on 29 trials with 1,253 participants [35]. Subgroup analysis revealed medium effect sizes for D-serine and N-acetyl-cysteine for negative and total symptoms, and for glycine and sarcosine for total symptoms. When added to clozapine, none of the drugs demonstrated therapeutic potential, and addition of glycine worsened positive symptoms. Taking into consideration the number of trials and sample sizes in subgroup analyses, D-serine, N-acetyl-cysteine and sarcosine as adjuncts to non-clozapine antipsychotics revealed therapeutic benefit in the treatment of negative and total symptoms of chronic schizophrenia.

Recently de Bartolomeis et al. [177] critically updated preclinical and clinical data on the modulation of glutamate NMDA receptor activity by NMDA-receptors co-agonists, glycine transporters inhibitors, AMPAkines, mGluR5 agonists, NMDA- receptors partial agonists. Though promising preclinical findings have been reported for virtually all compounds, clinical efficacy has not been confirmed for D-cycloserine. Contrasting evidence has been reported for glycine and D-serine that may however have a role as add-on agents. More promising results in humans have been reported for glycine transporter inhibitors.

Thus, although hypofunction of NMDA receptor-mediated neurotransmission is proposed to play an important role in the pathophysiology of schizophrenia, results of clinical trials of small molecules that enhance the NMDA function are inconsistent.

8 Hormonal Agents

It is a well-established fact that schizophrenia, and related psychoses may have a significant hormonal, mainly neuroprotective, component in the pathogenesis of the disease. Findings from the current literature support the role of neurosteroids and the estrogen protection hypotheses.

8.1 Neurosteroids

Neurosteroids such as dehydroepiandrosterone (DHEA), pregnenolone (PREG), and their sulfates (DHEAS and PREGS) display multiple effects on the central nervous system.

After discovering that PREG and DHEA are produced in the brain Baulieu [178] introduced the term “neurosteroids”. Current knowledge concerning PREG and DHEA metabolism, the enzymes mediating these reactions, and their localization was recently summarized [179, 180]. Clinical studies revealed low levels of PREG in individuals with major depression [181], generalized anxiety disorder [182], generalized social phobia [183], and chronic medicated schizophrenia patients [184]. Comparisons of the values of blood DHEA and DHEAS levels of schizophrenia patients with healthy controls were found to differ among studies, ranging from normal, to low, and to high levels [185–193]. A meta-analysis of differences in mean concentrations of serum DHEA(S) between schizophrenia patients and control subjects shows a significant non-zero effect (p  <  0.001), and significant heterogeneity of data (p  <  0.001; [194]).

Alterations in PREG(S) and DHEA(S) in schizophrenia may be associated with impaired stress-response. Several lines of evidence have shown that a variety of stressors result in a shift in the balance of cortisol and DHEA(S), in that there is an increase in cortisol synthesis and a decrease in androgen synthesis. During acute psychological stress, stimulation of adrenal steroid release is accompanied by a shift towards DHEA release [195]. Furthermore, DHEA(S) were shown as mediators of the HPA axis adaptation to extreme stress and the psychiatric symptoms associated with posttraumatic stress disorder [196]. PREG is increased in rodent brain and plasma after HPA activation by acute stress or ethanol administration [197]. The antiglucocorticoid properties of DHEA [198] and neuromodulatory effects of DHEA(S) on GABA, NMDA and sigma receptors in the brain [199–201] may contribute to symptom severity, including behavioral functions such as response to stress, anxiety, aggressive behavior, learning and memory [202]. This, in turn, may lead to dysregulation in neurotransmission, and neuroprotective mechanisms and result in chronic and progressive deterioration in emotional, cognitive, and psychosocial functions of patients.

8.1.1 Mechanism of Action

Experimental and clinical observations suggest that PREG, DHEA and their sulfates (PREGS, DHEAS) [together abbreviated as PREG(S) and DHEA(S)] display multiple effects on the central nervous system (CNS) such as modulation of neurotransmitter receptors [203–205], anti-stress effects [206], neuroprotective properties [207], cognitive-enhancing effects [208, 209], androgenic, estrogenic activities, and neuropsychopharmacological effects [210, 211]. In particular, they regulate the growth of neurons, enhance myelinization and synaptogenesis in the CNS, affect synaptic functioning, and thus may be effective as brain protectors [212, 213]. In elderly populations they are reduced to 20–30% of the peak levels of young adulthood [214, 215]. Studies in experimental animals revealed important roles of neuroactive steroids in the control of central nervous system functions in physiological and pathological conditions, suggesting that they may represent good candidates for the development of neuroprotective strategies for neurodegenerative and psychiatric disorders [216]. Specifically, neurosteroids have various functions associated with neuroprotection, response to stress, mood regulation and cognitive performance. In addition, neurosteroid levels are altered in stress-related neuropsychiatric disorders, see review, e.g., [36].

8.1.2 Clinical Studies

Several randomized, double-blind, placebo-controlled clinical trials were conducted with PREG [217, 218] and DHEA [219–224] for the treatment of schizophrenia and schizoaffective patients. Comparative critical analyses of these clinical trials were published [36, 225]. Overall, the results of these clinical trials with two neurosteroids are based on 117 patients who received DHEA and 34 patients treated with PREG. The clinically significant benefits of both DHEA and PREG augmentation remain unclear. Limitations of the studies reviewed include small sample sizes. It is crucial to replicate these trials with larger samples of schizophrenia or schizoaffective patients, and for a longer duration of treatment.

In summary, experimental and clinical observations support the speculation that neurobiological alterations in PREG(S)/DHEA(S) neurosteroids are related to the pathophysiology of schizophrenia and other neuropsychiatric disorders. Based on the accumulated evidence, it is also possible to conclude that PREG(S)/DHEA(S) might play a relevant role in the expressions of stress response, anxiety, and cognitive deficit in schizophrenia. Finally, these insights underscore the need for development of novel treatment strategies such as neuroprotective strategies using neurosteroids and other compounds, to help overcome the limitations of current antipsychotic drugs and to improve the cognitive deficits and negative symptoms, as well as functioning and quality of life outcomes of people affected by schizophrenia. Pilot clinical trials indicate that PREG and DHEA augmentation may improve some clinical symptoms and neurocognitive response in schizophrenia. Clinical trials for the evaluation of these neurosteroids pose a few challenges, and further investigation of neurosteroid treatment in schizophrenia and related disorders is warranted.

8.2 Estrogen, Raloxifene and Testosterone

There is a wealth of historical and circumstantial evidence to suggest that female patients with schizophrenia may suffer from a deficit in estrogenic function [226]. Epidemiological and life-cycle data point to significant differences in the incidence and course of schizophrenia between men and women, suggesting a protective role of estrogen. In-vitro and in-vivo preclinical research has confirmed estradiol’s interactions with central neurotransmitter systems implicated in the pathogenesis of schizophrenia [227, 228].

8.2.1 Mechanism of Action of Estrogen

Estrogen is known to have diverse neuroprotective properties; in particular, estrogenic compounds can protect brain cells against injury from excitotoxicity, oxidative stress, inflammation and apoptosis [229–231]. They can also enhance neurogenesis, angiogenesis, synaptic density, plasticity and connectivity, axonal sprouting and remyelination and expression of neurotrophic factors [232, 233]. Furthermore, estradiol has been found to significantly interact with the dopaminergic, serotonergic and glutamatergic systems, giving it properties similar to those of FGAs [234, 235].

8.2.2 Clinical Studies

Estrogen has recently been used as an adjunct to standard antipsychotic medication in quite a few studies of female schizophrenia patients [236, 237]. Cochrane review and meta-analysis summarized four studies with a total of 108 women and concluded that adjunctive estrogen with or without progesterone does not appear to offer convincing advantages over placebo [238]. In men, consideration of estrogen therapy has been impacted by concerns of feminising side effects, however, clinical trials of the use of estrogen in treating prostate cancer, bone density loss and even aggression and psychosis in dementia or traumatic brain injury, show this to be a safe and effective therapy. A 14-day randomised placebo-controlled trial involving 53 men with schizophrenia was conducted to evaluate the efficacy of 2 mg oral estradiol valerate as an adjunct to FGAs [239]. Results demonstrated a more rapid reduction in general psychopathology that occurred in the context of greater increases in serum estrogen levels and reductions in FSH and testosterone levels in participants that received estradiol. Approximately 28% of the estradiol participants did not achieve an increase (at least a 50% from baseline) in serum estrogen suggesting that further research is needed to refine the type, dose and administration route for estrogen therapy in men.

8.2.2.1 Raloxifene

Another therapeutic strategy may be related to add-on raloxifene hydrochloride. It is a selective estrogen receptor modulator that acts as an estrogen antagonist in breast tissue and may have agonistic actions in the brain, potentially offering mental health benefits with few estrogenic side effects [240]. Kulkarni et al. [241] examined the effect of a therapeutic dose of adjunctive raloxifene (120 mg/day, n  =  13) versus oral placebo (n  =  13) in postmenopausal women with schizophrenia. Analysis of variance found significant interaction effects for total and general PANSS scores. The demonstrated benefit of adjunctive treatment with 120 mg/day raloxifene hydrochloride offers support for the potential role of this selective estrogen receptor modulator in treating postmenopausal women with schizophrenia.

Usall et al. [242] conducted a 12-week, double-blind, randomized, placebo-controlled study with 33 postmenopausal women with schizophrenia who exhibited prominent negative symptoms. The addition of raloxifene (60 mg/day) to regular antipsychotic treatment significantly reduced negative (p  =  0.044), positive (p  =  0.031), and general psychopathological (p  =  0.045) symptoms during the 12-week trial as compared to the add on placebo group. If more extensive and longer-term studies confirm and expand upon these positive results, the use of raloxifene could be recommended in postmenopausal patients with schizophrenia.

8.2.2.2 Testosterone

To explore the therapeutic effect of testosterone augmentation of antipsychotic medication on symptoms in male patients with schizophrenia, Ko, Lew, Jung et al. [243] performed a placebo-controlled, double-blind trial with 30 schizophrenic men, using either 5 g of 1% testosterone gel or a placebo added to a fixed dosage of antipsychotic medication over a period of 4 weeks following a 2-week washout period. Results indicated a significant improvement of negative symptoms in both the last observation carried forward and the completer analyses and a nonsignificant trend for the improvement of depressive symptoms in completers. There were no significant changes in serum hormone levels except total and free testosterone. The findings of this study suggest that testosterone augmentation may be a potential therapeutic strategy in patients with schizophrenia.

9 Retinoid-Based Strategy

Retinoids are a family of molecules that are derived from vitamin A. Several studies reported that retinoids are involved in neurodevelopment [244] and regulation of genes thought to be important in the pathogenesis of schizophrenia [245]. It has been suggested that retinoid dysregulation might be involved in the pathogenesis of schizophrenia. It is hypothesized that the availability in the brain of retinoid acid, the final product of the retinoid metabolic cascade, influences the onset of the disease [246, 247]. Defects in retinoid acid signaling have been implicated in several neurological diseases, including schizophrenia, movement disorders, and motor neuron disease [246, 248]. Because the retinoid acid level is controlled by genes involved in retinoid acid synthesizing, metabolizing and transporting, Chunling Wan et al. [249] investigated the polymorphisms of seven genes involved in these functions to reveal the possible role of retinoid acid in schizophrenia.

9.1 Mechanism of Action

There are two types of retinoid nuclear hormone receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Both belong to the corticosteroid receptor superfamily and co-exist in most cells. The alpha, beta, and gamma subtypes of the RARs and RXRs have distinct and conserved amino and carboxy terminal domains. Each receptor subtype has a specific pattern of expression during embryonal development and a different distribution in adult tissues. This differential expression of receptor subtypes is thought to regulate the expression of distinct sets of genes. Heterodimers of the RARs and RXRs bind and regulate a specific DNA sequence known as the retinoic acid response element, which is located in the promoter region of genes such as the RAR-b2 gene, reviewed in [250].

Retinoids modulate neurotransmission. The expression of D2 receptors been shown to be regulated by retinoid acid [251], and single and compound null mutations for the RARB, RXRB 8 and RXRG in mice result in reduced expression of D1 and D2 receptors and impaired dopamine signaling [252]. Retinoid analogs have therefore been proposed as candidates for the treatment of schizophrenia [253, 254].

9.2 Clinical Study

Bexarotene (Targretin) belongs to the group of synthetic medicines derived from vitamin A (retinoid). Its chemical name is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid [255]. To date this medication has been exclusively used as treatment of neoplastic or dermatological diseases. Adverse events potentially related to bexarotene include lipid abnormalities, hypothyroidism, headache, asthenia, rash, leucopenia, anemia, nausea, and increased risk of infection, peripheral edema, abdominal pain, dry skin, dizziness, hyperesthesia, hypoesthesia, and neuropathy. Based on the retinoid hypothesis in schizophrenia, our group conducted a 6-week open label trial in two mental health centers [256]. It was assumed that the combined effect of antipsychotic agents and bexarotene would have a beneficial effect in treatment of psychopathological symptoms in chronic schizophrenia patients. Since high daily doses of bexarotene can produce numerous adverse effects, the first trial was aimed to examine safety and preliminary efficacy of a low daily dose (75 mg/day) of bexarotene in an open label pilot study. Twenty-five patients with chronic schizophrenia received a low dose of bexarotene (75 mg/day) augmentation. Significant improvement from baseline to endpoint was observed on the total PANSS score, general psychopathology, and on the positive and the dysphoric mood factor scores. Low doses of bexarotene were well tolerated. Bexarotene was found to be a safe medication as measured by all laboratory parameters with the exception of increased total cholesterol serum levels. This short-term pilot study supports bexarotene as a potential valuable adjunct in the management of schizophrenia. A double-blind controlled study is currently underway to replicate these preliminary results.

10 Nonsteroidal Anti-inflammatory Drugs (NSAID)

This strategy is based on the hypothesis that immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia, and, consequently, to the use of anti-inflammatory drugs (cyclo-oxygenase-2 inhibitors, acetylsalicylic acid) [257, 258].

10.1 Mechanism of Action

A literature search identified more than 100 articles pertaining to suspected immunologic influences on schizophrenia published over the past 15 years [259]. Evidence suggests that a (prenatal) infection is involved in the pathogenesis of schizophrenia. Due to an early sensitization process of the immune system or to a (chronic) infection, which is not cleared through the immune response, an immune imbalance between the type-1 and the type-2 immune responses takes place in schizophrenia [257]. For instance, the differential activation of the enzyme indoleamine 2,3-dioxygenase and of the tryptophan/kynurenine metabolic pathway, resulting in the increased production of kynurenic acid in schizophrenia, and a possible increase in quinolinic acid in depression, also may play a key role in these diseases. Such differences are associated with an imbalance in glutamatergic neurotransmission that may contribute to increased levels of NMDA agonism in depression and NMDA antagonism in schizophrenia. In addition, immunological imbalance results in the increased production of prostaglandin E2 in schizophrenia and depression, as well as increased cyclooxygenase-2 (COX-2) expression in schizophrenia [260].

10.2 Clinical Studies

10.2.1 Cox-2 Inhibitors

The selective cyclooxygenase-2 inhibitor (celecoxib) is a non-steroidal anti-inflammatory drug that selectively targets the COX-2 enzyme. A study of 50 patients undergoing acute exacerbation of their symptoms reported a significant improvement in their PANSS total score using 400 mg/d for 5 weeks; a reanalysis showed that it had the most effect in patients with an illness of less than 2 years’ duration [261]. A follow-up study of 40 patients using 400 mg/d for 8 weeks reported no overall effect; however, a reanalysis showed that patients with recent-onset illness showed the most improvement [262]. One study of 35 patients with chronic schizophrenia, average duration of illness 20 years and using 400 mg/d for 8 weeks, reported negative results [263], but another trial of 60 patients with chronic schizophrenia, average duration of illness 8 years and “in an active phase of illness,” also using 400 mg/d for 8 weeks, reported a significant improvement in positive and total symptoms on PANSS [264]. Most recently, a study of 49 individuals with first-episode schizophrenia, using 400 mg/day for 6 weeks, reported significant improvement in negative and total symptoms on PANSS [265].

10.2.2 Acetylsalicylic Acid

Laan et al. [266] reported findings from a randomized (aspirin 1,000 mg/d or placebo), double-blind, placebo-controlled study with 70 antipsychotic-treated inpatients and outpatients with a DSM-IV-diagnosed schizophrenia spectrum disorder from ten psychiatric hospitals. Patients were randomized to adjuvant treatment with aspirin 1,000 mg/d or placebo. The authors report a mean modest reduction of the PANSS total score. Effect size was approximately 0.5. Aspirin did not significantly affect cognitive function. No substantial side effects were recorded.

Sommer et al. [37] summarized five double-blind, randomized, placebo-controlled trials, with a total of 264 patients. Four studies applied celecoxib, and one used acetylsalicylic acid. Authors found a mean effect size of 0.43 (p  =  0.02) in favor of NSAIDs on total symptom severity. For positive and negative symptom severity, the mean standardized difference was about 0.3 (p  <  0.05). These results suggest that NSAID augmentation could be a potentially useful strategy to reduce symptom severity in schizophrenia. Since these initial studies were conducted on small samples, the obtained results should be interpreted with caution.

11 Acetilcholinesterase Inhibitors

Alterations in the central cholinergic system of patients with schizophrenia such as reduced numbers of muscarinic and nicotinic receptors in the cortex and hippocampus may contribute to the cognitive impairment associated with schizophrenia [267]. Furthermore, several lines of evidence suggest that cholinergic deficits may contribute to the pathophysiology of schizophrenia, depression, and dementia [268, 269]. Therefore, pharmacological treatments that enhance central cholinergic function may be useful as cognitive enhancers in schizophrenia.

11.1 Mechanism of Action

To understand the underlying mechanism for the clinical effectiveness of, for example, galantamine, neuropharmacological studies have been performed in animal models of several psychiatric disorders. These studies suggest that the nicotinic receptor-modulating properties as well as muscarinic receptor activation contribute to the galantamine’s antipsychotic effect and contribution to the improvement of cognitive dysfunction [270]. Donepezil is an acetylcholinesterase inhibitor that appears to enhance cognitive functioning in patients with dementia [268].

11.2 Clinical Studies

11.2.1 Donepezil

In a randomized placebo-controlled add-on trial, schizophrenia patients were randomly assigned to donepezil titrated up to 10 mg/day or placebo for 12 weeks (donepezil, n  =  121; placebo, n  =  124). Donepezil did not improve performance on any cognitive test compared to placebo and was associated with worsening of negative symptoms [271].

11.2.2 Galantamine

Add-on galantamine to the FGAs of patients with schizophrenia did not produce a change in the cognitive function or state of psychopathology [272]. Lindenmayer and Khan [273] performed a 52-week double-blind, randomized study of treatment with long-acting injectable risperidone (25 mg or 50 mg every 2 weeks). Adjunctive galantamine (up to 24 mg/day) or placebo treatment was administered from month 6–12. Galantamine showed no ameliorative effects on cognitive measures in this 6 month trial.

11.2.3 Meta-analysis

Ribeiz et al. [274] conducted a literature search (up to December 2008) for randomized, double-blind, placebo-controlled trials with donepezil, rivastigmine or galantamine in patients with SZ/SA disorder. The meta-analysis of 13 double-blind studies (four with rivastigmine, six with donepezil and three with galantamine) suggests that specific cognitive deficits (memory, and the motor speed and attention part of executive function) of patients with SZ/SA disorder respond to rivastigmine, donepezil and galantamine as adjunctive therapy.

Recently, Singh, Kour, and Jayaram [269] evaluated the clinical effects, safety and cost effectiveness of acetylcholinesterase inhibitors by analyzine all clinical randomized trials comparing acetylcholinesterase inhibitors with antipsychotics or placebo either alone, or in combination, for schizophrenia and schizophrenia-like psychoses. The acetylcholinesterase inhibitor plus antipsychotic showed benefit over antipsychotic and placebo in the following outcomes: PANSS negative and general psychopathology, improvement in depressive symptoms, cognitive domains—attention, visual memory, verbal memory and language and executive functioning. Confirmatory studies are needed to determine the clinical utility of this treatment strategy.

12 Purinergic-Related Drugs

A purinergic hypothesis of schizophrenia postulates that increased adenosinergic transmission reduces the affinity of dopamine agonists for dopamine receptors [275]. This model also addresses the systemic aspects of schizophrenia, based on peripheral roles of purines, such as modulation of the immune system.

12.1 Mechanism of Action

Allopurinol, a xanthine oxidase inhibitor, may increase circulating pools of adenosine and may have antipsychotic and anxiolytic effects [276].

12.2 Clinical Studies

12.2.1 Allopurinol

Clinical trials show that adjuvant allopurinol may benefit treatment refractory schizophernia patients. Allopurinol is well tolerated by most patients [276]. In another trial, 59 schizophrenia outpatients (51 patients completed the trial) were randomly assigned to receive adjunctive allopurinol 300 mg bid or identical placebo for 8 weeks after a 2-week placebo run-in [277]. A total of 4 of 31 in the allopurinol group and 0 of 28 in the placebo group had at least a 20% reduction in total PANSS score at the final study visit (p  =  0.049). Among the completers (n  =  51), individuals in the allopurinol group rated themselves as more improved than those in the placebo group (p  =  0.025). Allopurinol was well tolerated. Allopurinol may be an effective adjunctive medication for some patients with persistent schizophrenia.

Weiser et al. [278] performed a multicenter, 8-week randomized clinical trial of allopurinol vs. placebo added to anti-psychotic medications in 248 patients with SZ/SA disorder. Both groups showed improvement in the PANSS (effect size  =  1.13) and in clinical and cognitive measures. No between group differences were observed in any outcome measures. These findings do not support allopurinol as a treatment for schizophrenia.

13 Psychostimulants

13.1 Mechanism of Action

Psychostimulants increase the release of dopamine and norepinephrine and are a well-established treatment for attentional disorders.

13.2 Clinical Studies

13.2.1 D-amphetamine

In schizophrenia patients treated with haloperidol, D-amphetamine was found to enhance prefrontal cortical activation during performance of the Wisconsin Word Sort Test and to improve processing speed, whereas performance on memory and attentional tasks did not improve significantly [279]. Barch and Carter [280] found that, compared to placebo, D-amphetamine improved reaction times on spatial memory and Stroop tests, working memory accuracy, and language production when added to first generation antipsychotics. Healthy subjects displayed a similar pattern of cognitive improvement, though there was no change in working memory accuracy. Pietrzak and colleagues [281] reported improvement in executive function, attention, and speed of processing with D-amphetamine compared to placebo in chronic schizophrenia patients.

13.2.2 Modafinil

Modafinil is a Food and Drug Administration—approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a complex profile of neurochemical and behavioral effects, distinct from those of amphetamines. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, substance-dependence, and schizophrenia [282–284].

Compared to placebo, modafinil achieves positive but mainly variable results on different clinical and cognitive measures. Several studies have shown promising preliminary results in clinical domains when modafinil was added to antipsychotic treatment regimens [285, 286]. However, other clinical trials did not reveal any effect of modafinil on negative symptoms [287, 288] or wakefulness/fatigue or cognition compared to placebo [288, 289]. In a 4-week study, adjunctive armodafinil was not associated with an improvement in cognitive measures, and the negative symptoms of schizophrenia [290].

There were no significant differences in neurocognitive measures between adjunctive armodafinil (150 mg/d) and placebo in this 6-week study in 60 patients with schizophrenia or schizoaffective disorder. However, armodafinil was associated with significant improvement in the Scale for the SANS anhedonia-asociality (F1,41  =  4.1, p  =  0.05), but not other negative symptom domains [291]. Scoriels et al. [292] aimed to establish modafinil’s role in the adjunctive treatment of cognitive impairments. Forty patients with first episode psychosis participated in a randomized, double-blind, placebo-controlled crossover design study to assess the effects of a single dose of 200 mg modafinil on measures of executive functioning, memory, learning, impulsivity and attention. Modafinil improved verbal working memory, spatial working memory errors and strategy use. It also reduced discrimination errors in a task testing impulsivity. Modafinil showed no effect on impulsivity measures, sustained attention, attentional set-shifting, learning or fluency. Thus, modafinil selectively enhances working memory in first episode psychosis patients. Modafinil significantly improved the recognition of sad facial expressions in first episode psychosis, while there was no effect of modafinil on subjective mood ratings, on tasks measuring emotional sensitivity to reward or punishment, or on interference of emotional valence on cognitive function [293]. Thus, evidence for the use of modafinil or armodafinil as add-on therapy to antipsychotic drugs in schizophrenia is inconclusive owing to small sample sizes and methodological differences of the various trials (cognitive testing). Adverse events include insomnia, headache, nausea, nervousness and hypertension. Further research is required to address the potential benefits and risks of chronic administration of modafinil to patients with schizophrenia.

14 Beta Blockers

14.1 Mechanism of Action

Propranolol is a non-selective beta-adrenergic receptor blocking agent. It has no other autonomic nervous system activity. Propranolol is a competitive antagonist which specifically competes with beta-adrenergic receptor stimulating agents for available beta-receptor sites. The most serious adverse effects that may be encountered with propranolol are congestive heart failure and bronchospasm.

14.2 Clinical Studies

14.2.1 Propranolol

High dose propranolol up to 1,200 mg/day has been shown to augment antipsychotic efficacy in treatment refractory schizophrenia. Reported beneficial effects include an ability to treat akathisia, increase antipsychotic serum levels, and decrease anxiety symptoms [38]. The latest Cochrane review and meta-analysis included only five studies with 117 patients and did not support the efficacy of antipsychotic augmentation with beta-blockers [294].

14.2.2 Pindolol

Treatment of aggression in schizophrenic patients is a major challenge. Caspi et al. [295] examined the efficacy of augmentation of antipsychotic treatment with pindolol in the amelioration of aggression. Thirty male inpatients meeting DSM-IV criteria for schizophrenia, aged 20–65 years involved in four or more aggressive incidents in the two previous months, were enrolled in a double-blind crossover study. Aggression was evaluated per incident, with the Overt Aggression Scale. Patients received either pindolol or placebo augmentation 5 mg × three times a day until crossover, and then switched. revealed a significantly decline in the number According to Overt Aggression Scale scores, pindolol, with its dual beta and 5-HT1A blocking effect ameliorated both number of aggressive incidents (0.59 versus 1.46, p  <  0.02; 1.96 versus 3.23, p  <  0.05, respectively).and severity of incidents towards objects and other persons (0.89 versus 3.58, p  <  0.0001; 2.89 versus 6.85, p  <  0.004, respectively). Influence on severity may be associated with a 5-HT1A antagonistic effect.

15 Dietary Supplements

There is considerable scientific disagreement about the possible effects of dietary supplements on mental health and SZ/SA disorder.

15.1 Omega-3 Fatty Acids

Decreased n-3 fatty acid levels have been reported in patients with depression, schizophrenia, and Alzheimer’s disease. Recently, eicosapentaenoic acid (EPA) was used to treat several psychiatric and neurodegenerative diseases due to its anti-inflammatory and neuroprotective effects [296, 297]. Published results are conflicting, and the antipsychotic efficacy of such augmentation strategies is not well established. A Cochrane review and meta-analysis included six short-term trials with 353 participants. The results were contradictory, leading the study authors to conclude that this treatment still needs further investigation [298]. A recent meta-analysis included double-blind, randomized, placebo-controlled studies using purified or EPA-enriched oils in schizophrenia: the database included 167 schizophrenic subjects under the placebo arm matched with 168 schizophrenic subjects in the EPA arm. The meta-analysis did not show a consistent significant beneficial effect for EPA augmentation on psychotic symptoms in schizophrenia [39].

15.2 L-Theanine

L-theanine is a unique amino acid present almost exclusively in the tea plant. It possesses neuroprotective, mood-enhancing, and relaxation properties.

15.2.1 Mechanism of Action

L-theanine is a water-soluble amino acid. L-theanine has been shown to have a direct influence on brain activity, such as reducing stress [299, 300]. At high doses (higher than usual doses found in a cup of black tea about 20 mg), it has the ability to relax the mind without causing drowsiness. Thirty-five participants were given either 50 mg of L-theanine or placebo. Electroencephalogram tests were done at baseline and then at specified times afterwards (45, 60, 75, 90, and 105 min). Researchers found that there was a greater increase in alpha activity in those who took L-theanine compared to placebo, demonstrating that the amino acid had an effect on the participants’ general state of mental alertness and arousal.

15.2.2 Clinical Study

Ritsner et al. [301] conducted a first study designed to evaluate the efficacy and tolerability of L-theanine augmentation of antipsychotic treatment of 60 patients (40 patients completed the study protocol) with chronic SZ/SA disorder during an 8-week, double-blind, randomized, placebo-controlled study. 400 mg/day of L-theanine was added to ongoing antipsychotic treatment. Compared with placebo, L-theanine augmentation was associated with reduction of anxiety (p  =  0.015) and positive (p  =  0.009) and general psychopathology (p  <  0.001) scores (measured by the PANSS 3-dimensional model). According to the 5-dimension model of psychopathology, L-theanine produced significant reductions on PANSS positive (p  =  0.004) and activation factor (p  =  0.006) scores compared to placebo. The effect sizes (Cohen d) for these differences ranged from modest to moderate (0.09–0.39). L-theanine was found to be a safe and well-tolerated medication. Regression models among L-theanine-treated patients indicate that circulating levels of brain-derived neurotrophic factor (BDNF) and cortisol-to-DHEAS*100 molar ratios were significantly associated with the beneficial clinical effects of L-theanine augmentation [302]. Variability of serum BDNF levels accounted for 26.2% of the total variance in reduction of dysphoric mood and 38.2% in anxiety scores. In addition, the changes in cortisol-to-DHEAS*100 molar ratio accounted for 30–34% of the variance in activation factor and dysphoric mood scores and for 15.9% in anxiety scores. Regression models among placebo-treated patients did not reach significant levels (p  >  0.05). Thus, L-theanine augmentation of antipsychotic therapy can ameliorate positive, activation, and anxiety symptoms in SZ/SA disorder patients. Furthermore, results indicate that circulating BDNF and cortisol-to-DHEAS*100 molar ratio may be involved in the beneficial clinical effects of L-theanine as augmentation of antipsychotic therapy in schizophrenia and schizoaffective disorder patients. Long-term studies of L-theanine are needed to substantiate the clinically significant benefits of L-theanine augmentation.

15.3 S-Adenosyl-L-methionine

S-adenosyl L-methionine (SAMe) is the natural, universal methyl group donor, participating in transmethylation reactions, known and commonly used as a dietary supplement since 1952 [303]. It plays an important role in the synthesis of neuromediators and melatonin and mechanisms of epigenetic regulation. Since SAM-e is involved in several metabolic processes, its administration may have a role in the amelioration of several disorders.

15.3.1 Mechanism of Action

SAM-e is able to cross the blood-brain barrier. SAM-e’s predominant function is as a primary methyl group donor for a wide range of compounds including catecholamines, membrane phospholipids, fatty acids, nucleic acids, porphyrins, choline carnitine and creatinine. Following release of its methyl group, SAM-e is converted to S-adenosyl-homocysteine which, in turn, acts as a competitive inhibitor of SAM-e-mediated methylation reactions. An important function of SAM-e involves methylation of certain phospholipids, particularly phosphatidylethanolamine, and proteins which aid in the maintenance/control of the fluidity and microviscosity of cell membranes. Intact SAM-e metabolism is also considered vital for myelin maintenance [304].

15.3.2 Clinical Study

The efficacy of SAM-e in managing schizophrenia symptomatology in patients with a low activity catechol-O-methyltransferase polymorphism was investigated in a pilot study [305]. Eighteen patients with chronic schizophrenia were randomly assigned to receive either SAM-e (800 mg) or placebo for 8 weeks in a double-blind fashion. Results indicated some reduction in aggressive behavior and improved quality of life following SAM-e administration. Female patients showed improvement of depressive symptoms. Clinical improvement did not correlate with serum SAM-e levels. Two patients that received SAM-e exhibited some exacerbation of irritability. This preliminary pilot short-term study cautiously supports SAM-e as an adjunct in management of aggressive behavior and quality of life impairment in schizophrenia.

16 Conclusions and Future Directions

Development of new antipsychotic drugs over the last decade has not produced dramatic improvement in the treatment of schizophrenia. To find better alternatives to the existing antipsychotics, novel receptors are being targeted to develop third-generation antipsychotic agents [306–308]. Other less classic pathways are also under study and have led to some agents that are in very early stages of development such as those acting on sigma receptors, cholecystokinin antagonists, neurotensin agonists, neurokinin receptor antagonists, GABAergic enhancers, and cannabinoid receptor modulators [309].

Despite the availability of different classes of drugs for the treatment of SZ/SA disorder, there remains a high prevalence of drug resistance, partial response, subsyndromal symptomatology, and relapse. When treating patients who did not adequately respond to their first antipsychotic therapy, there are three additional options: (1) switch to a different antipsychotic; (2) combine two antipsychotics; or (3) augment the current drug treatment with a non- antipsychotic agent. In present clinical practice non-dopaminergic drugs are usually prescribed in order to gain an enhanced therapeutic effect when the response to antipsychotic monotherapy has been disappointing.

There is a range of potential augmenting agents in SZ/SA disorder, each with varying available evidence regarding efficacy and tolerability. The rationale behind the augmentation strategy is to simultaneously target different brain functions in the hope of providing symptom relief. It is increasingly evident that various non-dopaminergic receptors have an important role in the clinical profile of schizophrenia—with noradrenergic, glutamatergic and serotonergic receptors involved in the pathogenesis of positive and negative symptoms. These agents include multiple antidepressants, lithium, antiepileptic agents, hormone, stimulants, and others. Table 8.1 summarizes some evidence regarding improvement in the specific dimension of schizophrenia after add-on adjunctive agents or supplements while no adjunctive agent has been clearly demonstrated to be markedly efficacious. Although there is an increasing volume of augmentation trials, some of the available studies reveal conflicting results, and recommendations are based upon theoretical assumptions rather than upon evidence-based knowledge. Augmentation is generally considered the best option when a first drug provides partial relief but does not completely alleviate symptoms [38, 310]. Disadvantages of this strategy include cost of additional treatment and (if drug augmentation is used) increased likelihood of side effects, drug interactions, and the general lack of evidence for effectiveness.

Table 8.1
figure 00083

Possible improvement in schizophrenia dimensions after add-on adjunctive agents or supplements [22, 29–39]. DHEA dehydroepiandrosterone

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