Clinical Management of Negative Symptoms of Schizophrenia: An update (2015)

It’s a topic close to my heart and finally an excellent review has been published:

Clinical Management of Negative Symptoms of Schizophrenia: An update (2015)

Overwhelming research evidence suggests that the negative symptoms of schizophrenia (NSS) contribute more to impaired quality of life and poor functioning than positive symptoms, and that NSS, including affective flattening, alogia and avolition are present in at least one-fifth of patients diagnosed with schizophrenia. Despite this, management of NSS continues to be a major clinical unmet need as treatment with current antipsychotic medication seems to reach at best modest efficacy.

A critical review of the current pharmacological, non-pharmacological and psychosocial treatments available for NSS is presented here, using data retrieved from the MEDLINE/PUBMED, the Cochrane Database of Systematic Reviews and the ClinicalTrials.gov databases. An early and accurate diagnosis using selective scales is essential for documentation and monitoring of change in NSS according to treatment response. Typical and atypical antipsychotic drugs, showed modest efficacy in managing NSS. Conflicting results were obtained with the use of glycinergic neuromodulators, anticholinergics, antidepressants, anticonvulsants, psychostimulants, modafinil and 5-HT₃ receptor antagonists. Moreover, non-pharmacological therapies including psychological therapies have failed to address NSS effectively.

At present, it appears that the best effective approach for clinical management of NSS is achieved by complementing drug therapy with psychosocial therapies. Continuing basic and clinical research for the understanding of the genetic, behavioral and neural basis of NSS should yield novel pharmacotherapies with superior efficacy, tolerability and long-term maintenance for improved treatment of NSS.

Pharmacological interventions

Antipsychotic drugs and negative symptoms

• Tandon and Jibson (2002): antipsychotics seem to show some improvement on NSS through their effect on positive symptoms
• Lieberman et al. (2005): perphenazine was found similar in effectiveness to newer medications (with the exception of olanzapine) and there were no significant advantages in efficacy for any of the atypical antipsychotics with regards to negative symptoms
• Jones et al. (2006): The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), where 1227 people with schizophrenia were randomised to either a typical (chlorpromazine, flupenthixol, haloperidol, loxapine, sulpiride, zuclopenthixol) or atypical drug other than clozapine (amisulpride, olanzapine, quetiapine or risperidone) found no significant differences for either class of drug in symptom reduction
• Stip and Tourjman (2010): aripiprazole was associated with improvement in both positive and negative symptoms and with a benign safety profile
• Darbá et al. (2011) concluded that atypical antipsychotics are significantly better than typicals, with amisulpride and ziprasidone showing the highest effect sizes.
• Amr et al. (2013): quetiapine (200mg/d) was found to be more effective than haloperidol (5mg/d) in decreasing NSS but not in decreasing general psychopathology.
• Pilla Reddy et al. (2013) found that positive symptoms of schizophrenia responded well to all antipsychotics and olanzapine showed a better effect towards negative symptoms than the other atypical antipsychotics and haloperidol.
• Khanna and colleagues (2014): aripiprazole was similar in effectiveness with risperidone, better than ziprasidone and not as effective as olanzapine but with better tolerability and fewer side effects
• Shafti and Gilanipoor (2014): In a 12-week double-blind clinical trial, olanzapine displayed superior efficacy with respect to negative symptoms in comparison with the risperidone.
• CATIE study concluded that “each drug might be most useful in particular situations depending on several factors such as illness course and extrapyramidal symptoms.”
• Only one-third of patients respond well to clozapine. Although clozapine augmentation is common practice, meta-analytic studies examining antipsychotic polypharmacy suggested a small effect in managing treatment resistant schizophrenia (Taylor et al., 2009, 2012)

Antidepressant augmentation of antipsychotics:

“Due to similarities between negative and depressive symptoms in schizophrenia patients and the effectiveness of antidepressants in treating depressive symptoms in schizophrenia, treatment combination of antipsychotics with selective serotonin reuptake inhibitors (SSRI) has repeatedly been suggested as a promising strategy in NSS (Zullino et al., 2002). Indeed there are several clinical guidelines recommending the antidepressants in addition to antipsychotic treatment for schizophrenia patients with persisting negative symptoms”

• Spina and colleagues (1994): addition of fluoxetine (20 mg/day) to typical antipsychotics gradually improved negative symptoms.
• Berk et al. (2001): mirtazapine combined with haloperidol had a significant positive impact on improving NSS
• Rummel-Kluge and colleagues (2006): combination therapy showed significant clinical improvement in NSS compared to patients who received only antipsychotic medication
• A meta-analysis by Singh and colleagues (2010): fluoxetine, trazodone and ritanserin produced a statistically significant effect whereas mirtazapine, reboxetine, mianserin, fluvoxamine, sertraline, paroxetine and citalopram failed to provide similar outcomes (number of RCTs included in the meta-analysis was very small and so the actual effect size of each individual antidepressant might have lost great power). They concluded combined antipsychotic/antidepressant therapy is more effective in treating NSS than antipsychotics alone
• Cho et al. (2011): when  mirtazapine was used as an add-on therapy to risperidone, the mirtazapine group exhibited a statistically significant improvement in negative symptoms.
• Caforio et al. (2013): olanzapine/mirtazapine treatment was more effective than olanzapine alone in improving NSS
• Stryjer and colleagues (2013): a significant improvement in the total PANSS scores after administering escitalopram as adjunctive therapy to antipsychotics
• Tsai et al. (2014) found the combination of escitalopram with aripripazole to be effective in improving NSS.
• “…most studies point to the importance of including an antidepressant agent for improving treatment of NSS, this finding has not been replicated by other studies that found no beneficiary effect of antidepressants in reducing NSS”

Glutamatergic interventions:

“…it was hypothesized that hypofunction of the NMDA receptor contributes to the development of schizophrenia symptoms and that the use of direct augmentation of glycine receptor agonists such as glycine and D-cycloserine, which indirectly stimulate NMDA receptors, would prove effective in managing NSS. Buchanan et al. (2007) conducted a sixteen-week double-blind, placebo-controlled trial in 157 patients diagnosed with schizophrenia and schizoaffective disorder and treated with glycine or D-cycloserine as adjunctive therapies to antipsychotic drugs. Findings revealed that the two glutamanergic agents were ineffective in reducing NSS. Lane et al., (2005) also reported no significant association between D-serine and NSS in a six-week trial on 65 individuals with schizophrenia, but reported beneficial effects from the use of sarcosine (N-methylglycine) as adjunctive therapy to risperidone. This finding replicated earlier findings (Tsai et al. 2004). Weiser and colleagues (2012) conducted a 195-patient, multicenter, double-blind, randomized, placebo-controlled, 16-week trial of d-serine 2 gm/day as add-on treatment to antipsychotics. Participants receiving d-serine showed an improvement on the SANS scores however, the authors failed to report a significant difference between augmentation with d-serine and placebo. Bitopertin (RG1678; RO-4917838) is a glycine reuptake inhibitor, which was under development by Roche as an adjunctive therapy to antipsychotics for the treatment of persistent NSS. However, preliminary results of two of six phase III studies have been disappointing as they did not meet their primary endpoints. In a press release, Roche announced that the investigational drug failed to significantly reduce NSS as measured by PANSS after 24 weeks compared to placebo, and the program was halted. Another selective glycine uptake inhibitor of type 1 glycine transporter, Org 25935, did not differ significantly when compared to placebo in the reduction of NSS as measured with the SANS and the PANSS (Schoemaker et al., 2014). The latter findings raised questions about the therapeutic potential of glycinergic neuromodulation in treatment of NSS (Kingwell, 2014).”

“…memantine, a weak NMDA receptor antagonist, has been investigated in various studies that aimed to test its efficacy in treating negative symptoms in schizophrenia. De Lucena et al. (2009) conducted a double-blind, placebo-controlled study in patients with refractory schizophrenia who received either 20 mg/d of memantine (n = 10) or placebo (n = 11), in addition to clozapine, for 12 weeks. Data showed that memantine was associated with significant improvement in reducing NSS as measured with the BPRS. In a more recent study, Rezaei et al. (2013) administered memantine (20 mg) as add-on therapy to risperidone in 38 patients with schizophrenia, for a period of 8 weeks. The authors reported that the negative symptoms were significantly improved in memantine-treated patients vs. placebo when assessed with PANSS.”

Cholinergic interventions:

“Choi and colleagues (2013) conducted a meta-analysis, consisting of 26 double-blind, placebo-controlled studies, to examine the efficacy of cholinergic, glutamatergic and serotonergic agents as adjunctive pharmacotherapies to treat negative symptoms and cognitive deficits in schizophrenia. Results showed that medications targeting acetylcholinesterase, such as the acetylcholinesterase inhibitors donepezil and galantamine, had a moderate effect size (d = 0.58) as add on therapy to antipsychotics for the improvement of NSS.”

Anticonvulsant augmentation:

“…adjunctive administration of anticonvulsant drugs, such as carbamazepine, topiramate and lamotrigine, has been proposed as a useful treatment strategy for treatment resistant schizophrenia patients but remains controversial. Augmentation with lamotrigine as adjunctive medication specifically to clozapine, has been reported to decrease NSS. Premkumar and Pick (2006) conducted a meta-analysis of 5 double-blind, placebo-controlled trials to evaluate the efficacy of lamotrigine as add on therapy to various antipsychotics including clozapine. Findings revealed a significant decrease in the negative symptom scores, assessed with PANSS, from baseline. On the other hand, Goff and colleagues (2007) failed to replicate these results. The authors conducted a randomized, double-blind, parallel group study, to examine the effect of lamotrigine augmentation on schizophrenia symptomatology. Results showed that after 12 weeks, negative symptoms assessed by the SANS, improved more with placebo than lamotrigine.

Similarly, augmentation with topiramate to antipsychotic medication has produced controversial results. Tiihonen et al. (2005) examined whether topiramate is more effective than placebo in reducing symptoms in schizophrenia. The authors recruited twenty-six patients with treatment resistant schizophrenia and added 300 mg/day of topiramate to the patients’ ongoing treatment for a period of 12 weeks. Data revealed that topiramate was effective in reducing overall psychopathology but did not reach significance in reducing negative and positive symptoms.”

Anti-inflammatory agents are covered:

“Pregnenolone is an endogenous neurosteroid in the central nervous system (CNS). It is thought to improve N-menthyl-D-aspartate (NMDA) receptor function and GABA receptor responsiveness (Marx et al., 2011). Despite many limitations, clinical trial data utilizing pregnenolone seems promising. Marx and colleagues (2009) found that pregnenolone (500 m/d) used as add-on therapy to antipsychotics for 8 weeks significantly decreased negative symptoms as measured by SANS. Further support derives from a recent study conducted by Ritsner and colleagues (2014). They reported that pregnenolone significantly reduced NSS, in particular especially avolition, blunted affect and anhedonia. The effect of pregnenolone was even greater when patients were not treated with concomitant mood stabilizers.”

Aspirin: “Laan et al. (2010) conducted a double blind, placebo controlled study recruiting 70 patients with moderate to severe schizophrenia. Patients were randomized to adjunct treatment with aspirin 1000 mg/d or placebo and were treated for three months. Positive and negative symptoms were assessed by PANSS. Blood samples for immunological measurements were taken and cytokines were analysed using ELISA-assays. They found that the more altered the patient’s immune system was, the more beneficiary proved to be add on therapy with aspirin. They reported a statistically significant decrease in positive symptoms and a decrease to a lesser extent in the NSS.”

“The therapeutic benefit of COX-2 inhibitors on the reduction of symptoms in schizophrenia has been investigated by Muller and colleagues (2010). The authors conducted a double-blind, placebo-controlled, randomized trial of celecoxib augmentation (400 mg) to amisulpride treatment in 49 first episode schizophrenia patients. Compared to the group with amisulpride plus placebo, the treatment group showed significant reduction (p = 0.03) in the NSS as assessed with the PANSS. Chaudhry et al. (ClinicalTrials.gov NCT01602029, 2013) are currently studying the effect of adjunct therapy with ondansetron and/or simvastatin on negative symptoms of schizophrenia. They conduct a double blind placebo controlled study where a total of 216 patients will be recruited over a period of three years from both inpatient and outpatient settings and will be treated for six months. Based on past research findings of the efficacy of COX-2 inhibitors in managing NSS their main assumption is that addition of ondansetron and/or simvastatin to standard treatment in patients with schizophrenia will show a significant improvement in the reduction of their NSS”

“Minocycline (INN) is a broad-spectrum tetracycline antibiotic and anti-inflammatory drug and its use in the treatment of NSS has been encouraged by evidence derived from animal models (Monte et al., 2013). Khodaie-Ardakani and colleagues (2014) examined the efficacy of minocycline (200 mg/d) on NSS as an add-on therapy to risperidone on 38 patients with stable schizophrenia over a course of 8 weeks. Results revealed a clinically significant improvement in NSS in patients treated with combined therapy (p < 0.001). Further support comes from the study of Liu et al. (2014) who tested the efficacy of minocycline as adjunctive therapy to risperidone in 92 patients with early stages of schizophrenia. NSS were assessed by administering PANSS and SANS, and both scales showed significant score reductions (p < 0.001) after 16 weeks of treatment. Chaudhry et al. (2012) conducted a double-blind, placebo controlled study to examine the efficacy of minocycline in reducing negative symptoms in early schizophrenia. NSS assessed with PANSS were significantly reduced compared to placebo after 1 year of co-administering minocycline with antipsychotics. The authors pointed out the beneficial effect of minocycline but debated the exact mechanism of action of minocycline (i.e. anti-inflammatory, neuroprotective or other) which remains under investigation. Further support comes from a study by Levkovitz et al. (2010), where 72 patients with early phase schizophrenia showed reductions in NSS as assessed with the SANS after minocycline (200 mg/day) was added to their standard medical treatment for a period of twenty-two weeks. Miyoka and colleagues (2008) conducted an off-label clinical trial study in 22 patients with treatment resistant schizophrenia. Minocycline augmentation lasted 8 weeks and NSS were measured with PANSS at baseline, 4 weeks and 8 weeks. The authors reported profound changes in the negative symptom scores (55.8% and 57.2% change from baseline at 4 and 8 weeks respectively).”

“… N-acetylcysteine (NAC) [has] been investigated in several clinical trials showing reduction of schizophrenia symptoms including negative symptoms such as apathy and motivation. Farokhnia et al. (2013) conducted a double-blind, placebo controlled, parallel-group study with a total sample of 42 patients with schizophrenia who scored 20 points or higher in the negative symptoms subscale of PANSS. After 8 weeks of add-on of high doses of NAC (2gm/day) to risperidone, a significant decrease in NSS was measured but not in the positive symptoms or general psychopathology.”

“Omega-3 fatty acids are polyunsaturated fatty acids with various important biological roles including scavenging of toxic free radicals. Past research findings suggest that oxidative stress and generation of toxic free radicals exist in schizophrenia (Mahadik et al., 2006; Perez-Neri et al., 2006). Oxidative damage of the brain has long been associated with reduction of polyunsaturated fatty acids (PUFA) membrane in the brain (Mahadik et al., 2001) and therefore intake of essential fatty acids, especially omega-3 and omega-6, which suggested as a possible solution to damaged membrane structures (Mazza et al., 2007). Further support for the role of polyunsaturated fatty acid deficits in schizophrenia comes from a clinical trial study conducted by Sethom et al. (2010). After measuring the level of PUFAs at baseline, the authors administered typical antipsychotic medication to 36 drug free patients for a period of 3 months. Results revealed that PUFA deficiencies are associated with both negative and positive symptoms. Joy and colleagues (2006) conducted a meta-analysis of five studies, which examined the effect of PUFAs in schizophrenia symptoms. They reported statistically significant but not clinically meaningful reduction in the PANSS scores”

Psychostimulants and wake-promoting agents:

 “…despite a number of medicinally important pharmacological effects, the therapeutic use of psychostimulants is limited because of their abuse liability and the induction of psychosis following long term use. Serotonin 5-HT1A receptor agonists can inhibit amphetamine and apomorphine-induced psychosis hence co-administration of 5-HT1A agonists may help prolong any therapeutic use of psychostimulants. Preclinical and clinical studies are warranted to evaluate the effects of co-administration of 5-HT1A agonists on potential therapeutic profile of psychostimulants in the treatment of schizophrenia (Haleem, 2013).

Lindenmayer et al. (2013) conducted a literature review to examine the efficacy of various psychostimulant agents as add-on therapy to antipsychotics in managing negative symptoms. Findings revealed that DA agonists may improve NSS, partly due to their ability to stimulate mesocortical pathways, without exacerbating positive symptoms in patients with stable schizophrenia. The authors pointed out that larger controlled clinical trials are needed to further investigate the impact of psychostimulants in NSS. A recent open label study conducted by Lasser and colleagues (2013)examined the efficacy of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug of the phenethylamine and amphetamine classes, as adjunctive therapy to antipsychotics in an open label clinical trial over a period of four weeks, in a sample of 69 patients with stable schizophrenia and predominant negative symptoms. Data analysis showed that LDX appeared to be associated with significant improvements in NSS as measured with the SANS scale and the PANSS, though these findings require further validation (Hutson et al., 2014).”

“…Arbabi et al. (2012) reported that modafinil (200 mg/day) as an adjunct therapy to risperidone was beneficial in managing negative symptoms and cognitive deficits of schizophrenia. These results are in accordance with earlier findings (Peloian and Pierre, 2008).”

“Armodafinil, the R-isomer of modafinil, is a non-amphetamine, wakefulness promoting medication. Kane and colleagues (2012) investigated the efficacy and tolerability of adjunctive armodafinil for the treatment of negative symptoms. They conducted a parallel-group, 24-week study, where patients with schizophrenia received one of 3 doses of once-daily armodafinil (150 mg, 200 mg, or 250 mg) or placebo, adjunctive to oral olanzapine, risperidone, or paliperidone for ≥ 6 weeks. Negative symptoms, measured with the PANSS, did not benefit from armodafinil augmentation when compared to placebo.”

5-HT3 antagonists:

“A growing body of evidence illustrates that 5-HT₃ receptor antagonist drugs may be beneficial in the treatment of NSS. Tropisetron, ondasetron and granisetron are traditionally used as anti-emetic drugs for chemotherapy-induced and postoperative emesis. Noroozian et al. (2013) assessed the efficacy of tropisetron as adjunctive therapy to risperidone in treating NSS, in a sample of 40 patients with chronic, stable schizophrenia during an 8-week placebo-controlled trial. Tropisetron resulted in greater improvement of negative symptoms as assessed with the PANSS. Bennett and Vila (2010) reviewed 6 clinical trials that evaluated ondansetron for the treatment of schizophrenia and reported that ondansetron may be effective as an adjunct to antipsychotics for the treatment of NSS. Finally, a double-blind, randomized, placebo-controlled study with 38 patients with stable schizophrenia evaluated the effects of combined granisetron/risperidone on NSS for a period of 8 weeks. The granisetron/risperidone group showed statistically significant improvement in NSS compared to the placebo/risperidone group”

Psychological therapies:

Family psychoeducation:

“The diagnosis of schizophrenia has devastating consequences for family members on emotional, social and economic levels. It is important to educate families about the nature of the disorder, its prognosis and its multi-symptoms including negative symptoms. Family members are often frightened and confused by the patient’s strange new beliefs or behaviors, decreased energy levels and loss of motivation (Song et al., 2014). Families and caregivers become more supportive and less critical towards the patient when they realize that amotivation and anhedonia are symptoms of the illness rather than behaviors reflecting the individual’s character (Velligan and Alphs, 2014). Indeed, expressed emotion (EE) which refers to the caregivers’ attitudes towards a person with a mental disorder, has been found to be one the most robust predictors of patients’ relapse in schizophrenia (Amaresha and Venkatasubramanian, 2012) and poor quality of life (Philips et al., 2002). Moreover, most often families do not know how best to respond to these changes and need guidance and direction. It becomes vital therefore, that family members should receive psychoeducation as early as possible following diagnosis (Sin and Norman, 2013).

The goal of the psychoeducational approach is to persuade and teach family members of a schizophrenia patient that the way they will behave towards the patient may facilitate recovery by compensating for deficits and sensitivities specific to the disorder.”

Cognitive Behavioral Therapy CBT:

“There is a large body of scientific evidence supporting the role of CBT in treating NSS and improving functional outcomes and quality of life.”

“…lower negative symptoms significantly predicted higher patient and therapist rated alliance. The authors concluded that negative symptoms might be a barrier to the development of therapeutic alliance and therefore influence the therapeutic outcome. Jones et al. (2012) conducted meta-analyses of 20 randomized trials to examine the efficacy of CBT (described as a talk/active therapy) on the reduction of symptoms, relapse and rehospitalisation, function and quality of life compared to non-active interventions such as supportive therapy. Results revealed some long-term effect in the reduction of affective symptoms. Overall, findings did not favour a particular type of therapy in terms of social function or quality of life.”

Art therapy:

“Art therapy (art, music, body movement, dance and drama therapy) is a form of psychotherapy to manage the negative symptoms of schizophrenia as adjunctive therapy to antipsychotics. Its nonverbal aspect is thought to help people express their thoughts and feelings in a no-destructive way and therefore offers the potential of improving patients’ quality of life and enhancing their clinical outcome by reducing the negative symptoms of the disorder.”

Also covered:

• Repetitive transcranial magnetic stimulation (rTMS)
• Electroconvulsive therapy (ECT)
• The Role of Genes
• Future directions on treating negative symptoms in schizophrenia

“Pharmacological treatments seem to have little impact on negative symptoms. In recent years, the recovery in mental health relies heavily on the optimum standard and quality of life. Psychosocial interventions are therefore, important components in the management of schizophrenia. The selection of appropriate psychosocial treatment should be guided by the individual circumstances of each patient; the severity of their symptoms, their needs and their social context.”

“New medications are being developed to focus on targets other than or in combination to the dopaminergic system in order to efficiently reduce globally the symptoms of schizophrenia. Furthermore, the role of pharmacogenomics is growing in an effort to help determine which medical treatment is appropriate for each individual, based on their genetic makeup. Clinicians have started putting more emphasis on managing the negative symptoms of the disorder, as it is by now well established, that they account for most of the reported impaired functioning and low quality of life.”