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Down the Rabbit Hole
Paul Kiritsis, PsyD candidate, DPhil., MA (Psychology), MA (History)


The Treatment of Schizophrenia

Paul Kiritsis - Wednesday, October 26, 2016


Without a doubt, the zealous prescription and sometimes overprescription of neuroleptic medications dominating the treatment and management of acute schizophrenic disturbances today is residue from an anachronistic Kraepelinian epoch most fallacious in its core assumption that the phenomenology of psychosis was tantamount to brain disease (Bentall, 2003). Most congruent with this belief, the corpus of clinical and experimental research in the last fifty years focused on the prematurely inflated role of genetic inheritance or nature in the development of psychosis while ignoring existing environmental factors altogether. Indeed, the treatment options available and the prioritization and prominence of pharmacotherapies over psychotherapeutic interventions in the acute psychiatric care units of hospitals today reflects wholesale, hitherto undisputed, and often distorted perceptions pertaining to this core assumption.    

            All the same if we returned to the clinical landscape of the 1950s it would not be difficult to imagine how the accidental discovery of neuroleptic drugs and their eventual usurpation of the more archaic and barbaric somatic therapies (i.e. hydrotherapy, frontal lobotomy, and insulin coma therapy) which had been used to “cure” schizophrenia since the turn of the twentieth century fueled a major revolution in psychiatric treatment, and further, why this phenomenon has been exalted as a groundbreaking moment in medicine by some historians of science (Fanu, 1999).

In 1952, an adroit French psychiatrist working at the Ste-Anne mental hospital in Paris by the name of Jean Delay arbitrarily stumbled upon a mysterious compound, 4560RP, with sedative properties purported to elicit genuine apathy and equanimity in patients who ingested it. Delay recognized its potential value to psychiatry and wasted no time in soliciting the help of his colleague Pierre Denker for inaugural clinical trials with acute patients. Together they discovered that 4590RP, later renamed to chlorpromazine (brand name Thorazine), reduced the frequency and severity of hallucinations whilst also diminishing concurrent delusions (Healy, 2009). Immediately recognized by other practitioners as noninvasive and therapeutically superior to mostly ineffectual and complicated alternatives, chlorpromazine swept around the globe on swift wings and within a few years had become the preferential treatment for patients with schizophrenia.

The ostensible panacea bequeathed by these antipsychotics drugs could not be denied. They stifled perceptual excesses and enhanced reality-testing by silencing hallucinations and dampening delusions (Guttmacher, 1964). The gradual reduction of total symptoms spurred by pharmaceutic agents is undisputed gospel, as one recent randomized trial assigning 498 patients with a first psychotic episode to a variety of acknowledged neuroleptic treatments for schizophrenia has shown (Kahn et al., 2008).  Later the underlying mechanism of action through which neuroleptics worked to gradually reduce these positive symptoms was also illuminated; antipsychotic agents blocked D2-dopamine postsynaptic receptors in the overactive temporalimbic system (Healy, 2002; Miyamoto et al., 2003; Blom & Sommer, 2011). By the1970s it had also become apparent that when patients continued taking medications during periods of remission the likelihood of relapse diminished exponentially (Marder & Wirshing, 2003; Stroup, Kraus, & Marder, 2006). But despite these remarkable benefits it soon came to light that neuroleptic use wasn’t without its own set of problems and limitations.

Even with the improvement in symptom severity and reduction of relapse, antipsychotic agents cannot amend role impairments in social and vocational functioning caused by the ancillary negative symptoms and cognitive deficits (Kingdon & Turkington, 2005). Put another way they are unable to positively affect the trajectory of the disorder. Improving the dearth of occupational and social skills is largely dependent on modifying cognitive schemata as to [re]build interpersonal awareness and attunement for more satisfying relational engagement, something neuroleptics cannot do.

Another caveat pertains to treatment resistance. A number of patients diagnosed with schizophrenia, as many as 10-20%, are non-responsive to pharmacotherapy (Kane, 1996) whilst others swiftly develop tolerance and suffer relapse even when adhering to their personalized medication regimen. This leaves pharmaceutical companies with the overwhelming and often inexorable mission of synthesizing new antipsychotic drugs with different receptor profiles to which these previously treatment-refractory patients might respond. Surmounting this impasse was just one of the reasons why second generation antipsychotics with different mechanisms of action [which antagonize both serotonin and dopamine] were introduced into the circle of pharmacotherapies in the 1980s. One of these, Clozaril (Clozapine), was tooted as therapeutically superior to many others in inciting responses in 30% of treatment-refractory patients (Turner & Stewart, 2006) however as many as 40-70% of them will respond quite poorly to treatment (Kane et al., 1988). These poor treatment outcomes pose major concerns and questions for a public health care system perpetually investing in more costly second-generation antipsychotics without bearing witness to concomitant improvements in the symptoms and reduced quality of life for these ultra-resistant patients.

Neuroleptics spur ancillary changes in other non-targeted albeit interconnected neurotransmitter systems of the brain, manifesting as idiosyncratic side effect profiles. For most patients these deleterious side effects are a distressing complication, further compounding the formation of objective opinions about their actual worth. The first generation antipsychotics like chlorpromazine (Thorazine) and its sister compounds haloperidol (Haldol) and perphenazine (Trilafon) are associated with extrapyramidal side effects like dystonia (a movement disorder involving involuntary muscle contractions), Parkinsonism (slowness and rigidity from involuntary tremors), and akathisia (subjective feelings of restlessness, especially in the lower limbs). Steep dose increases and higher dosages have been known to cause acute dystonia and epileptic seizures (Ciranni et al., 2009; Hedges et al., 2003) while protracted use may cause an involuntary, irreversible movement disorder called tardive dyskinesia (Kane, 2004).The most salient features of this condition–spasms of the extremities, tongue protrusions, and lip smacking–are a source of emotional distress for both patients unfortunate enough to develop it and their relatives.  

Second generation antipsychotics with different receptor profiles like clozaril (brand name Clozapine), risperidone (Risperdal), and olanzapine (Zyprexa) were introduced into psychiatric practice in the 1980s because the pharmaceutical companies responsible for their synthesis believed they were superior in terms of efficacy; less likely to exacerbate cognitive deficits; and far less likely to generate adverse side effects than their traditional counterparts (Kane, 2004; Healy, 2002). While the newer “atypical” antipsychotics weren’t as detrimental to the body as their predecessors (Geddes et al., 2000), the passage of time has gradually exposed them as exaggerated, overrated, and overvalued worn-out pretenders that failed to deliver. Clozapine, in particular, was identified by pharmaceutical companies as a product with lucrative potential if marketed aptly because of its low profile of extrapyramidal side effects along with additional benefits spurred in perceptual domains (i.e. negative symptoms, disorganized behavior, thought disorder, suicidal ideation, and depression) that were hitherto impermeable to pharmacological influence. Lamentably, though, these advantages were counterbalanced and neutralized when clinical trials soon churned up evidence that one in 200 patients ingesting it developed agranulocytosis, or leukocytopenia, an immune system dysfunction characterized by cessation of white cell genesis. Save for generating treatment-resistant infections this condition can also prove fatal (Atkin et al., 1996). Clozapine has also been linked to irreversible heart disease in the guise of pericarditis, cardiomyopathy, or myocarditis (Kamphuis et al., 2010). Hence any patients considering clozapine therapy must express conscientiousness and shrewd judgement in weighting the cons and pros.

And to date the universal picture emerging on the utility of neuroleptic drugs is that cons sometimes overshadow the pros. Methodologically sound research studies have consistently failed to validate the theorized differential in efficacy rates and neurocognition between the older and newer generation of neuroleptic medications (Liebermann et al., 2005; Keefe et al., 2007). Moreover they may induce weight gain, sexual dysfunction, and sedation, introducing ancillary somatic issues into the clinical picture which may further deflate a sufferer’s wavering self-esteem, exacerbate negative symptoms like depression and affective blunting, and indirectly burgeon mortality rates (Kingdon & Turkington, 2005). What the aforementioned discourse has illumined, if anything, is that for positive outcomes to be achieved a prudent prescription of neuroleptics must be coupled with interventions that address the cognitive deficits and deficiencies in occupational and social skills–in other words the patient’s psychological needs. 

In the last twenty years the generic disgruntlement associated with medication-resistant negative symptoms and neurocognitive deficits alongside the deplorable life quality experienced and subjectively reported by patients who are ultra-resistant to conventional neuroleptic treatments has driven clinical interest toward psychological interventions (Chadwick et al., 1996). Quite unlike the reductive biomedical approach with its affinity for circuitous endorsement of passivity, faithful adherence to, and sometimes overdependence on an authority figure, cognitive models of schizophrenia adopt a less oppressive stance and demonstrate respect for an individual’s will. In truth, they attempt to proliferate remission and convalescence through [re]empowerment, that is, by educating patients to think of themselves as active intercessors and advocates for positive self-change and encouraging them to reevaluate existing relationships within their own mental worlds. Randomized controlled trials conducted [mostly] in the United Kingdom consistently demonstrate that cognitive therapy generates sustained positive change in both positive and negative symptom domains, indicating its invaluable worth as an adjunctive to pharmacotherapy in the treatment of schizophrenia (Gould, Mueser, Bolton, Mays, & Goff, 2001; Pilling et al., 2002).

Thus far traditional cognitive therapy has targeted the perceptual excesses in schizophrenia, that is the hallucinations and associated delusions, however auspicious results are also emerging for other cognitive-affective domains like negative symptoms. An impressive quantitative review of 13 randomized controlled trials involving 1,484 patients (Zimmermann, Favrod, Trieu, & Pomini, 2005) found cognitive therapy to be effective in ameliorating the symptoms of individuals with chronic schizophrenia; of individuals with acute psychosis residing in inpatient psychiatric hospital units; and of patients who had previously graduated from cognitive therapy treatment. Individuals in the three treatment groups experienced improvements which were, on average, 0.33, 0.5, and 0.33 standard deviations above the mean for those in the non-cognitive therapy control group, respectively. In other reviews and meta-analyses of sixteen randomized controlled studies (Dickerson, 2000; Rector  & Beck, 2001; Gould et al., 2001; Pilling et al., 2002) cognitive therapy was shown to be efficacious in reducing positive and negative symptoms in individuals with chronic schizophrenia. It should also be stressed that patients who participated in these studies were all medicated. Together, these empirical studies suggest unremitting benefits lasting between six to twelve months for patients receiving twenty sessions of cognitive therapy from a competent psychotherapist proficient in its administration (Kingdon & Turkington, 2005). They also revealed that patient adherence to these psychological interventions was correlated with the decreased likelihood of discontinuing medication regimens and with augmented rates of recovery in hospital settings. From a financial perspective cognitive therapy is relatively cost-efficient, making it an attractive adjunctive to pharmacological and other psychosocial interventions.   

Grippingly, cognitive behavioral therapy (CBT) has emerged as the psychological treatment of choice for auditory verbal hallucinations, one of the principal hallmarks of schizophrenia (McCarthy-Jones, 2012). Deployed under the psychological model of voice-hearing, CBT interventions attempt to normalize the idiosyncratic experience of hearing voices and concomitantly reduce debilitating epiphenomena (i.e. the emotional distress) through systematic restructure of the hyperactive negative appraisal system. The nature of findings thus far are mixed and equivocal. Case studies and non-controlled trials have been fertile hunting grounds, revealing short-term effectiveness for interventions of CBT (Morrison, 2001) but randomized control trials, the golden standard of experimental design, have not followed suit (McCarthy-Jones, 2012). In the last fifteen years only one randomized control trial (Morrison et al., 2004) has reported a significant post-intervention shift (from 39% to 63%) in the percentage of hallucination-free patients within a CBT treatment group. One viable explanation is that methodological flaws such as unreliable and unspecific outcome measures and small sample sizes are failing to detect improvements in certain facets of voice-hearing and encumbering detection of smaller effect sizes, phenomena which may be keeping the veridicality of CBT as an effective intervention concealed from quantitative illumination. Clarification of this issue would require modifications to the CBT interventions and/or larger trials.

            One longitudinal study utilizing single-bind randomized control trials (Sensky et al., 2000) stands as one of the most conspicuous embodiments and showpieces of how effective cognitive therapy can be with the spectrum of schizophrenic symptoms. This investigation involved a nine- month comparison of the therapeutic trajectory of two groups, one treated with cognitive therapy and the other with a simple interpersonal technique called “befriending.” According to the researchers the rationale for using the latter as an active control treatment instead of a more passive or waitlist control was to account for nonspecific therapeutic factors (i.e. unconditional positive regard, empathy, the quality of the therapeutic alliance ,interpersonal rapport) known to be operant in and conducive to convalescence. Post-treatment measures revealed significant improvements in positive, negative, and depressive symptom domains for both groups. The nine-month follow up-period, however, revealed divulging clinical pictures and symptomological courses for each group: while the cognitive therapy group maintained or enhanced their existing gains, the “befriending” group experienced loss of these gains, a gradual regression back to the languishing symptomatic state before the intervention. Moreover in the five years following the initial treatment individuals in the cognitive therapy group reported lesser negative symptoms (Turkington et al., 2008) than their “befriending” counterparts. Implied here is that training in social and occupational skills for interpersonal effectiveness and [possibly] reversal of role impairments must be woven into psychological interventions as to protect against regression to the baseline and sustain positive change.

From the aforementioned precedents one may extrapolate that cognitive therapy along with its many variants and adaptations are promising treatments for schizophrenia. Because the present study intends to use computerized cognitive remediation or training the rest of this section will focus on reviewing literature pertaining to that specialized intervention. Despite its relatively recent appearance in the therapeutic landscape,  a significant body of research reveals computer assisted cognitive training as having been used substantially and systemically in the treatment of heterogeneous clinical populations, and specifically individuals suffering from schizophrenia, attention deficit hyperactivity disorder (ADHD), and traumatic brain injury (Shinaver & Entwistle, 2015).

With respect to schizophrenia a plethora of randomized control trials conducted with methodological rigor along with subsequent meta-analyses have revealed computerized cognitive training to be efficacious in enhancing general and social cognition, verbal and working memory, processing speed, vigilance, and the attentional mechanism (Shinaver & Entwistle, 2015). Compliance and adherence to these top-down training programs has been shown to alter the underlying neural pathways and synapses supporting executive functions as to secure sustained benefits over time. These observations have certainly been influential in coloring the professional opinions of contemporary investigators and at times rousing seemingly premature, strong, and generalized statements; one review in particular (Barlati et al., 2013) openly celebrated the “usefulness of cognitive remediation when applied in the early course of schizophrenia and even in subjects at risk of the disease (p. 1)” and identified the medium as “a promising approach to improve real world functioning in schizophrenia,” one which “should be considered a key strategy for early intervention in the psychoses (p. 1).”

Some of the earliest meta-analyses attempting to examine the efficacy of computerized cognitive training were speculative and equivocal. For instance Kurtz and Moberg (2001) reported that there was insufficient evidence to vindicate a definitive correlation, nonetheless enhancements in verbal memory could be reaped with “semantic and affective elaborate encoding strategies” and performance on sustained attention increased with “practice based attention drills.” After much deliberation and examination another meta-analysis incorporating finds from seventeen studies (Twamley et al., 2003) made a case in support of its efficacy, declaring that, “the different types of approaches, whether computer assisted or not, all  have affective components that hold promise for improving cognitive performance, symptoms and everyday functioning (p. 359).”  

Interestingly, the paucity of explicit differentiation between cognitive training and computer mediated cognitive training in contemporary research can probably be attributed to the fact that most cognitive therapy programs targeting cognitive flexibility and the improvement of executive functions in individuals with schizophrenia incorporate a computerized component anyway (Shinaver & Entwistle, 2015). The aforementioned meta-analysis by Barlati et al. (2013) mentions that eight of the studies they examined used computer-assisted programs while five went without. On the other hand another meta-analytical investigation (Grynszpan et al, 2011) singling out computer-assisted cognitive remediation (CACR) identified effect sizes for improvements in general and social cognitive to be .38 and .64, respectively. Smaller effect sizes were noted for enhancements in specific domains like working memory, verbal memory, the attentional mechanism and vigilance, and processing speed which wrought a conclusion much more measured and circumspect: “The results lend support to the efficacy of CACR with particular emphasis on social cognition: the difficulty in targeting specific domains suggests a ‘non-specific’ effect of CACR (p. 163).”

As of late an impressive systematic review of fifteen reports involving 19 randomized controlled trials published between 2002 and 2015 (Isaac & Januel, 2016) investigated neurophenomenological enhancements in the cognitive and functional abilities of individuals diagnosed with schizospectrum disorder or schizophrenia proper following evidence-based behavioral treatments like cognitive remediation or training. The studies encompassed a staggering 455 adult patients with 271 receiving anywhere between 10 to over 100 sessions of cognitive remediation, itself designed to improve the neurocognitive deficits in attention span, planning, working memory capacity, and cognitive flexibility most prevalent in acute and chronic schizophrenia patients. After rigorous examination of these hybrid studies, all of which deployed an assortment of social and non-social training programs involving desk-work for the entrainment of affect recognition and/or computerized exercises for the entrainment of auditory, visual, and social cognition within individual or group contexts, the authors concluded that cognitive remediation therapy or training improves observed neurocognitive impairments in individuals with schizophrenia or a schizospectrum disorder.

Treatment-induced alterations to the neural activation patterns underlying these functional enhancements were explored through Magnetic Resonance Imaging (MRI), Magnetoencephalography (MEG), or Electroencephalography (EEG). The neuroimaging trials observed increased activation in the dorsolateral prefrontal cortices, the attention and working memory networks, along with the frontopolar cortex, the anterior cingulate gyrus, and the parietal and occipital cortices after the cognitive remediation training (Isaac & Januel, 2016), intimating enforcement of a top-down neuroplastic effect on the brain through functional reorganization.  Neuroimaging techniques have consistently shown that when patients with schizophrenia are confronted with working memory task demands under controlled conditions they demonstrate a dearth in prefrontal activation (known as hypofrontality) not seen when the exact same tasks are presented to healthy controls (Haut, Lim, & MacDonald, 2010). However in the aftermath of cognitive remediation training these same patients exhibit a burgeoning of functional activity in these hitherto unresponsive brain regions coupled with adaptive behavioral and social adjustments characteristic of the non-clinical population. One functional magnetic resonance imaging (fMRI) study designed to detect functional alterations in neural activation patterns (Haut, Lim, & MacDonald, 2010) explicated these improvements in task performance to be predicated on increased frequency and intensity of activation in a subset of the said cortical regions. Taken together, the observations pose a robust argument supporting the contention that neural mechanisms underlying social cognition may be altered through cumulative efforts in cognitive remediation therapy.

The systematic review offers convincing evidence for the neurobiological effects of cognitive remediation training in individuals diagnosed with schizophrenia or a schizospectrum disorder, however several methodological limitations in the experimental design of each study should draw one’s dutiful attention to the caveat that any interpretation must be preliminary, tentative, and made with utmost caution. The authors described, among other things, the problems posed because some of the studies utilized smaller sample sizes, partial randomization, partial or absent binding, data substitution, and financial compensation; impartially selected reports of correlation between neurobiological and behavioral data for inclusion; and allowed for discrepancies in control groups and financial conflict of interest. Moreover, even though contemporary meta-analytic studies have revealed no difference in the performance of neuroleptic-naïve and medicated patients on cognitive tasks and games (Fatouros-Bergman et al., 2014), including patients who were receiving neuroleptic drugs in addition to cognitive remediation training in the randomized trials may have influenced the results. Of course, clarification and ratification of these may be garnered through further testing with more representational samples across diverse treatment settings.

Several pioneering studies on learning-induced cortical plasticity in a cohort of patients with schizophrenia are worth mentioning. Employing a randomized controlled trial design with subjects matched on multiple variables like age and education, Genevsky et al. (2010), for instance, showed how fifty hours (one hour per day spread over five days per week) of targeted computerized cognitive training that placed increased but not overwhelming demands on the limited auditory and verbal processing powers of these adult patients enhanced their working memory capacity, verbal learning memory, and global cognition. Consistent with Sensky et al. (2000), the six-month post-treatment follow-up also revealed cognitive gains to be durable and improvements to quality of life for those who’d received the computerized cognitive training.

Another pilot study with a quasi-experimental design (Sacks et al., 2013) sought to isolate the intervention constituents driving long-term functional gains in neurocognition and social cognition. In this instance nineteen stable patients underwent fifty hours of computerized training involving set tasks in auditory perception and verbal learning that gradually increased in difficulty level and an additional twelve hours for computerized tasks in social perception, theory of mind, and the identification of emotional states (a total of sixty-two hours of training). Post-intervention measures showed significant improvements across neurocognitive and social cognitive domains, with significant functional gains made in the areas of self-referential source memory, social perception, and emotional identification. These occurred in concert with a reduction of negative symptoms like affective flattening, avolition, anhedonia, and alogia. The dangers of overgeneralizing results becomes all too salient in light of the study’s methodological limitations which span sample size (small), demographic specificity (all participants were highly educated) and the absence of a control group (introducing the confound of potential practice effects). Yet the authors convey much hopefulness and optimism in laying bare the implications of successful replication, pronouncing that a longitudinal multimodal treatment armamentarium steered by cognitive remediation therapy could connote more scalable, efficacious, and cost-efficient options for chronic sufferers of schizophrenia and their families.

In the final analysis the actual medium couching cognitive remediation appears to be inconsequential and irrelevant in determining cognitive outcomes and the two principal types, computerized and non-computer assisted, could be statistically indistinguishable from one another. This is exactly what Wykes et al. (2011) reported, claiming that improvements in global cognition and functioning witnessed in individuals with schizophrenia who underwent cognitive training was not at all impacted by factors like computer use, duration of treatment, and remediation approach. In retrospect, the meta-analytical studies, reviews, randomized controlled trials, and quasi-experimental designs delineated above support the overarching contention that computerized cognitive training is efficacious in enhancing targeted areas.


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