Chapter 5: Schizophrenia May Represent a Disinhibited and Defensive Response to Adversity

Schizophrenia Defined:

Schizophrenia is a mental disorder in which people interpret reality abnormally. Schizophrenia may result in some combination of hallucinations, delusions, and extremely disordered thinking and behavior that impairs daily functioning, and can be disabling. People with schizophrenia often require lifelong treatment.   Psychosis: Schizophrenia involves psychosis, a type of mental illness in which a person can’t tell what’s real from what’s imagined.   Hallucinations: Schizophrenia usually involves seeing or hearing things that don’t exist. Yet for the person with schizophrenia, they have the full force and impact of a normal experience.   Delusions: Schizophrenia usually involves false beliefs that are not based in reality.   Disorganized thinking: Schizophrenia usually involves disorganized thinking that is inferred from disorganized speech.   Negative symptoms: Schizophrenia usually involves reduced or lack of ability to function normally.

The Existence of Schizophrenia Poses a Paradox

Schizophrenia is a mental disorder characterized by disorganized thinking, paranoia, delusions, and hallucinations (typically hearing voices). Usually, when someone has gone crazy, is affected by madness, or has become psychotic, the underlying cause is schizophrenia. Patients with schizophrenia often exhibit incoherent speech and behavior and act in inappropriate ways for a given situation. Schizophrenia often results in difficulties holding a job or carrying out daily activities and can have serious adverse outcomes. It is strongly linked to severe trauma, and treatment includes antipsychotic medication, psychotherapy, and social support. The disorder was described by Hippocrates in the 4th century BCE. Perhaps the first description dates to 1500 BCE in the Egyptian Ebers Papyrus. When you see movies or television shows that feature people that are insane or being held in asylum a very large portion of those people have schizophrenia and it is more or less synonymous with insanity. A large percentage of homeless people have schizophrenia.

The fact that schizophrenia occurs in all cultures at similar frequencies [1] has influenced researchers to conclude that it was an established entity before the formation of the first genetically isolated ethnic groups [2]. In fact, schizophrenia has been observed in indigenous Australians [3,4], a group that became genetically isolated more than 60,000 years ago. This strongly suggests that it existed well before humans left Africa over 100,000 years ago [5, 6]. The presence of schizophrenia-like symptoms in other species indicates that it is much older than this. Just like in humans, the symptoms manifest in primates and rodents in response to stress suggesting that schizophrenia may have its origins in plastic responses to environmental adversity going back tens of millions of years.

Several articles have attempted to explain the high prevalence of schizophrenia in human populations in terms of adaptive properties that it may have conferred to schizophrenic individuals in the ancestral environment (balanced polymorphism). Other theories have purported that schizophrenia itself is not adaptive but that the genes responsible for the susceptibility to it may provide as-yet-undiscovered benefits to non-schizophrenic humans (genetic pleiotropy). The formulation of these hypotheses has been encouraged by the fact that the lifetime morbid risk of developing schizophrenia is near 1.0 percent [7], making it a highly prevalent “disorder” from an evolutionary perspective [8].

Disorders like schizophrenia that are so prevalent that they exceed expected mutation rates are thought to have persisted because the genes responsible for them conferred some advantage in the ancestral environment [9]. In attempts to explain this “paradox,” researchers have put forth various evolutionary hypotheses, including that schizophrenia may represent an extreme variant of normal social behavior [10], a tendency that promoted creativity and territorial instincts [11], or a psychological mind-state that allowed for charismatic leadership [12] and even shamanism [13].   

This chapter makes the case that schizophrenia is a predictive, adaptive response to predicted ecological adversity. It is a response to severe stress that is characterized by disinhibition, hypervigilance, and high emotional reactivity (Reser, 2007). This hypothesis will be analyzed using the “phenotypic plasticity” paradigm, according to which adverse prenatal events can cause an organism to express genes that would typically remain unexpressed, resulting in a phenotype better suited for a stressful or deprived environment [14]. The phenotypic characteristics of many organisms, from plants to insects to mammals to humans, have been shown to make plastic responses to environmental events, which are thought to represent defensive or reproductive strategies [15]. For example, phenotypic plasticity is responsible for the determination of caste membership (drones, queens, workers, etc.) in eusocial insects like ants and bees. As such, it determines their brain type as each has a brain specialized to do a different job.

Phenotypic plasticity is also responsible for the two male morphs that occur in many beetle (Onthophagus) populations. The less prevalent beetle morph is far smaller, weaker, hornless, and utilizes “sneaky” reproductive tactics. The risk factor for this morph is low nutrient availability during early development [16]. This alternate phenotype was initially thought to be maladaptive until it was observed in its natural habitat outcompeting the standard type- but only, of course, in the context of nutritional scarcity.

Genetic investigations, including family, adoption, and twin studies have confirmed that genetic and environmental determinants contribute to the development of schizophrenia [17]. Unfortunately, the genes responsible for the plasticity have persisted into modern times, causing many individuals with the genetic susceptibility for schizophrenia to be vulnerable to specific environmental risk factors.

The major environmental risk factors for schizophrenia include maternal malnutrition [18], maternal stress [19, 20], twinning [21], short duration between births [22], and anxiety-provoking postnatal events [23, 24]. Here these risk factors are interpreted as cues for alternative gene expression. In the following sections, we will look at the symptoms of schizophrenia and consider how they might have proven adaptive in the context of these adverse circumstances.

The Adaptive Properties of Hippocampal and PFC Hypometabolism

Neural tissue is highly metabolically expensive. For instance, brain tissue’s metabolic rate is over 22 times that of skeletal muscle [25]. In fact, humans utilize between 20 and 25% of their resting metabolic rate in their brains alone. In contrast, most primates utilize between 8 and 9% [26]. An ability to attenuate the energy spent in the brain in response to environmental adversity could conceivably allow an organism to survive periods of prolonged scarcity. This aptitude may be present in schizophrenia.

Schizophrenia is accompanied by loss of brain volume [27, 28], loss of grey matter [29], reduced prefrontal cortex metabolism [30, 31], impairment in frontal lobe function [32, 33, 34] and lower densities of neurons in several brain regions, including the prefrontal cortex [35]. These reports are consistent with the idea that a capacity to develop schizophrenia may have been a preferentially selected trait that helped diminish neural tissue’s high metabolic costs. Brain areas essential for vital functions, waking activity, emotion, and sensory and motor activity do not show substantial neuron loss. However, the evolutionarily (phylogenetically) newer areas thought to allow humans the patience and analytical ability to engage in cognitively rigorous foraging activities, including the hippocampus and the frontal lobes, are adversely affected. This selective loss may suggest that individuals with schizophrenia in the ancestral environment may have occupied a less cognitively rigorous ecological niche which may have been similar to the ones occupied by ancestral hominids. For example, they may have utilized foraging strategies that were less mentally demanding than the sophisticated tool-driven hunting and complex food extraction/preparation techniques implemented by contemporary hunter-gatherers.

Many animal studies have emphasized the importance of the hippocampus in skill-intensive foraging. In fact, studies of birds and mammals have shown that the hippocampus can respond plastically to environmental cues, adaptively varying both metabolic rate and volume with ecological rigor [36, 37, 38, 39]. Several species have been shown to decrease energy expenditure in the hippocampus in response to environmental deprivation [40], malnutrition [41, 42], and reduced need to forage [43] and these findings have been interpreted widely as examples of adaptive, phenotypic plasticity [37]. Hippocampal hypometabolism often results in an alternate, less rigorous ecological strategy. It is often accompanied by other physiological modes of energy conservation. This compensatory mechanism may be present in schizophrenia.

Multiple neuropathological abnormalities have been localized to the hippocampus in schizophrenia. For instance, hippocampal size in vivo is reduced [44, 45, 46], and schizophrenics show significantly lower metabolic rates of glucose in the hippocampus [47]. In fact, of all the brain regions studied, the hippocampus has been the one that most reliably distinguishes schizophrenics from healthy controls [48] and has been hypothesized to be central to the pathophysiology [49]. This conspicuous abnormality in the hippocampus may be analogous to the hippocampal deficits seen in ecologically deprived animals.   Because family members of schizophrenics are more likely to have volume reductions of the hippocampus than are randomly selected controls, [50] reduced investment in hippocampal neurons appears to be an inherited (polymorphic) cognitive strategy, and schizophrenia, an extreme form of this strategy.

Hippocampal size is also known to show plasticity in rodents, monkeys, and humans in response to environmental stress [29]. When an animal encounters stress-provoking situations related to predation, conspecific threat or nutritional scarcity, its adrenal glands secrete cortisol (a glucocorticoid). Chronically elevated cortisol is known to reduce hippocampal neuron number. If the levels are sufficient, the “stress cascade” effect can be initiated, resulting in significant deficits in hippocampus-dependent learning and memory [51,52]. The three major components of the stress cascade, cortisol dysregulation, reduced hippocampal volume and impairment in hippocampus-dependent memory, are also major components of schizophrenia [53]. Furthermore, like the stress cascade, the onset of schizophrenia is well known to be precipitated by stressful life events [54, 24]. For reasons that will be explored, both schizophrenia and the stress cascade may be predictive, adaptive responses to poor environmental conditions which allow bioenergetic conservation and a more impulsive, less analytical behavioral phenotype.

The Adaptive Properties of The Stress Response

A popular animal model for schizophrenia does not have to utilize pharmacological or genetic intervention to create schizophrenic behavior in lab animals. In fact, it shows that both brain and behavioral symptoms can be programmed in mice [55, 56] and monkeys [57] simply by stressing their mothers during pregnancy.

These symptoms, including impulsive behavior and attention and learning deficits, are attributed to decreased neurogenesis in the hippocampus and cerebral cortex [57, 58]. Prenatal maternal stress is also known to initiate up-regulation of the hypothalamic-pituitary-adrenal (HPA) axis in rodents and primates, causing the stress response to become more pronounced and more easily triggered [59]. If it generalizes to rodents and primates, it probably generalizes to most mammals. These findings are consistent and replicable in different species, suggesting that heightened stress response and impulsive behavior may benefit animals that face adversity.

The adrenal or stress response is an essential adaptive mechanism that allows energy stores to be catabolized quickly, enabling animals to react to environmental threats with speed and strength. Because the environment that rodent offspring encounter is often very similar to that of their parents, a stressed mother’s offspring will likely encounter environmental adversity themselves. According to Zhang et al. (2004) [59], the up-regulated stress response seen in rodents born from stressed mothers may be a predictive, adaptive response that allows the animals to attain an ecological advantage by being better prepared to react to stress-provoking stimuli [59]. 

Schizophrenia may be an embodiment of this response in our species. Prenatal maternal stress is thought to play a prominent role in the development (etiopathogenesis) of schizophrenia in humans [53, 19, 20]. Also, individuals with schizophrenia are well known to feature an exaggerated stress response [60, 61] and an up-regulated HPA axis [62]. In fact, schizophrenic patients are highly anxious, and anxiety disorders frequently present comorbidly with schizophrenia [63]. An exaggerated stress response in animals and excessive anxiety in humans have been attributed adaptive value in ethological and evolutionary literature [64]. Stress and anxiety increase attentiveness to the environment and cause animals to make more concerted efforts to avoid potential threats [9]. This may have given a profound behavioral advantage to individuals with schizophrenia in the ancestral environment during times of hardship.

The Adaptive Properties of Habituation Deficits

Aside from hippocampal and prefrontal hypometabolism and the exaggerated stress response, other neurobehavioral issues that present in schizophrenia patients are so pronounced that any evolutionary account should offer a convincing explanation for these as well. This section will focus on the adaptive properties of the neurobehavioral anomalies, which present as sensory gating deficiencies, specifically, prepulse inhibition and habituation deficits. 

Habituation is an automatic, mental filter that allows an animal to ignore (or “gate out”) extraneous stimuli, presumably so that it can concentrate on the stimuli it deems informative. Individuals with schizophrenia show large deficits in the ability to habituate to sensory stimulation [65]. The habituation deficits cause them to be hypersensitive to environmental stimuli and unable to regulate reflexive, automatic responses using normal inhibitory mechanisms [29]. This vulnerability to external stimulation has caused researchers to describe schizophrenics as “hypervigilant” and inclined to respond to extraneous environmental stimuli most people can ignore [66]. This may have served as an apt survival strategy because in a stressful world with uncontrollable variables, an individual is less likely to be able to accurately determine, on their own, which elements of their sensory experience to attend to.    

Signal detection theory, a means to quantify the ability to distinguish between signal and noise, may be relevant here. The natural tendency in schizophrenia to attend to the most salient sensory stimuli in the environment may decrease the probability of a “miss,” a failure to detect a vital signal amid background “noise.”  In other words, even though this deficit in habituation fragments concentration, it may keep people with schizophrenia from inhibiting instinctual responses to salient sensory stimuli. This would require that they react to the most critical aspects of their environment. Conversely, it seems that a very high degree of habituation might cause an individual to gate out too much environmental information causing it to become oblivious to important sensory stimuli. Perhaps the adaptive value of habituation used by an organism may vary with specific environmental variables and involve a trade-off. Just as we saw with hippocampal diminishment, first-degree relatives of schizophrenics who do not have schizophrenia show habituation deficits [29]; once again suggesting that schizophrenia may be on the far side of a natural cognitive continuum.

Studies of prepulse inhibition (a measure used to quantify habituation deficits) show that individuals with schizophrenia, unlike normals, cannot inhibit their autonomic startle responses to a loud auditory stimulus. This is true even though they know the noise is coming and it poses no threat [67]. Prepulse inhibition deficits are considered one of the best neurobehavioral markers of schizophrenia. They may have been responsible for orienting schizophrenics to potential threats quickly and reliably. For example, someone experiencing a severe schizophrenic episode may have difficulty following a complex conversation. Still, they will be keenly alerted to any threatening intonations of the speaker’s voice, just as they would be to a startling rustle in the bushes. 

Interestingly, habituation and prepulse inhibition deficits can be induced in rodents through prenatal [68] or postnatal stress [69] and certainly may represent an adaptive response to adversity in rodents as well. After hours in the library, when I found that early life stress created the same habituation deficits in rodents, that is when I felt certain that schizophrenia must be a conserved, adaptive response to hardship. It cannot be a coincidence, the mammalian brain is liable to being retuned to deal with catastrophe and calamity.

The behavior of prepulse inhibition deficient rodents is similar to that of reptiles in that it is marked by “stereotypy,” a smaller behavioral repertoire that features only the essential responses. Similarly, schizophrenia may represent a phylogenetic step toward the past where lower brain systems are emphasized, resulting in less methodical but pertinent and primal behavior.

Hallucinations and Delusions may Be Maladaptive Side Effects

Two neurocognitive hallmarks of schizophrenia, hallucinations and delusions, are not- at first glance- well accounted for by the present hypothesis. The question arises: “how could hallucinations and delusions have been adaptive in an ancestral environment?”  They were probably not adaptive but may represent a trade-off. This author believes that they are costly side effects of adaptive habituation deficits. The habituation deficient rodents mentioned earlier become oriented to salient stimuli reliably but behave repetitively and inefficiently in specific contexts. Their smaller behavioral repertoire leads to behaviors, such as “increased head turning perseveration,” that are rigid and inflexible. Head turning perseveration is when an animal has an irrational preference to turn to one side (either right or left) even when turning to the other side would be quicker. I think this is comparable to the rigid, often unreasonable, behavior seen in human patients in psychotic states.

Interestingly, a well-supported model for understanding hallucinations frames the hallucinatory experience as a failure to inhibit irrelevant memories [70]. Much like the rodents, the distorted perceptions and thinking seen in schizophrenia might be due to a tendency to interpret sensory stimuli in an unadaptable manner based on quick interpretations that refer back to a limited number of recalled concepts. In other words, instead of being versatile and perceptive enough to see a complex situation as it is, an individual experiencing a hallucination may be shoehorning their experience into familiar, although often inaccurate, caricatures. In a hallucination, the most salient aspects of a stimulus are often exaggerated, possibly orienting the animal to the most crucial part. This process of forcing a small number of well-known schemas onto incoming stimuli (either internally or externally generated) might account well for hallucinations and other forms of psychotic and distorted thinking. 

In sum, despite the accompanying distortions in thought, it may have benefited individuals with schizophrenia during prehistory to limit their behavioral responses to external sensory stimuli to a smaller (more easily manageable) number of essential reactions. Only a minority of schizophrenia patients experience recurring visual hallucinations, and the hallucinations themselves may well have been less disruptive in an ancestral environment. An individual with schizophrenia living in a modern setting might easily feel inundated with alarming sensory stimulation: in a shopping center, on a busy street or in front of a television. However, they would likely have experienced fewer false alarms on a prehistoric savanna where their inability to inhibit involuntary interpretations may have produced reliable, survival behavior.

The Adaptive Properties of Instinct and Impulsiveness

The neurobehavioral symptoms described may stem from several neurological abnormalities, yet some seem especially telling. For instance, studies have shown that one of the most conspicuous brain tissue (neurohistological) findings in schizophrenia is a low number of inhibitory brain cells (interneurons) [71, 72, 73]. Inhibitory neurons are responsible for regulating the excitability of other neurons and generally stop an animal from fulfilling its instinctual response. Such a deficiency of interneurons may be an adaptive alteration that allowed schizophrenics to be, simply enough, less inhibited. A tendency for impaired central nervous system inhibition might have helped schizophrenics react without the normal inhibitory pressures on their reflexes and natural instincts. This paucity of inhibitory pressure may explain why schizophrenia has been linked to accelerated reflex conditioning and facilitated simple learning [74], traits that may have contributed to survival in a wild environment. 

Behavioral disinhibition may also have permitted schizophrenics to react without deliberately reflecting on their decisions, helping them to escape harm and attain resources quickly and without hesitation. Interestingly, schizophrenia is strongly associated with addictive behavior [75] and is often comorbid with substance abuse [63]. This tendency toward addiction may represent a foraging strategy emphasizing hedonism and the disinhibition of gratification. It is clear that to survive, all animals must gratify internal drives. Those that can do so without having to first break inhibitory barriers- quick-acting opportunists- should fare better when the environment has proven adverse and erratic. The characteristically human predisposition for gating out both external stimuli and internal drives (which allows concentration and heightened mental systematization during predictable times) may have led to inattentive, preoccupied, evolutionarily-aimless behavior during unpredictable times.

As we have seen, individuals with schizophrenia have learning and working memory deficits. The difficulties that these deficits create for them in a modern setting might cause some people to doubt that adults with schizophrenia could be self-sufficient foragers if placed in a natural environment. However, it is essential to understand that adult schizophrenics from modern society never had the opportunity to spend their early, formative years in the wild learning foraging techniques and refining their hunting and gathering abilities. Individuals that developed schizophrenia in the ancestral environment would have spent their childhoods honing their survival strategies and motor praxes in the “prodromal” (early, less clinically prominent) stages of schizophrenia. Furthermore, the vast majority of animals have learning and memory deficits compared to humans. Still, if they are placed in the wild from a young age, even the least encephalized animals can rank among the most self-sufficient.

The Adaptive Properties of Amygdala Sensitivity

The ancient, “paleo-mammalian” amygdala is a limbic structure responsible for the automatic (unconscious) identification of threatening and emotionally laden stimuli. Cell growth (hypertrophy) in the amygdala, which is thought to be responsible for increasing stress reactivity, can be programmed in rats through stress or through reducing maternal care [76]. The amygdala seems to be similarly affected in schizophrenia. The human nucleus accumbens, a projection area that commands motor output, receives input from the amygdala, hippocampus, and prefrontal cortex.

In schizophrenia, input to the nucleus accumbens from the hippocampus and the prefrontal cortex is diminished, but input from the amygdala is accentuated [77].   The priority assigned to the amygdala in schizophrenia may be responsible for the characteristic impulsivity, paranoia, thought blocking, poor impulse control, and other behavioral symptomatology [77]. This selective regulation that favors amygdala input is consistent with our conceptualization of schizophrenia as a vigilance/fear-based cognitive strategy. 

In schizophrenia, higher-order learning areas, such as the hippocampus, show diminished activity but the “lowly” amygdala shows disproportionately increased activity. These two changes taken together may represent a neuroecological strategy where “environmentally activated” areas are preferentially employed over “volitionally activated” areas. All mammals are endowed with access to higher-order cognitive abilities, but heightened accessibility to these executive functions may impair the responsiveness to environmental predicaments. This may be why the amygdala (a truly involuntary, environmentally activated area) is allowed to intrude into conscious thought in schizophrenia to ensure that the individual will find environmental stimuli arresting and impelling.  

In a seminal paper in 1974 [78], Ernst Mayr distinguished between a “closed genetic” program where a species’ behavior is instinctual and inflexible from birth (invertebrates, fish, amphibians) and an “open genetic” program where a species’ behavior is influenced predominantly by past learning (reptiles, birds, mammals). Perhaps during stressful times, it is better, in terms of reproductive success, for the organism to rely on automatic, innate, time-tested behaviors (similar to a “closed genetic” program) instead of giving the brain the liberty to willfully devise its own behavioral strategies (an “open genetic” program).

The Adaptive Properties of Bioenergetic Thrift

Malnourished mothers of many different species are known to give birth to babies with predictive, adaptive physiological alterations that emerge later in life [79].  These plastic alterations, brought about by differential gene expression, are thought to allow the individual to conserve calories, increase fat deposition and adopt a sedentary nature [80,81].  According to the “thrifty phenotype” hypothesis, humans, programmed by prenatal malnutrition to express low metabolic rates, enjoy a survival advantage under nutritional scarcity but increased risk of negative health consequences if born into an environment marked by nutritional abundance [82, 83]. The health consequences (which are highly prevalent today but are thought to have been much less prevalent in the ancestral environment) include diabetes mellitus, cardiovascular disease, obesity and up-regulated HPA activity which together comprise the metabolic syndrome [83]. As the table below demonstrates, each of these disorders has been strongly tied to drug naïve schizophrenia. Once again, a polymorphic continuum (with schizophrenia at one end) is suggested by the finding of increased frequency of the metabolic syndrome in the relatives of patients with schizophrenia [84].

Thrifty Disorders Associated with Schizophrenia:

Cardiovascular Disease [85, 86, 62]

Insulin Resistance [62, 87, 88]

HPA Axis Up-regulation [60, 61]

Low Daily Energy Expenditure [89]

Metabolic Syndrome [62, 90]

Obesity [91, 92, 62]

These data suggest that schizophrenia may be a form of thrifty phenotype that would be physiologically well prepared for nutritional scarcity.

The Prenatal Risk Factors Associated with Environmental Adversity

This section will look closely at different risk factors for schizophrenia, the environments under which these risk factors are likely to occur, and the adaptive value of schizophrenia in such settings. Just like the metabolic syndrome, associations between schizophrenia and low maternal body mass index, low birth weight [21] and thinness during childhood are highly significant [18]. There is also a strong correlation between schizophrenia and prenatal exposure to famine [93, 94]. Offspring born to a mother that is malnourished will probably encounter a habitat marked by nutritional scarcity.  The widely accepted epidemiological association with early malnutrition provides strong evidence for the prenatal programming hypothesis of schizophrenia.  

Short birth interval, where a mother has two children in short succession is highly correlated with schizophrenia [22]. The same goes for multiple birth where a mother has more than one child at a time (twins) [21]. It is a common observation in anthropological and primatological literature that a mother who must care for two infants simultaneously will have difficulty allocating adequate resources to both of them [95]. Such a mother may also be ill-prepared to provide the instructions necessary to teach her offspring to implement complex foraging techniques. Thus, under maternal deprivation, it may be adaptive to initiate programming that will influence the offspring to adopt a less cerebral foraging style and an energy conserving phenotype that can subsist off of low-yield foraging strategies. Supporting this idea is the fact that depriving rats of their mothers early in life is a reliable way to program schizophrenic symptoms, including habituation deficits, prepulse inhibition deficits and hippocampal hypometabolism [69]. Analogously, early maternal separation in humans is the most critical factor differentiating genetically high-risk children who develop schizophrenia and high-risk children who do not [96].

Many researchers have concluded that (analogous to the relationships seen in rats and monkeys) maternal stress plays a prominent role in the etiology of schizophrenia [19, 20]. It seems logical to assume that stress may be associated with insufficient maternal investment. In fact, several studies have shown that high maternal stress levels in humans are related to impoverished childcare [97, 98, 99]. Furthermore, the vulnerability (diathesis) to schizophrenia that is created by prenatal, maternal stress might prepare the offspring for the stressful environment it is likely to encounter after birth. One that is not favorable to advanced cognition but is better negotiated by less calculating, less restricted, and more defensive behavioral tendencies

Risk Factors for Schizophrenia:

Low Maternal Body Mass: [18]

Low Birth Weight: [21]

Prenatal Exposure to Famine: [93]

Short Birth Interval: [22]

Multiple Birth: [21]

Maternal Stress: [19, 20, 100]

Stressful Life Events are Often Responsible for Onset and Relapse

This chapter posits that an adaptive propensity for schizophrenia can be created by an interaction between a genetic susceptibility and prenatal adversity, allowing the phenotype to adopt a less cognitively rigorous ecological niche and a defensive behavioral strategy. However, events after birth (postnatal) are well known to play a role in the development (pathogenesis) of schizophrenia as well.

For example, identical twins show average concordance rates of 50%, whereas rates near 100% would be expected if the postnatal environment played no role [17].   Furthermore, both the first onset of schizophrenia and subsequent acute psychotic episodes (relapses) are routinely precipitated by psychosocial stressors [17] and stressful life events [23, 24]. Further drawing a link between environmental stress and the programming of “full-blown” schizophrenia is the strong positive correlation between stressful life events and the severity of symptoms [23, 101]. People diagnosed with schizophrenia are advised to avoid stressful situations, practice deep breathing exercises, sleep well, eat well, exercise regularly, and engage in other stress-mitigating activities to avoid re-hospitalization [54]. The well-established epidemiological link with life stressors strengthens the interpretation of schizophrenia as a predictive response to a stressful environment. That rodents share with us an ability to develop schizophrenic symptoms in response to postnatal life stressors [69] strengthens the interpretation of schizophrenia as an ancient, seemingly well-conserved example of phenotypic plasticity.

The human species has evolved a strategy, relative to other animals, that emphasizes the use of careful deliberation and time-honed analytical skills to control and influence the social and ecological variables in the environment [102, 103]. Severe stress in the ancestral environment probably signified that this strategy was ineffective and that the environmental variables were too unpredictable to control using deliberation and concerted analysis. Interestingly, schizophrenics report that during a relapse, they feel that they cannot exercise control over the complex variables in their life and have great difficulty completing tasks requiring concentration for accuracy [104]. This conceptualization frames schizophrenia as a cognitive strategy suited for an environment that discourages (or fails to reward) deliberative concentration, tool and craft making, long-term planning, and delayed gratification. Adopting this cognitive strategy may seem animalistic, but it should not seem tenuous. A method marked by impulse, instinct, and more fundamental cognitive processing can be very powerful and widely applicable, as evidenced by the fact that humans are the only species of primate to deviate from it appreciably.

Phenotypic Plasticity and Epigenetic Programming in Schizophrenia

It is known that many organisms can make predictive, adaptive responses to informative environmental cues resulting in the development of alternate phenotypes. This “phenotypic plasticity” is a strategy used by a wide variety of species that seems to respond to the most threatening species-specific contingencies [16].

Many of these adaptive responses are accomplished through alterations in metallic molecules that attach to the DNA. These epigenetic alterations involve two processes (methylation and acetylation). Specific environmental events can cause specific cells to express genes that would normally be methylated and thereby barred from transcription and translation. This kind of phenotypic plasticity, employing variations in DNA methylation, has been shown to be responsible for the up-regulation of the stress response seen in maternally deprived rat pups and for the thrifty cardiovascular alterations seen in malnourished fetuses- two phenotypes widely thought to represent predictive, adaptive responses [105].

Several researchers have concluded that schizophrenia is likely due to prenatal, epigenetic “defects” in DNA methylation initiated by environmental stressors [106, 107]. Studies that have analyzed schizophrenia inheritance in families have found concordance rates consistent with an epigenetic model (but not gene haploinsufficiency of Mendelian origin) [108]. Other nonmendelian irregularities seen in schizophrenia that are consistent with an epigenetic cause include the existence of clinically indistinguishable sporadic and familial cases and the observed fluctuating course of disease severity [109]. These findings are consistent with the present argument, except here, the epigenetic changes are not interpreted as defects but as the molecular mechanisms for the predictive adaptive response. Thus, to uncover the underlying molecular causes and to make progress in both developmental and gene therapy it will be important to reconcile the various risk factors with their epigenetic (chromatin architectural) correlates. 

Phenotypic plasticity is responsible for a large proportion of species’ adaptive variation (allometric, morphologic and physiologic). There is every reason to consider that specific neurological variations in our species, especially largely prevalent variants that appear to be programmed by the environment, may be adaptive. As we will see in later chapter, an assortment of “neuropathological disorders” may have their origins in predictive, adaptive responses to various environmental cues.

Because the assertions in this chapter are based on comparative physiology, an objective discussion of falsifiability is somewhat elusive. Schizophrenia is well known to be a heterogeneous entity, and the symptoms in animals that approximate schizophrenic symptoms also show heterogeneity and can even be likened to symptoms of psychiatric disorders other than schizophrenia. Far more interdisciplinary research is certainly needed to determine if there is a definite relationship between schizophrenic symptoms and adaptive phenotypic plasticity. However, that humans may have an adaptive vulnerability to specific environmental stressors should influence schizophrenia researchers to utilize knowledge from diverse disciplines such as evolutionary biology, ethology, life history, methylomics, nutrigenomics, optimal foraging theory, phenotypic plasticity, and physical anthropology to more precisely define the risk factors that are responsible for the programming of schizophrenia.

Furthermore, by using the phenotypic plasticity paradigm and emphasizing the (seemingly homologous) animal models, researchers may be able to determine the cellular and molecular mechanisms responsible for susceptibility so that steps can be taken to minimize exposure of the developing fetus and child to schizophrenia-inducing risk factors.   

Discussion

The present chapter has suggested that in an environment characterized by nutritional deprivation and severe stress, the importance of moderation, restraint, and premeditation is diminished, and the adaptive value of schizophrenic behavior is accentuated. The physiological “symptoms” of schizophrenia may have permitted bioenergetic conservation in the face of scarcity and allowed the secretion of more adrenaline during times of threat. The cognitive “symptoms” of schizophrenia may have minimized extraneous thinking, maximized exploitative foraging, facilitated attentiveness to the environment and increased efforts to avoid potential threats. The capacity to carefully analyze a situation and to prepare for the future may be ineffectual under volatile environmental circumstances, where instead, it may be more efficacious to live in the present and to adopt a myopic cognitive strategy. 

Since antiquity, people with schizophrenia have been identified as individuals that have trouble integrating into the rest of society. In the modern occupational and professional sphere, individuals with schizophrenia often struggle to fit in. Consequently, their ability to acquire status and increase their reproductive success is impaired [112].

Yet, schizophrenics in prehistoric, hunter-gatherer settings probably had less trouble integrating. In fact, it has been documented that schizophrenics in developing countries are more easily assimilated [113, 114], framing the schizophrenia “paradox” as a construction of industrial society. Moreover, schizophrenics who found themselves in a famine/severe-adversity setting should have fit in quite well, especially when one considers that under such a setting, the incidence of schizophrenia would have been vastly higher due to the ubiquity of prenatal and postnatal stressors.

Chapter Summary

• Schizophrenia may be adaptively programmed by early environmental adversity permitting physiological and behavioral characteristics that would have created a fitness advantage in the ancestral environment under conditions of nutritional scarcity and severe environmental stress. 
• This proposition will be analyzed in terms of phenotypic plasticity theory, which explains how and why specific environmental stressors can alter regular gene expression, resulting in an alternative phenotype better suited for an adverse environment. 
• That the primary neurophysiological symptoms of schizophrenia can be induced in animals through exposure to prenatal and postnatal stressors and that schizophrenia is known to be associated with exposure to stress during development supports the view that the “disorder” may represent a predictive, adaptive response to adversity.  M
• Maternal malnutrition, maternal stress, multiparity, short birth interval, and stress-provoking postnatal events are well-recognized epidemiological risk factors for schizophrenia that may represent cues for the initiation of epigenetic programming. 
• Behavioral and physiological characteristics of schizophrenia are interpreted as protective in the context of environmental hardship.  
• The hypometabolic areas of the schizophrenic brain- the hippocampus and the frontal lobes- are the same areas known to become adaptively hypometabolic in response to starvation, stress and variations in ecological rigor in birds and mammals. 
• Individuals with schizophrenia are also genetically inclined to develop metabolic syndrome, widely thought to allow developmentally deprived mammals to conserve energy under poor circumstances. 
• It is well known that schizophrenia features an up-regulated hypothalamic-pituitary-adrenal axis and an exaggerated stress response- both alterations thought to represent predictive, adaptive responses to stress in mammals- which may have increased attentiveness to the environment and created a defensive, vigilance-based behavioral strategy. 
• The habituation deficits characteristic of schizophrenia- which can be induced in other mammals through stress- may represent a cognitive strategy that alerts the organism to salient, potentially informative stimuli and that permits it to be more impulsive and vigilant.  
• Inability to calm instinctual drives, ignore arousing stimuli, and inhibit transient desires are all core characteristics of the disorder, which predict social and vocational disabilities in modern times, but may have amounted to a robust, selfish strategy in prehistoric times.

References

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