Article IV
Schizophrenia & Phenotypic Plasticity:
Schizophrenia may represent a predictive, adaptive response to severe environmental adversity
that allows both bioenergetic thrift and a defensive behavioral strategy.
Medical Hypotheses, Volume 69, Issue 2, 2007, Pages 383-394
Jared E. Reser
Abstract
It is well recognized that investigation into the relationship between early life programming and
subsequent neurological disorders may have powerful implications for understanding the human
vulnerability to psychopathology. The present article will propose that 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 normal gene expression resulting in an alternative
phenotype that is 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 itself 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. In fact, 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 will be analyzed and interpreted
as protective in the context of environmental hardship. For instance, the hypometabolic areas of
the schizophrenic brain- the hippocampus and the frontal lobes- are the same areas that are
known to become adaptively hypometabolic in response to starvation, stress and variations in
ecological rigor in birds and mammals. Individuals with schizophrenia are also highly genetically
inclined to develop the metabolic syndrome, which is 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.
Keywords
Evolutionary Psychiatry, Habituation Deficit, Inhibition Deficit, Hippocampus, Phenotypic
Plasticity, Thrifty Phenotype, Metabolic Syndrome, Evolutionary Neuropathology, Latent Inhibition
1. Introduction
The fact that schizophrenia occurs in all cultures at similar frequencies [1] has influenced
researchers to conclude that it had been an established nosological 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 provides a minimum estimate of origin of at least 60,000 years [5] although some
theorists have speculated that the disorder is probably much more ancient [6]. This article will
consider the significance of findings of schizophrenic symptomatology in other mammalian
species. 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 that predate the aforementioned minimum estimate by tens of millions of years.
Several articles have attempted to explain the high prevalence of schizophrenia observed 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 common 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 contended 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] or shamanism [13].
This article makes the case that schizophrenia is a predictive, adaptive phenotype that is
programmed by environmental events signifying that ecological adversity is impending or highly
probable. 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
normally remain unexpressed, resulting in a phenotype that is better suited for a stressful or
deprived environment [14]. The phenotypic characteristics of a large number organisms ranging
from plants to insects to mammals to humans have been shown to make plastic responses to
environmental events, many of which are thought to represent defensive or reproductive
strategies [15]. For example, phenotypic plasticity is responsible for the canalization of caste
(drones, queens, workers) determination in eusocial insects and for the two male morphs that
occur in many beetle (Onthophagus) populations. The less prevalent beetle morph is far
smaller, weaker, hornless, utilizes “sneaky” reproductive tactics, and 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
normal type- but only, of course, in the context of nutritional scarcity.
Schizophrenia may also represent an alternate, adaptive phenotype that (like most
programmable phenotypes) is more readily induced in individuals that have a genetic
susceptibility (diathesis) for the predisposing risk factors. Consistent with this hypothesis,
genetic epidemiological investigations, including family, adoption and twin studies have
confirmed that both 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 diathesis for schizophrenia to be
susceptible to specific environmental risk factors.
The major environmental risk factors for schizophrenia (each of which are interpreted here as
cues for alternative gene expression) include maternal malnutrition [18], maternal stress [19, 20],
multiparity [21], short birth interval [22] and anxiety provoking postnatal events [23, 24]. In the
sections that follow we will look at the symptoms of schizophrenia and consider how they might
have proven adaptive in the context of these adverse circumstances.
2. The adaptive functions of hippocampal and frontal lobe hypometabolism
Neural tissue is highly metabolically expensive. For instance, the mass specific metabolic rate
of brain tissue 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, whereas 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 gray 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 to diminish the large metabolic costs of neural
tissue. Brain areas essential for vital functions, waking activity, emotion and sensory and motor
activity do not show substantial neuron loss, however, the 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 physically and mentally demanding than the sophisticated tool-driven hunting and
complex food extraction/preparation techniques that are 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 decreased 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 and 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 bilaterally
[44, 45, 46] and schizophrenics are found to 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 a 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). Cortisol is known to reduce hippocampal neuron number, and 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 dysregualtion, reduced hippocampal volume and impairment in
hippocamupus-dependent memory are also major components of schizophrenia [53].
Furthermore, like the stress cascade, onset of schizophrenia is also 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.
3. The adaptive functions of the stress response during periods of adversity
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
neuroanatomical and behavioral symptoms, that closely approximate schizophrenic symptoms,
can be programmed in mice [55, 56] and in monkeys [57] simply by stressing their mothers
during the gestational period. 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]. The fact that these findings are
very consistent and replicable in different species, suggests that a heightened stress response
and impulsive behavior may well benefit animals that find themselves facing adverse ecological
conditions.
The adrenal or stress response is an essential, adaptive mechanism that allows energy stores
to be catabolized quickly, enabling animals to react to environmental threat 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 be highly likely to 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 large role in the etiopathogenesis of schizophrenia in humans [53, 19,
20], and schizophrenics are well known to feature an exaggerated stress response [60, 61] and
an up-regulated HPA axis [62]. In fact, schizophrenic patients are known to be highly anxious
and anxiety disorders very frequently present comorbidly with schizophrenia [63]. Both 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.
4. The adaptive functions of habituation deficits during periods of adversity
Aside from hippocampal and prefrontal hypometabolism and the exaggerated stress response,
other neurobehavioral sequelae 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, non-associative learning mechanism that allows an animal to
ignore (or “gate out”) extraneous stimuli, presumably so that it can concentrate on the stimuli that
it deems to be 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 to be 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 that most people are able to 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. 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 discern an
important signal from background “noise.” In other words, this deficit in habituation, despite the
fact that it fragments attentive concentration, may keep schizophrenics from inhibiting instinctual
responses to salient sensory stimuli- requiring that they react to the important 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 may 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 despite the fact that they know the noise is coming and that it poses
no threat [67]. Prepulse inhibition deficits are thought to be one of the best neurobehavioral
markers of schizophrenia and may have been responsible for orienting schizophrenics to
potential threats quickly and reliably. For example, someone in a severe schizophrenic episode
may have difficulty following a complex conversation, but 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. 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 the limbic system and other lower brain systems are emphasized
resulting in less methodical but pertinent and primal behavior.
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
epiphenomenal, costly side affects of adaptive habituation deficits. The habituation deficient
rodents mentioned earlier become oriented to salient stimuli reliably but also behave repetitively
and inefficiently in certain contexts. Their smaller behavioral repertoire (marked by stereotypy)
leads to behaviors, such as “increased head turning perseveration,” that are rigid and inflexible.
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 a very inflexible manner based on very 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. Often, in a
hallucination the most salient aspects of a stimulus are exaggerated, possibly orienting the
animal to the most important part. This process of forcing a small number of well-known
schemas onto incoming stimuli (either internally or externally generated) might account well for
both hallucinations and other forms of psychotic and distorted thinking.
In sum, despite the accompanying distortions in thought, it may have benefited individuals with
schizophrenia in the EEA to limit their behavioral responses to external sensory stimuli to a
smaller (more easily manageable) number of essential responses. 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 many fewer false alarms on a prehistoric savanna where their inability to
inhibit involuntary interpretations may have produced reliable, survival behavior.
5. The adaptive functions of impulsiveness and instinct driven behavior
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 neurohistological findings in schizophrenia is low number of inhibitory interneurons
[71, 72, 73]- brain cells responsible for regulating the excitability of other neurons. 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, during periods of adversity, to 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 towards addiction may
represent a foraging strategy that emphasized hedonism and the disinhibition of gratification. It
is clear that, in order 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 important 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 several years 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
when compared with humans, but if they are placed in the wild from a young age even the least
encephalized animals can rank among the most self-sufficient.
6. The adaptive functions of amygdala up-regulation
The ancient, “paleo-mammalian” amygdala is a limbic structure that is 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, normally receives input from the amygdala,
hippocampus and prefrontal cortex. In schizophrenia, input to the nucleus accumbens from the
hippocampus and the prefrontal cortex is attenuated, but input from the amygdala is up-
regulated [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. Any human can
volitionally call up memories, activate certain thoughts, and perform mental operations in its
mind, at will, without needing to know where these areas are located in its brain. In fact, all
mammals seem to be endowed with voluntary access to higher order cognitive abilities, but
increased “volitional” 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, naturally selected 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).
7. The adaptive functions of bioenergetically thrifty physiological traits
Malnourished mothers of many different species are known to give birth to babies that feature a
number of predictive, adaptive physiological alterations that present 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, who are 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]. Each of these disorders has been strongly tied to drug
naïve schizophrenia as the table below demonstrates. 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 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.
8. The prenatal risk factors for schizophrenia are tied to 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
environments. Just like the metabolic syndrome, associations between schizophrenia and low
maternal body mass index, low birth weight [21] and thinness during childhood have been shown
to be highly significant [18]. There is also a strong correlation between schizophrenia and
prenatal exposure to famine [93, 94]. It is highly probable that offspring born to a mother that is
malnourished will 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 is known to be highly correlated with schizophrenia [22] as is multiple birth
[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 memetic instructions
necessary to teach her offspring to implement complex foraging techniques. Thus, under
circumstances of 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 has been found to be
the most important factor that differentiates between genetic 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 large 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 levels of maternal stress in humans are associated with
impoverished childcare [97, 98, 99]. Furthermore, the diathesis for schizophrenia that is
created by prenatal, maternal stress might prepare the offspring for the stressful environment
that 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]
9. The role of stressful life events in onset and relapse
This article is positing that an adaptive propensity for schizophrenia can be created by an
interaction between genetic diathesis and prenatal adversity allowing the phenotype to adopt a
less cognitively rigorous ecological niche and a defensive behavioral strategy, later in life, if it
encounters stressful life events. Postnatal events are well known to play a role in the
pathogenesis of schizophrenia. For example, identical twins show average concordance rates
of 50% whereas rates near 100% would be expected if the postnatal environmental 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 schizophrenic 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 in order 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 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
attentive 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 that they have great difficulty completing tasks that require
concentration for accuracy [104]. This conceptualization frames schizophrenia as a cognitive
strategy that is suited for an environment that discourages (or fails to reward) deliberative
concentration, tool and craft making, long-term planning and delayed gratification. The adoption
of this cognitive strategy may seem inhuman but it certainly should not seem tenuous. A strategy
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 extant species of
primate to deviate from it appreciably.
10. Epigenetic Programming and 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 DNA methylation during the prenatal period- referred to as
epigenetic modifications. Specific environmental events can trigger endogenous chemical
responses that in turn are received by specific cells, causing genes that would normally be
methylated and thereby barred from transcription and translation, to be expressed, resulting in
abnormal phenotypic traits. “Phenotypic plasticity” by means of 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 that have been
interpreted to be consistent with an epigenetic model, but not gene halpoinsufficiency of
Mendelian origin [108]. Other nonmendelian irregularities seen in schizophrenia that are
consistent with epigenetic causality 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, in order 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 has been shown to be responsible for a large proportion of adaptive
allometric, morphologic and physiologic variation within species. 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 phenotypes. In fact, the
present author has hypothesized that a large number of “neuropathological disorders” may have
their origins in predictive, adaptive responses to various environmental cues [110, 111].
Because the assertions in this article 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. It is certain that far more interdisciplinary research is 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 in order to more
precisely define the risk factors that are responsible for the programming of schizophrenia.
Furthermore, by using the phenotypic plasticity paradigm and putting more emphasis on 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.
12. Discussion
The present article has suggested that in an environment characterized by nutritional deprivation
and severe stress, the adaptive value of analytical intelligence 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, thought by some to be exclusively human traits, 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. Especially in the modern, industrial/professional sphere,
schizophrenics have a very hard time fitting in and 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 modern 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.
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