Category Archives: Psychiatry

Reactive Depression: Lost in Translation!


The old classification of depression into Reactive and Endogneous that are still observed in the clinical practice cannot all be accommodated under the current rubric of Major Depression. This is because psychiatric nosology under DSM and its latest 5th edition is still descriptive, and not etiologic. In this article both reactive and endogenous categories of depression are revisited from the perspective of today’s understanding of etiological pathways. From an epigenetic perspective, the old dichotomy of Reactive vs. Endogenous are inter-related through the impact of the environment (e.g. stress). This includes familial or prenatal depression, where the environmental impact is before birth, or childhood depression where the early life stress is the precipitating factor to the genetic susceptibility. In conclusion, searching for both environmental impact (e.g. stressors) and genetic predispositions in depression, even at a clinical level could help clinicians with better therapeutic decisions.

 The differentiation of major depression into ‘reactive (stress-induced)’ vs. ‘endogenous (e.g. genetic)’ dates back to the German psychiatrist, Kurt Schneider (Schneider, 1920) who borrowed the term ‘endogenous’ from Emil Kraepelin. The differentiation was an early attempt at an etiological classification of depression (Mendels & Cochrane C, 1968). Despite the extensive use of these terms and despite the popularity of the catecholamine deficiency hypothesis of depression (Schildkraut, 1965) and the effectiveness of tricyclic antidepressants that began with the introduction of imipramine in the 1950’s, psychiatric nosology then gave up on the attempt of classifying depressions according to etiology.

 Although the aim of DSM-III in 1980 was for psychiatry to do what the rest of medicine does, to classify disease according to cause, this proved impossible and a non-etiological, purely descriptive system was devised that relied on categories based on symptoms and their severity. DSM-III divided the depressions into major and minor (DSM-III, 1980). Almost four decades later, DSM5 continues to be descriptive and non-etiological (DSM5, 2013). This has continued despite research that points to distinguishable pathways leading to the symptoms of major depression (Ghaemi & Vohringer, 2011; Malki et al. 2014; Mizushima et al. 2013; Parker 2000).

In this article an attempt depression is reviewed on a pathophysiological basis through 1) the impact of stressful events and their timing 2) gene-environment interactions and 3) biological circuits affected by different kinds of depression. The generic term of “depression” that has been used in this paper, refers mostly to major or unipolar depression, though it can at times also applies to minor depression and dysthymia. This article also excludes the normal reaction of mood to stress below clinical level of severity and dysfunction.

The timing of the stress onset:

In reference to stress leading to depression, there is a major differentiation between an early childhood adversary or later in life (adulthood) stress. While these two types of depression, one with an early onset in childhood or adolescence, and the other one with a later onset in adulthood, could be referred to as “Reactive Depression”, they are fundamentally different. (Hazel NA., et al., 2008) This differentiation between reactive depression in the past decade has been recognized in the literature as “Juvenile” and “adult” onset with different pathophysiological pathways that perhaps demand different treatment pathways as well. (Jaffee SR, et al., 2002; Weissman MM, 2002)

Other than the age of onset differentiation of these two reactive subtypes of depression, the juvenile-onset depression is associated with increased risk for depression among the first-degree relatives of depressed probands in clinical and community samples, perhaps related to the shared stressful environment. (Weissman MM, et al., 1984; Kovacs  M., et al., 1997; Neuman  RJ., et al., 1997; Klein  DN., et al., 2001) The children of depressed parents are also at higher risk for juvenile-onset depression compared with the children of non-depressed parents, and this association is explained by early parental age onset of depression. (Wickramaratne  P., Weissman  MM., 1998; Goodman  SH Gotlib  IH., 1999; Fergusson  DM., et al., 1996)

The findings while show shared stressful environments such as poor parenting, family discord, parental psychopathology, losses and abuses, they also implicate genetic risk factors in juvenile-onset depression. There has been evidence also that juvenile onset depression before age 20 has been caused by early onset environmental stress, but not a later onset. (Kessler  RC Magee  WJ., 1993) Even it seems that the juvenile onset depression is heterogeneous as there is differentiation between pre-pubertal and post-pubertal age of onset. It has been shown that the pre-pubertal onset has been associated with higher risk of suicide attempts, alcohol dependence, and conduct disorder. (Harrington  R., et al., 1997; Wickramaratne  PJ., et al., 2000)

From an epigenetic model of gene-environmental interaction perspective, the so called endogenous/biological or familial/hereditary depression could have been also caused by an earlier, prenatal onset stress. It is well known that the early onset prenatal stress adversely affects the brain development with neuronal loss and behavioral dysfunction, not limited only to endogenous or biological depression. (Bernhardt LK., et al., 2017) There is also more recent appreciation of the significance of risk of polymorphism such as associated epigenetic risk factors of SNPs (Single Nucleotide Polymorphism) as environmental causes of depression. That is why most genetic studies have failed in concluding candidate genes for depression as there are many polymorphisms and genetic mutations as a result of prenatal or even earlier impact of stress on the genetic make-ups of parents. (Gonda X., et al., 2018)

Therefore the future classification of depression needs to go beyond the dichotomy of reactive/endogenous/melancholic/biological/familial, but by following a pathophysiologic pathway model to classify different types of depression. Starting with the gene-environmental interaction, the stress of different kinds start a cascade of pathophysiologic changes in the emotional circuit of the brain, causing different symptoms and severity of depressions, from minor to major depression and dysthymia.  

The Gene-Environmental Interaction:

There is a clear difference between the onset time of stress on the brain, so that an early onset such as prenatal stress on the developing brain has a more severe damage than to a more developed and mature of an adult brain. Since the developing brain is less resistant to the oxidative toxicity of the stress, there is more alteration of the cellular homeostasis and damages to the young brain.(Gonda X., et al., 2018) Comparison studies of animal models of early vs. late onset depressions have shown each to have unique gene-expression profiles indicating divergent underlying molecular mechanisms. For example the early stress type shares 19%, while the late stress type share 11% gene overlap with the endogenous type. In fact the early stress or “chronic reactive depression” share more gene overlap with the endogenous type than with the late stress onset or “acute reactive type”. Gene pathway analysis has shown more neurodevelopmental impact by the early stress onset reactive depression, while the late stress onset reactive type being only associated with acute cell stress response and signaling. (Malki K., et al. 2014)

Most gene candidates in the pathophysiology of depression alone could be responsible for one third of major depression in the community. (Sullivan PF, et al., 2000) The gene candidates, e.g. BDNF, CRHE1, HTR2A, MAOA, NR3C1, SLC6A4 have been shown to be more causative when interact with early life stressful events such as childhood maltreatments, adversity and poor parenting. (Brown GW., et al., 2014; Bradley RG., et al., 2008; Jokela M., et al., 2007; Caspi A., et al., 2003; Karg K., 2011) There are differences among these gene polymorphisms in susceptibility to early or late onset stress to cause early or late onset depression. For example while the serotonin transporter gene length polymorphism (5-HTTLPR) in interaction with early life stress lead to early (juvenile) onset or endogenous depression, the BDNF may contribute in interaction with late life stress to adult onset depression. (Brown GW., et al., 2014)

Other than susceptible or mutated gene polymorphism in causing depression in interaction with destructive environments, there are protective genes and environments that prevent the causation of depression. For example low but not high MAOA gene activity, caused severe depressive symptoms in the face of early life maltreatments. Also sexual abuse and the 5-HTT short/short homozygote genotype, and not heterozygote or long/long alleles predicted higher depression, anxiety, and somatic symptoms. (Cicchetti D., et al., 2007) On a different account, carriers of the T/T or T/C genotype of the T102C polymorphism of the HTR2A gene were responsive to the protective aspects of nurturing mothering, and showed lower levels of depressive symptoms, opposed to the carriers of the C/C genotype. (Jokela M., et al., 2007)

Other than neurotransmitters gene polymorphism that contribute principally to the pathophysiology of depression through gene-environmental interactions, the hypothalamic-pituitary-adrenal (HPA)-axis related genes that regulate the response to stressful events, are contributing to the pathogenesis of depression. The gene polymorphism of glucocorticoid receptor (GR) that regulates the activity of the HPA-axis, in interaction with childhood adversity is also associated with increased risk for depression. For example the gene-environment interaction between the GR polymorphisms 22/23EK and 9beta and childhood adversity results in an increased risk of depression, while without childhood adversity there could be no such increased risk. (Bet PM., et al., 2009)

 The Biological Impact:

The catecholamine deficiency hypothesis of depression, on which original and current antidepressants are largely based, was an early theory of the chemical chain of events that results from the pairing of susceptibility genes with an adverse environment. The pathophysiology of depression has now progressed to include the involvement of other neurotransmitters such as GABA and glutamate, neuromodulators, inflammatory markers, all in an interaction between the genetic predisposition and the environmental impact or adverse events.    

As far back as the early 1980s, GABA receptor agonists, e.g. progabide, had been suggested as capable of modifying the activity of several brain neurotransmitter systems, including noradrenaline and serotonin (Bartholini, 1985; Zivkovic et al., 1983) and both GABA and glutamate drugs are currently used as adjunct treatments in major depression (Krystal, 2002, Pande, 2003; Showraki, 2007). Glutamate N-methyl-d-aspartate (NMDA) receptor antagonists such as ketamine have been shown since 1990s to possess properties that can rapidly reverse depressive symptoms (Duman & Aghajanian, 2012; Trullas, 1990) Most recently, the mechanism of action of the glutamate antagonists have been hypothesized to lie in their ability to restore protein expression levels disrupted by chronic unpredictable stress (Zhang, 2018).

The roles of neuromodulators such as endorphins, enkephalins and oxytocin are also being researched. The impact of endorphins and non-opioid enkephalins such as alpha-MSH has been shown to have antidepressant effects in animal models (Kastin, 1978; Terenius, 1977). More recently, endorphins and other opioids have been more shown to alter the release of other neurotransmitters and to result in a decrease of oxytocin and an activation of GABA (Bali, 2015).          

 The placental oxytocin that had been known for long to be involved in the maternal milk secretion induced by the infant sucking, vital in ending the conception period and starting the lactation stage, has been studied in the depression field since late 1980s. This hormone or neuromodulator has been shown in the animal models of depression to improve physical mobility and reducing learned helplessness and escape failures with superior efficacy to Imipramine. (Arletti R, Bertolini A., 1987) Later on and in recent years, back to its role in lactation and sucking of the infant, Oxytocin’s significant role in attachment between the mother and infant has been demonstrated. Therefore maternal depression or childhood maltreatment and deprivation could disturb this relationship synchrony and lead to early childhood depression. (Priel A., 2019; Krause S., 2018) Most recently a preliminary study has also shown that cord plasma antidepressant levels are more strongly associated than maternal antidepressant dose or circulating blood antidepressant levels with increased DNA methylation of a specific unit within the promotor region of oxytocin receptor gene (OXTR). (Galbally M., et al. 2018

Structurally it has also been shown how early prenatal stress impinges on the neurogenesis of the hippocampus, nucleus accumbens, dentate gyrus and amygdala through stress-induced oxidative damage to mitochondrial DNAs in neonates. (Kawamura T.,et al. 2006; Zhu Z.,et al. 2004) Repeated stress that is common in unfortunate home environments has also been shown to disrupt the neuroplasticity and dendritic architecture of the pyramidal neurons in amygdala and hippocampus, that could be protected by daily administration of agomelatine in animal studies. (Grillo CA. et al., 2015) Agomelatine that is a melatonin receptor agonist and a serotonin 5-HT2c receptor antagonist, has been shown in animal models to resynchronize circadian rhythm that is disturbed in many psychiatric conditions such as depression. (Racagni G. et al., 2011; Taylor D. et al., 2014) Circadian clock genes have been shown to regulate the release of the glucocorticoids that are so intimately linked to the stress response in humans (Landgraf et al., 2014).

 Stress, Inflammation and Depression:

Over the past couple of decades, the pathophysiology of depression has evolved to include an inflammatory and metabolic processes. (Rohleder N, Miller GE., 2008) It has long been known that depression could trigger and/or exacerbate medical comorbidities, which recently has been partly explained through inflammatory/metabolic pathophysiologic processes. This association have been hypothesized and shown to be facilitated through different inflammatory markers such as Interleukins such as 1 & 6, CRP (C-reactive protein), and Cytokines. (Douglas KM. et al., 2004; Miller AH. et al., 2009; Valkanova V. et al., 2013)

 In explaining the chain reaction of inflammation triggering or causing depression then comorbid medical conditions, the initial precipitating factor has been hypothesized and shown to be early life stress and adversity. (Slavich GM. Et al., 2010; Miller GE. et al., 2012; Slopen N. et al., 2012) This association and pathophysiologic process has been shown in depressed adults with a history of childhood maltreatment who exhibited larger stress-related increases in plasma IL-6 than healthy controls, with an enhanced DNA binding of the pro-inflammatory transcription factor nuclear factor-kappa B. (Pace TW. Et al., 2006) It has also been shown that depressed subjects with history of early adversity having low-grade inflammation indexed by a composite of CRP, fibrinogen, and leukocyte counts, while depressed subjects with no history of early life stress were statistically indistinguishable from controls. (Danese A. et al., 2008)

The pathophysiologic hypothesis of early life stress triggering inflammation and in turn leading to depression and comorbid medical conditions has been extended to include even late life morbidities and mortalities. It is thought that children reared in unfavorable socioeconomic circumstances show increased susceptibility to the chronic diseases of aging in the fifth and sixth decades of life, through up-regulation of genes conveying adrenergic signals to leukocytes, and down-regulation of genes signaling the glucocorticoid receptor, causing cortisol secretion and transducing anti-inflammatory reactions in the immune system. The subjects from low-SES (Socio- Economic Status) with higher frequency of early life stress have been shown to have more output of cortisol in daily life, and greater production of the pro-inflammatory cytokine interleukin 6. Although this inflammatory and anti-inflammatory reaction to stress could serve adaptive functions during acute stress, over the long term they might cost an allostatic toll on the body that ultimately contributes to depression and the chronic diseases of aging. (Miller GE. et al., 2009)


In summary “Reactive Depression” that used to be applied as reaction to stress, loss, adjustment and alike, is not purely psychological and non-biological. The epigenetics remind us of the significance of the interaction between genetics (susceptibility) and environment (insults, adversaries, stress, etc.) that result to a phenomenological by-product such as depression. By the same token, the other old term, “Endogenous Depression” is not purely biological, but has also the impact of environmental stress on its genetic predisposition to evolve to its symptomatic manifestation. From this perspective, therefore any types of depression could be both reactive while biological and the only differentiation of the importance is the timing, or the time of impact of the environmental factor or insult on the genetic make up of the individual.

Is it all Reactive?

The old dichotomy of Reactive vs. Endogenous Depression throughout the recent decades’ research have been shown to be in fact inter-related. What seemed to be reactive depression in response to stress of any types (loss, adjustments, etc.), it seems nowadays to be biological as well, through causing a cascade of neurochemical reactions, involving alterations in the mood neurotransmitters, neuromodulators, inflammatory processes and more. Endogenous or familial depression as well, have been shown in the recent decades to be in fact an early response to an early life stress, as early as prenatal through maternal depression.

 So if all unipolar depressions are in reality epigenetic, or the byproduct of early or late life stresses, causing imbalance in the neurochemical/anatomical architecture of the brain, then what are the depressions caused secondary to comorbid medical and mental conditions? It has been known for long that depression is a common comorbidity in many medical conditions such as MS (Multiple Sclerosis), Parkinson’s Disease, and cardiovascular diseases such as myocardial infarction. (Sadovnick AD. et al., 1996; Starkstein SE. et al., 1990; Forrester AW. et al., 1992) Although some of these conditions could be argued to be neurological, hence brain conditions affecting the limbic system, white matter and other components of emotional neuro-circuitry, there are other non-neurologic conditions such as cardio-vascular’s associated and causing depression. This causality of depression secondary to medical conditions could also be explained as “reactive” to physical/medical stress to the neuro-homeostasis of the body, through a cascade of metabolic/inflammatory processes causing alterations in the mood neurotransmitters and neuromodulators.

 The final dilemma would be within psychiatry itself and the relationship between depression and other mental conditions, such as the common comorbidity of depression and anxiety. Anxiety e.g. in GAD (Generalized Anxiety Disorder), as intrinsic stress without external triggers, specially in early life when untreated, it could be complicated with depression as well. (Showraki M., 2018)

 In closing remark, Reactive Depression, an old diagnostic category, long abandoned by the DSM, may come to a new light when the epigenetic of depression, or the environmental impact on the genetic susceptibility is appreciated. Therefore from this new perspective, all unipolar depressions (Major, Minor and Dysthymic) are endogenous and reactive. Endogenous in having a genetic predisposition and reactive in having an environmental impact such early or late life stress on the genetic susceptibility.

 Hereby the difference between different subtypes of unipolar depression at a symptomatic level observed clinically, depends on the timing of the environmental impact or stress. Stress or insult could be as early as prenatal, then postnatal, childhood, and as late as in adulthood and thereafter. Based on the timing of stress/insult there are different reactions of the mood neuro-circuitry to cause different types and severity of unipolar depressions. Based on the timing of the impact, the earlier development of depression leads to more chronic and refractory to treatment type of the illness. But the later in life impact and development of later life or acute types of depression are more responsive to interventions.


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 Wickramaratne  PJ Greenwald  MA Weissman  MM.( 2000) Psychiatric disorders in the relatives of probands with prepubertal-onset or adolescent-onset major depression.  J Am Acad Child Adolesc Psychiatry. 391396- 1405.

 Zhang WJ, Wang HH, Lv YD, Liu CC, Sun WY, Tian LJ.( 2018) Downregulation of Egr-1 Expression Level via GluN2B Underlies the Antidepressant Effects of Ketamine in a Chronic Unpredictable Stress Animal Model of Depression. Neuroscience.372:38-45.

 Zhu Z, Li X, Chen W, Zhao Y, Li H, Qing C, Jia N, Bai Z, Liu J. (2004) Prenatal stress causes gender dependent neuronal loss and oxidative stress in rat hippocampus. J Neurosci Res 78: 837-844. 

 Zivkovic B, Scatton B, Worms P, Lloyd KG, Bartholini G. (1983) Pharmacological and therapeutic actions of GABA receptor agonists. J Neural Transm Suppl. 18:319-39.

ADHD:Subtypes or one Type?


The literature on pathophysiology of ADHD is quite inconsistent with mixed results to synthesize all the findings in any domain of neuropsychological, neuroanatomical, neurochemical or genetics to link them to the correspondent clinical phenotypes of the current ADHD subtypes. On a descriptive level, the symptomatology of two distinct ADHD subtypes of hyperactive-impulsive (ADHD-HI) and inattentive (ADHD-I) are quite different and hardly seem to come under the same disease entity as it has long been categorized by DSM classifications with no change in the recent DSM5 (1). While ADHD-I or ADD as it was labeled in the past, it is an “attention-deficit” disorder, ADHD-HI beyond an attention-deficit disorder, it is a behavioural disorder with cardinal symptoms of hyperactivity, impulsivity and behavioural disinhibition (2-4). As a result, the majority of research samples, hence the conclusions of the literature for clinical practice have relied heavily on the “combined subtype” that is an ill-defined combination of both subtypes. This ill-defined combined subtype usually is not consisted of 6 symptoms of either subtypes as required by DSM5, but some of the symptoms of each, in a mixed and arbitrary construct with no clear underlying pathophysiology as either subtypes. This contradicting fact has long caused an intense argument in the literature on the total validity of ADHD as a homogenous or single disorder with a single pathophysiology or two or more heterogeneous disorders with different pathophysiology (5-7), that I will attempt to review and explore in this paper.

 ADHD: Homogenous or Heterogeneous?

In fact throughout the history, ADHD has been a homogeneous condition, first described as “hyperkinetic” or “hyperactive” syndrome or disorder of children, with recognition of “impulsivity” as a component of hyperactivity first by Laufer et al. (8) in 1957. The second edition of DSM, i.e. DSM-II in 1968, (9) published by the APA, that for the first time recognized the condition as a disorder, labeled it as “hyperkinetic reaction of children”. It was not until the third edition of DSM (10) in 1980 that recognized the condition as an attention deficit with hyperactivity and labeled it as such, i.e. ADHD, that we started facing a combined and heterogeneous disorder. Unfortunately since then the research samples have been mostly undifferentiated or of combined subtype with rare comparison between the two subtypes, so to clarify any distinctions between the two if any.

 The few available comparison studies between the subtypes have shown that there is a distinct difference between the two with the conclusion of the most that ADHD is a heterogeneous condition with differences not only in symptomatology and the course of illnesses across the brain development, but differences in cognitive functions and different etiopathophysiology (11-12). Goth-Owens et al. (13) in their comparison study of 572 children and adolescents with pure inattentive subtype (ADD), combined type (ADHD-C) and non-ADHD controls, reported slower cognitive interference speed in the ADD vs. ADHD-C and controls comparisons. A similar result was reported by Carr et al. (14) who reported an attenuated attentional blink versus controls and ADHD-combined addressed in a sample of 145 ADD/ADHD and typically developing comparison adolescents (aged 13-17). A similar result has been reported by Solanto et al. (15 ) that predominantly inattentive subtype show worse performance than combined subtype and control groups on the WISC-III Processing Speed Index. This has made some researchers to question the validity of DSM current diagnostic criteria of ADHD to include two distinct subtypes of inattentive and hyperactive/impulsive under the same diagnostic umbrella. (16) Martel et al. (17) in comparison between the two subtypes, reported “a composite executive function factor was significantly related to inattentive but not hyperactive-impulsive symptoms.” The authors concluded “Executive function weakness in adolescent ADHD is specifically related to symptoms of inattention-disorganization.” Nigg et al. (18) also reported that symptoms of inattention-disorganization were uniquely related to executive functioning when hyperactivity-impulsivity controlled. “Inattention was associated with slower response speed, and hyperactivity-impulsivity with faster output speed. Results were not accounted for by IQ, age, gender, education level, or comorbid disorders.” Also Marshal et al. (19) found academic underachievement in a group of 6-12 years old with ADHD without hyperactivity. Friedman et al. (20) have reported that such cognitive deficits continue until late adolescence and Nigg et al. (21) who report their extensions to adulthood.

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ADHD:Subtypes or one Type?

Anxiety or Depression: Chicken or Egg?!


In Medicine, the existing of more than one condition or disease is common and it is so called “Comorbidity”. This term by definition refers to the co-existence of two conditions without any relationship such as causal. In other word, comorbidity is the co-existing of two conditions in parallel with no relationship, or different pathophysiology and treatment paths. But in fact that is not the case in many situations, as one condition may give rise to another, or in a better sense, one is primary and the other is secondary. For example hypertension or high blood pressure can lead to stroke and its consequences such as hemiplegia, or diabetes as a primary condition could cause many complications as secondary conditions such as diabetic foot and poor vision, etc. The treatment of the primary condition such as diabetes or osteoporosis could prevent the secondary condition such as diabetic wounds and bone fractures.

 Although some of these co-conditions that are still commonly labeled as “comorbidity” are very obviously primary and secondary to each other with a causal or consequential relationship, some conditions specially in Psychiatry may not look that much related to each other. For example in ADHD, secondary conditions or complications such as depression, oppositional defiant and anti-social behaviours or disorders, substance use disorders, etc. while not much superficially related, they are in fact so, and treatment of ADHD would prevent majority of the others. For the first time, I coined the term “post-morbidity” in ADHD for these secondary conditions or complications that are still in the literature considered loosely “comorbidity” with no apparent causal relationships. (1-2)


A similar relationship exists between depression and anxiety that are commonly comorbid in psychiatry and it is still considered with no causal or temporal relationship as simply “comorbid” in the literature and among experts. If two conditions are causally related and not appreciated as such, it will affect their treatments and both conditions could be treated with two treatments, e.g. two or more medications. But if there is a causal relationship, the treatment of the primary condition would prevent and treat the secondary or “post-morbid” condition, while their pathophysiologic relationship is more appreciated and understood. In this paper, I will show for the first time that such a primary and secondary or “post-morbidity” relationship exists between depression and anxiety that has never to this date been recognized.


Depression and Anxiety: Are they related?

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ADHD: Attention deficit or Hyper-attentive?!


ADHD (Attention Deficit Hyperactive Disorder) as the most hereditary disorder of humans, physical or psychological/behavioural has been perhaps the most recognized truly in the field of medicine, even among the experts and researchers. This common disorder starting in childhood, but if untreated endures across the life span, has been known in different terms from the time of antiquity. Hippocrates (460-329 BC) (1), known as the father of medicine, observed patients who demonstrated “quickened responses to sensory experiences” and went on to describe their inability to stay focused “because the soul moves on quickly to the next impression.” Interestingly this ancient Greek physician recognized the condition both as a cognitive and behavioral nature together and not separate. But it took the field about two millennia to bounce back and forth, between recognizing it as predominantly a motoric (hyperactive) condition to a cognitive (inattentive) disorder until the present day. 

George Frederick Still (2), the father of British Pediatrics, in 1902 described and published in the Lancet, the descriptions of 43 children with serious problems of sustained attention and self-regulation, but at the same time paradoxically being “bright and intelligent”. Dr. Still was perhaps the first one to recognize the problem with “self regulation” instead of the label of “Moral Defect” on these children up until 20th century and also appreciating their high intelligence, that has not been widely acknowledged even today! In contrast with the positive and intelligent observation of Still, for the rest of 20th century and even now in 21st century, these children have been mislabeled negatively with having “mild brain damage”, “minimal brain dysfunction”, “mental deficiency”, etc. (e.g. 3-4) 

The pathophysiologic or causative theory of ADHD prompted by Charles Bradley (1902-1979) in 1937, a pediatric neurologist who by accident treated these children Benzedrine sulfate, an amphetamine product with great success, so to born the theory of “dopamine deficiency” prominent to this day. (5-6) In 1952, first edition of DSM (Diagnostics and Statistical Manual) of psychiatric disorders by the APA (American Psychiatric Association) (7) did not include any mention of an ADHD like disorder. Then in 1957, after Laufer and colleagues (8), reporting inattention and hyperactivity, both as two main features of the condition, the second edition of DSM in 1968, included the disorder as a formal diagnostic classification. (9) But before that another bright physician, Keith Conners in 1963 started his first study on the effects of Ritalin (Methylphenidate) in ADHD children and a year later published the first “Conner’s Rating Scale” for the official assessment and rating of the ADHD that is still in common use today. (10) 

In recent years first DSM-IV in 1994 (11) and most recently DSM5 in 2013 (12), have classified the disorder into two subtypes of predominantly inattentive (ADHD-I) and predominantly hyperactive/impulsivity (ADHD-HI), though these they often overlap at least in research samples as “combined”! Impulsivity as a very cardinal feature of ADHD that has been recognized only in recent decades in the disorder, has been poorly defined in DSM-IV & 5 as only “ blurting out” verbally, or “having trouble waiting one’s turn”, and “interrupting or intrudes on others” again more verbally. And the only change from DSM-IV to DSM 5 after a quarter of century has been extending the age of onset from 7 to 12, so prompting some to propose wrongly the new entity of adult onset ADHD. (13) 

 In this article that is a synopsis of my initial work (“ADHD: Revisited” and “ADHD: Hyperattentive, disinhibited, intelligent and evolutionary”) (14-15) I will dissecting into the true nature of ADHD, and reveal its misconceptions, misunderstandings, the shortcomings in its research and its current wrong classification and treatment.

Two young girls having fun painting everything. Childhood, learning, exploration family

 ADHD: One type or subtypes?

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Why antipsychotics for depression?: When the experts miss the concept!


The idea of recommendation and prescription of second generation of antipsychotics in the treatment of depression (major unipolar depression, bipolar depression, depression in schizophrenia and even a milder depressive condition such as dysthymia) started in early 2000’s. First the experts recommended these agents that are originally synthesized to treat psychotic disorders such as schizophrenia, as augmentation to anti-depressants in the treatment of refractory depressions. (1-3) Soon such studies that are mostly sponsored by pharmaceutical corporations, suggested the use of antipsychotics not as an adjunct, or for the treatment of depression in psychotic disorders, or even bipolar disorder that could be accompanied by psychotic features, but for the treatment of pure unipolar major depression and as the first line treatment. (4) Nowadays it is not uncommon that even primary care physicians, psychiatrists and family physicians prescribe antipsychotics in the treatment of a patient who suffers from a simple depression. The pharmaceutical companies synthesize and market such antipsychotics (e.g. Quetiapine, Aripiprazole, Lorasidone, etc.) (these are these generic names that in different markets are sold under different brand names) have also been able to acquire indication for the treatment of depression for their products. The market sales continue to rise and the treatment indications of these antipsychotics are expanding beyond depression to other psychiatric disorders such as anxiety disorders, PTSD (Post-Traumatic Stress Disorder) and beyond. (5-6)

 A curious and cautious consumer may wonder why he or she should be prescribed an antipsychotic while having no psychotic disorder (delusions, hallucinations, etc.) but a simple depression! This article attempts to explore this wonder and show throughout the history of psychiatry, that the use of antipsychotics have not been limited to the recent time and the second-generation antipsychotics, but such attempt in the past failed over time. The experts might respond to this critic that the new antipsychotics possess such chemical structure that work on the neurotransmitters involved in depression (mainly serotonin and norepinephrine). But our lay patient could respond back that what about the impact of the antipsychotic component of these medications?! If the depressed patient is not psychotic and does not have any imbalance or over-sensitively in his or her dopamine neurotransmission (involved in psychosis) what would be the consequences of taking an antipsychotic that affect this neurotransmission. For example would he or she develop side-effects such as EPS (Extra-pyramidal symptoms) or simply abnormal movement disorders such as tremors and akathisia (restlessness and feet fidgeting, etc?! What about dampening the lay patient’s dopamine system in the brain that he or she needs it for all his or her cognitive faculties, etc.?! Since the poor lay patient could not keep this dialogue long enough against the experts who are masters of twisting the facts around to prove their points of intentions per pharmaceutical giants’ order, this article will strive to do so on the behalf such lay depressed patient and million others across the globe.

Digging the grave of antipsychotics:

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Suicide species: Why some people kill themselves?

Suicide and suicidal behaviors are very rare in animals and seem to be more of defensive nature unlike in humans that is not so, but intentional and against life. (1-2) Suicide in humans is a global issue that has resulted in 842,000 deaths globally in 2013, up from 712,000 deaths in 1990. (3) This makes it the 10th leading cause of death worldwide. (4) 75% of suicides globally occur in the developing world. Rates of completed suicides are generally higher in men than in women, ranging from 1.5 times as much in the developing world to 3.5 times in the developed world. (5) There are an estimated 10 to 20 million non-fatal attempted suicides every year. (6) Non-fatal suicide attempts may lead to injury and long-term disabilities. In the Western world, attempts are more common in young people and females, and suicide is the second cause of death among adolescents after accidents. (7-8)


Factors that affect the risk of suicide include mental disorders, drug misuse, psychological states, cultural, family and social situations, and genetics. (8) Mental disorders and substance misuse frequently co-exist. (9) Other risk factors include having previously attempted suicide, the ready availability of a means to take one’s life, a family history of suicide. (7) For example, suicide rates have been found to be greater in households with firearms than those without them. (10) Socio-economic problems such as unemployment, poverty, Homelessness, and discrimination may trigger suicidal thoughts. (11) About 15–40% of people leave a suicide note. (12) Genetics appears to account for between 38% and 55% of suicidal behaviors. (13) War veterans have a higher risk of suicide due in part to higher rates of mental illness such as post traumatic stress disorder (PTSD) and physical health problems related to war. (14)


Half of all people who die by suicide may have major depressive disorder; and having a mood disorder such as depression or bipolar disorder increases the risk of suicide 20-fold. (6) Other mental disorders’ risk of suicide are Schizophrenia (14%) that leads about 5% of such patients die from suicide, borderline personality disorder, PTSD, eating disorder, and substance use disorders. (6-7, 15) Approximately 20% of suicides have had a previous attempt, and of those who have attempted suicide, 1% complete suicide within a year, and more than 5% die by suicide within 10 years. (7) Acts of self-harm are not usually suicide attempts and most who self-harm are not at high risk of suicide. Some who self-harm, however, do still end their life by suicide, and risk for self-harm and suicide may overlap. (16)

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Digital Addiction: The end of free thought and will


Since the industrial revolution of 17 to 18th century in Europe, humans who freed themselves from slavery, feudalism, monarchy and alike, were worried about their dependence and overcoming by their own scientific creations.(1) Perhaps the first of these fears is demonstrated in the popular story of Dr. Frankenstein in 1818, who became a victim of the torment of his own creation.(2) Later on in many stories and films such as Space odyssey 2001, this fear warned us all! Although none of the fears of human clone, machines or robots did not materialize, humans became addicted first to televisions, then video games and most recently to computers, internet, social media, cell phones and alike. This dependency and addiction has not been limited to only a small group of scientists and creators, but has become an epidemic world wide, affecting ordinary people of all ages and totally out of control and a real concern in all lands.


The free thought as expressed in philosophy for example by the popular phrase of Rene Descartes’ “I think therefore I am”, that was the foundation of humans’ modern achievements, has faded away.(3) Similarly the free will that was well expressed through existentialism, and well expressed for example by the popular phrase of Arthur Schopenhauer’s “The world is my representation.” has been totally lost. (4-5) Humans rapidly became slaves once again as in the remote past before the industrial revolution, but this time not to religion, or monarchies, landlords, or another human, but to their own byproducts. The computer that was initially created for fast computing, then as an information technology, soon was transformed to a social media and communication, brain idling and washing device. The invention of mobile devices has facilitated this addiction, dependency, obsession and loss of free thought and will globally and across the life span. In the following we will see how digital addiction has become the most common and worrisome addiction of all types, worse than addiction to gambling, and illicit drugs.


From TV to the Internet and beyond:

After the world war II, when TV invented and became a public entertainment device at home, addiction to it also started with its medical and psychiatric consequences such as reactive apathy and obesity. (6-7) Then soon came the video games such as Nintendo, and by the 80’s personal computers and by the 90’s internet. The medical concern grew so much that medical and psychological journals such as “Cyberpsychology Behaviour” for studying the medical and psychological complications of cyber-addictions were founded. (8) The obsessive and compulsive use of digital technology brought behavioural problems and symptoms similar to any addictive disorder, so the term “digital addict” and “digital addiction” were coined. (9)

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Digital Addiction: The end of free thought and will

Intelligence: What is it and are the IQ tests correct?!


According to Oxford dictionary, “intelligence” means “The ability to acquire and apply knowledge and skills.” Webster dictionary defines “intelligence” as “the ability to learn or understand things or to deal with new or difficult situations.” Webster has another definition for “intelligence” that is related to CIA and other governmental spy agencies as “Secret information that a government collects about an enemy or possible enemy; also : a government organization that collects such information.” The medical dictionary online has this definition for intelligence: “The ability to learn and to deal with new situations and to deal effectively with tasks involving abstractions.” Wikipedia has a broader definition: “Intelligence has been defined in many different ways including one’s capacity for logic, understanding, self-awareness, learning, emotional knowledge, memory, planning, creativity, adaptive behavior, problem solving and self-control. It can be more generally described as the ability to perceive information, and retain it as knowledge to be applied towards adaptive behaviors within an environment or context.”

 Intelligence has been defined in many forms, e.g., logic, abstract thought, comprehension, self-awareness, learning, emotional, retaining, planning, invention, creation, problem solving, etc. An editorial statement by fifty-two researchers defines the intelligence as “A very general mental capability that, among other things, involves the ability to reason, plan, solve problems, think abstractly, comprehend complex ideas, learn quickly and learn from experience. It is not merely book learning, a narrow academic skill, or test-taking smarts. Rather, it reflects a broader and deeper capability for comprehending our surroundings—”catching on,” “making sense” of things, or “figuring out” what to do.” (1)

 Generally speaking of intelligence, comes of mind IQ or Intelligence Quotient that is measured by different tests including Stanford-Binet, Raven’s progressive matrices, the most currently used Wechsler intelligence scales for children and adults, the Kaufman assessment battery for children, etc. Some tests consist of a single type of task; others rely on a broad collection of tasks with different contents (visual-spatial, verbal, numerical) and asking for different cognitive processes (e.g., reasoning, memory, rapid decisions, visual comparisons, spatial imagery, reading, and retrieval of general knowledge). The psychologist Charles Spearman early in the 20th century carried out the first formal factor analysis of correlations between various test tasks. He found a trend for all such tests to correlate positively with each other, and named it g for “general intelligence factor”. He interpreted it as the core of human intelligence that, to a larger or smaller degree, influences success in all cognitive tasks and thereby creates the positive manifold. This interpretation of g as a common cause of test performance is still dominant in psychometrics. (2)

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Children of a lesser God: When guardians shatter the Futures!

“I loved music, until my music teacher got upset at one of my classmates, aggressively grabbed him by the neck, kicked him out of the class and swore at him” Sebastian in grade 5.

 Still I cannot believe what Sebastian told me and happened in his school, in “Beverly Acres Public School” in Richmond Hill, Ontario, Canada, about a maltreatment, physical and verbal abuse of a 10 years old child in front of the whole class! When I told Sebastian that I am going to write up the incident in my website and the world will know about it, he was excited to hear what others might think of the situation and condemn the abuse by their teacher!

 “Children of a lesser God” is originally a play by Medoff that in 1986 was adapted to a feature film, about a school for the deafs, their sufferings and struggles to learn. While any physical defect of a child could be considered by some or the child himself or herself as being of a lesser attention by the God to him or her, the mental defects of a child and more importantly so, the trauma, maltreatment and abuse that befall on a normal and healthy child could be taken as such.

A search in “pubmed” of the NIH (National Institute of Health) of the United States, reveals the following number of research papers: on child abuse in total:40331; child abuse by teachers:412; by clergy:115; by preiests:123! The child welfare of the US government reports that relatives, babysitters, and foster parents are the common perpetrators. The American humane association reports the following rate of common child abuse and maltreatments: neglect 62.8% as the highest type of abuse; physical abuse 16.6%; sexual abuse 7.1%; emotional and psychological abuse 7.1%; medical neglect 2% and “others” at 14.3%. Canadian child welfare agency, reports that in 2007, there were an estimated 67,000 children in out-of-home care across Canada. The Canadian Incidence Study of Reported Child Abuse and Neglect reports an increase of abuse reports from 135,261 in 1998 to 235,315 in 2003 and 235,842 in 2008. Neglect and exposure to intimate partner abuse and violence has been reported at 34% to be the highest, followed by physical abuse at 20%, emotional maltreatment at 9% and sexual abuse at 3%, different than the statistics in US, though both are similar in being western, mainly English speaking societies with multi-cultural striatum. Child issues that perhaps triggered more abuse by the perpetrators have been reported to be Academic difficulties: 23%; depression, anxiety, withdrawal: 19%; Aggression: 15%; Attachment issues: 14%;Intellectual & developmental disabilities: 11%; and ADD/ADHD: 11%. Care-givers risk factors have been reported to be the highest among the victims of domestic violence and abuse at 46%. Schools have been the most common source of abuse reports at 24%.

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Children of a lesser God: When guardians shatter the Futures

Obsessions, Compulsions, Undo harm, Rituals, Superstitions: OCD


“The boy who could not stop washing” or “When once is not enough”, two book titles on Obsessive Compulsive Disorder (OCD) that tell a lot about this devastating behavioural and mental condition. This illness that can start as early as early teens, is not limited to washing and cleaning, but obsessions about tidiness, orderliness, checking, rechecking and more. Obsession is a repetitive anxiety provoking thought that something is not clean, tidy, organized, in order, not right, etc. that will not leave the inflicted individual alone. Then the person feels obliged to do something to stop the burdening thought (compulsion) that leads to “compulsive act” that is washing, cleaning, ordering, tidying, checking and rechecking until feels satisfied that is hard to reach. Associated or underlying this chain of thought (obsession), urge to act (compulsion) and the act (compulsive act) are, “doubt” and “superstition” that things are not clean or right the way should be, and if not act upon, some harms will befall on the individuals or beloved ones. Then rituals will come to play, and the person in the eyes of others could appear not anymore as a clean, tidy, or a “perfectionist”, but as totally insane who has lost his touch with reality and cannot be convinced by others. The cases that come to medical attention, are usually more than a mere perfectionism and consists of all the above, that makes it very hard to treat.

The big question is that what causes OCD, specially from an early age. Is it a personality that is labeled “obsessive compulsive personality”, or is it rooted in “perfectionism”, or in anxiety-ridden subjects, or is it genetic and familial? The fact is that many of OCD patients, have had no obsessive compulsive personality, or perfectionism, no history of previous anxiety and none of their other family members suffer the same. The etiology is still unknown, hence the treatment is incomplete and failure in many instances and prevention is not in agenda as nobody knows how! In this article, I will attempt by search in the available literature to answer some of these dilemmas and somewhat clear the path to the treatment and hopefully the prevention.

 Did it all start from a “sore throat”?

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Microbial Dance: How infections swing the mood

Mood swing is the cardinal clinical feature of bipolar disorder of the present or manic depression of the past. This common disorder of mood swing, has been recognized from the age of antiquity. Hippocrates, the father of medicine, has described the mania, that without it, bipolar disorder or manic depression could not be diagnosed, as a state of high energy and euphoria. He appreciated the importance of the brain to be the site of all these mood changes and not the heart: “Men ought to know that from the brain and from the brain only arrives our pleasures, joys, laughter and jests, as well as our sorrow, pains, grieves and tears…wherefore, I assert, the brain is the interpreter of the consciousness.” (1, 2)

 The differentiating fact between the unipolar disorder or depression and bipolar disorder or manic depression, known well in the ancient world, was buried in history until in mid-nineteen century when in 1854, the French psychiatrist, Falret, brought it back to recognition under the term “La folie circulaire”. (3) But it was not until Emil Kraeplin (4) in 1919 popularized the disorder under the term of “manic-depressive insanity” in his historical text-book, elaborating on all his predecessors including Karl Kahlbaum’s concept of “cyclothymia” (5)

Clinically bipolar disorder or manic depression, is characterized by mood swings at different rates and severity, and on that basis is classified to classical or type I, with long cycles of severe elevation and depression of mood, of at least a few months each. Milder form of the disorder or mood swings has been classified as type II, with less severe depressive and high mood (called “hypomania”). Shorter cycles of these mood swings, form days to weeks are classified as rapid cycling and within day, as ultra cycling bipolar disorder or mood swings. The high mood state that could manifest as elation or agitation and aggression, is accompanied with elation in many mood and cortical functions, such as thought racing, pressured speech, self-esteem elevation, high physical and mental energy, shopping spree, risk taking behavior, hypersexuality, less need for sleep, etc. The depressive cycle is similar to unipolar or usual depression with an inversion of almost all the mood and mental states to the low side. It seems that the higher the mood elevation, the more severe the downfall of depression would be, such as the higher risk of suicide in bipolar depression than the unipolar or major depression (26-6% vs. 17.8% suicide attempts) (6).    

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Still Alice: Golden Globe and Oscar Awards For: Julianne Moore and Alzheimer’s Disease

As many already know and have watched the movie “Still Alice”, based on the same name bestselling novel by Lisa Genova in 2007, is the story of a university professor in linguistics with an early onset Alzheimer’s disease. The movie brought more recognitions and many awards across the globe and finally the most prestigious of all, Golden Globe and Academy awards, for Julianne Moore who played the role of Alice Howland, the Columbian University professor.

While it is commendable that Hollywood addresses medical and mental suffering of people at large, but it also needs to consult with the medical profession for the validity of its portrays on the screen. Although anybody can catch any disease including Alzheimer’s but there are certain protective factors against almost any disease, as high education and intelligence is against development or clinical presentations of Alzheimer’s disease, so there would be a lower risk or late and slow clinical presentations of the disease in a highly educated university professor. This fact proven by many research over the past couple of decades has created the “cognitive reserve” theory and the possibility of non-pharmaceutical prevention and intervention of this devastating disease by maintaining our brains active as a safeguard to certain degree! Therefore it had been more prudent if Julianne Moore, whom I have a great adoration, would have said more about Alzheimer’s disease in her Oscar acceptance speech, instead of saying “ I have read an article that winning Oscar, leading to living 5 years longer!” that was totally inappropriate and unexpected. To finish off this introduction and leave Hollywood with their more informed film making and interpretations of real life problems and diseases, I need to emphasize the importance of high education and intelligence and keeping our brains active as the only probable preventive measures against this man knocking down disease at the present time.

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Personality and Personality Disorders:Revisited

The word “Personality” is derived from the Latin and Greek word “persona” or “prosopon”, meaning a mask worn by an actor to play certain roles or characters! The personality disorders conceptually from the ancient time until modern time, has meant deviation from the normal personality! But what has been considered a “normal personality” has been the big, not yet answered question throughout the time.

The ancient Greek philosophers such as Theophrastus described 29 ‘character’ or personality types, deviations from the norm, and Hippocrates 4 humours or character types. Physicians in the early 19th century expanded the concept to include some forms of insanity involving disturbed emotions and behaviors but seemingly without significant intellectual impairment, delusions or hallucinations, e.g. ‘manie sans délire’ or “insanity without delusion”, “moral insanity”, arguably based in part on religious, social and moral beliefs! Later on as we move into 20th century, these moral judgments are expanded to many deviations from normal personality or behavior, mostly biased by cultural factors, e.g. the use of labels such as “psychopaths”, sadists and masochists!

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Psychiatry or Neuroscience?!

The term “psychiatry” like “psychology” derive from the greek word “psych” meaning “soul”! For ages, before the inception of “psychiatry” and even to this date, the field has been conceived as a specialty to treat the “soul” first by priests, then witches, philosophers, psychics, rituals, incarcerations, burnings, etc.  That has been so much that patients even with common illnesses such as depression were thrown into “asylums” instead of hospitals and chained instead of treatment with medicines.  The patients were labeled “mentals”, “psychos”, “cuckoos”, and the psychiatrists as “shrinks”!    

This is while psychiatry is perhaps the medical speciality mostly contributing to the neuroscience and the scientific studies of our brain. In fact the “psych” is the function of the brain in different domains, e.g. behavioural, emotional, cognitive and so on.  But now it is the time that the field “psychiatry” that does not deal with “psych” any longer, changes its title to “Neuroscience” or else to fit the current position of the speciality.  This is perhaps the only way of salvation of this important field of medicine to get its true identity among the other medical specialties and get rid of an ancient aged stigma for itself and its patients!

Dr.Mostafa Showraki, MD, FRCPC                                                               Lecturer, University of Toronto,Head, Community Psychiatrists Association of Toronto (CPAT),Author: “ADHD:Revisited” Book “”/””

Depression: Revisited

Depression or a depressed state of mind and emotions has existed since antiquity and has been described by the father of medicine, Hippocrates(460-370 BC) as “melancholia” that was a common term to describe and label until the modern time and the advent of DSM and ICD systems. DSM (Diagnostics and Statistical Manual) of APA (American Psychiatric Association) and ICD (International Classification of Diseases) while prior to 1980 had a distinction between the reactive and endogenous depression including the old melancholia, to reach validity and reliability among experts, took on a non-etiological approach. Hereby depression became a descriptive or symptomatic diagnosis and the only differences among the different types of depression were laid in the difference in severity, e.g. minor vs. major depression, spectral e.g. unipolar vs. bipolar, associative with other symptoms e.g. with psychotic feature or melancholia. This happened at the era where psychiatry had started to become largely biological and a condition such as  depression became to known as a “chemical imbalance” and its mainstay treatment was with anti-depressants to fix such imbalance! This way any depression even an acute one as long as it had been going on for 2 weeks, justified the use of anti-depressants and was considered a “chemical imbalance”, even if reactive to a situation and short-lived!

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Attention Deficit Hyperactivity Disorder(ADHD)

ADHD is a unique brain disorder that shows signs and symptoms as early as age 4, but perhaps as early as infancy, but diagnosed a long time later and continues with its course throughout the rest of life like a river wild. At the same time, ADHD while is the most treatable condition in the whole psychiatry, it has been the most misunderstood and unrecognized condition for its true nature! ADHD is a disorder of developing brain and at the same time is an evolutionary condition of the brain,as in contrast to the currently held beliefs even in medical literature, it is associated with high intelligence than learning disabilities, autism and mental retardation and alike!

To read more, visit “” and the book, ADHD:Revisited” available at Amazon, Kindle books.