Schizophrenia and Insight

Though it only affects about one percent of the population ( in the United States or any country), schizophrenia is ranked by the World Health Organization as being in the top ten of the most disabling adult diseases (Fischer & Buchanan, 2013). People who have schizophrenia usually experience a combination of positive and negative symptoms. Positive symptoms include psychosis, such as auditory and visual hallucinations, delusions, and difficulty organizing thoughts. Persons with schizophrenia may also experience negative symptoms such as poverty of speech, a flat emotional presentation, lack of social skills, and cognitive difficulties with attention, memory, and making decisions/prioritizing (Sadock, Kaplan, & Sadock, 2007). A majority of people with schizophrenia experience a lack of insight or awareness that they are ill; some in mental health would classify this as a negative trait, while others term it as positive (Osatuke,  Ciesla, Kasckow, Zisook, & Mohamed, 2008).

Schizophrenia tends to strike young people just as they are entering adulthood; the disease begins in men between the ages of 15 to 22; for women, the disease process starts a bit later, from ages 25-35, with another small group for whom the age of onset is after forty (Sadock, et al, 2007).   Initiating treatment for schizophrenia can be tricky because at least fifty percent of people who have the disease do not believe they are ill; this is called a lack of insight or anosognosia, and should not be underestimated (Amador & Gorman, 1998). The effect is similar to when a person who has had a stroke believes they can move a limb, but they no longer can; there is simply no reasoning or logic that will ‘convince’ a person that they are ill if they are afflicted by lack of insight (Amador & Johanson, 2000). It is also important to note that a person with schizophrenia is not ‘in denial’ of their illness, the way a person might be in denial of how much alcohol they drink. Lack of insight is not a coping mechanism, it is actually a feature of the disease itself, a recent study that reviewed over forty research studies concluded (Mintz, Dobson, & Romney, 2003).  This psychiatric definition of ‘insight’ relates not only to the individual’s unawareness of being ill, but also includes whether one is aware of the need for treatment  or comprehends what symptoms they might be experiencing (Mintz, et al, 2003). While often people choose not to follow a doctor’s advice about weight loss, what food to eat, or even whether to take their medications, many individuals with schizophrenia are unable to make choices about their illness because they simply do not realize that they are ill, and that their behavior has changed.

Lack of insight is a critical problem because if left untreated, schizophrenia progresses; affected individuals may not be able to attend school, work, retain housing, or maintain relationships with their families and loved ones.  In fact, there are studies documenting changes in the brain such as ventricular enlargement as being a feature in schizophrenic persons with lack of insight (Mintz, et al, 2003). There are also at least six research studies which implicate the frontal lobes of the brain as being involved in producing lack of insight; however there are five studies which found no association (Mintz, et al, 2003). One of the difficulties that researchers face is that the concept of insight itself is fairly subtle, and somewhat problematic to measure. Scientists often have differing definitions of insight, or frequently don’t measure it in the same way (Osatuke, et al, 2008).

Differing methods of measurement again emerged as a factor when researchers examined fifteen studies retroactively in order to determine whether lack of insight was a possible influence in the largest cause of death for people with schizophrenia, suicide (López-Moríñigo,  Ramos-Ríos, David, & Dutta, 2012). Interestingly, despite the documented finding that lack of insight is often accompanied by low mood, that same lack of awareness was not found to be an indicator for suicide. Unfortunately, the study confirmed that people with schizophrenia have a high risk of attempting suicide, about twenty percent, often in the first few years after diagnosis (López-Moríñigo, et al, 2012). While insight itself was not implicated as a risk factor, the researchers did find that one of the highest predictive indicators for suicide was a person’s sense of hopelessness (López-Moríñigo, et al, 2012).

Besides being associated with low mood, lack of insight has been shown to be a determinant as to whether people with schizophrenia seek treatment, how long it takes them to begin treatment, and whether they are willing to take medications (Osatuke, et al, 2008). One of the best books about this topic details the true story of a man, Xavier Amador, whose brother gets schizophrenia; Amador tries to help his brother, but is unable to convince him to get treatment (Amador & Johanson, 2000). Amador goes to medical school and becomes a psychiatrist and researcher who studies insight, all in an effort to help his brother and others like him. Despite his heroic efforts, ten years pass before Amador’s brother begins reliably participating in treatment. Conversely, patients whose insight is unaffected do seek treatment earlier in the course of their disease, and often experience better outcomes (Sadock, 2007).  Given that schizophrenia is a lifelong disease process for which there is currently no cure, lack of insight continues to be one of the most troubling roadblocks that people face when attempting to learn to live with this disease.

Amador, X. F., & Gorman, J. M. (1998). Psychopathologic domains and insight in schizophrenia. The Psychiatric Clinics of North America, 21, 1, 27-42.

Amador, X. F., & Johanson, A.L. (2000). I am not sick, I don’t need help! Helping the seriously mentally ill accept treatment: a practical guide for families and therapists. Peconic, N.Y: Vida Press.

Fischer, B.A. & Buchanan, R.W. (2013) Schizophrenia: Clinical manifestations, course, assessment, and diagnosis. In S. Marder (Ed.) UpToDate. Available from

López-Moríñigo, J. D., Ramos-Ríos, R., David, A. S., & Dutta, R. (2012). Insight in schizophrenia and risk of suicide: a systematic update. Comprehensive Psychiatry, 53, 4, 313-22.

Mintz, A. R., Dobson, K. S., & Romney, D. M. (2003). Insight in schizophrenia: a meta-analysis. Schizophrenia Research, 61, 1, 75-88.

Osatuke, K., Ciesla, J., Kasckow, J. W., Zisook, S., & Mohamed, S. (2008). Insight in schizophrenia: a review of etiological models and supporting research. Comprehensive Psychiatry, 49, 1, 70-77.

Sadock, B. J., Kaplan, H. I., & Sadock, V. A. (2007). Kaplan & Sadock’s synopsis of psychiatry: Behavioral sciences/clinical psychiatry. Philadelphia: Wolter Kluwer/Lippincott Williams & Wilkins.

Chasing Schizophrenia

Ever since Emil Kraepelin first described dementia praecox over one hundred years ago, the origin of schizophrenia has proven at once to be one of psychiatry’s greatest fascinations and frustrations (Andreasen, 2000).  While many scientists have argued that this disease is a primary disorder of the brain, the neurobiological foundations of schizophrenia have eluded researchers for generations.

Traditionally, schizophrenia is diagnosed by the presence of delusions, hallucinations, disorganized speech, disorganized motor behavior, and negative symptoms that occur over an active phase of one month, and persist in a residual capacity for at least six months (APA, 2013).  Although the underlying pathology of this mental illness has been a topic of ongoing debate, clinicians have always agreed that schizophrenia is marked by its chronicity and heterogeneity (Tamminga, 2009, 1432).

For much of the early to mid-20th century, neo-Freudian thought dominated American psychiatry, and many psychoanalysts speculated that psychosis involved the unconscious sequestration of the id, ego, and superego secondary to serious trauma or unresolved conflict with the external world (Freud, 1924).  During this period, the neo-Kraepelinian perspective, which emphasized the biological etiology of schizophrenia, was equally as speculative (Klerman, 1978).  Over the years, many theories regarding the nature of schizophrenia have come and gone, and our progress has been slow-going.  However, after several advances were made in medicine and technology, the neurobiological foundations of this severe illness slowly began to surface.

In 1952, the development of chlorpromazine, a dopamine receptor antagonist, was shown to be the first effective treatment for psychosis and signaled a turning point for psychiatry.  The advent of this and other first-generation antipsychotics played a role in the deinstitutionalization movement and helped establish the so-called “dopamine hypothesis,” which asserted that schizophrenia and other psychotic disorders were caused by an excess of dopamine within the synapses of the brain (van Rossum, 1966).  More recent research indicates that although dopamine suppression is associated with a reduction the positive symptoms seen in schizophrenia and acute psychosis, antipsychotics are not curative (Weinberger et al., 1984; Moncrieff, 2009), and the pathophysiology of schizophrenia is more likely to involve an array of neurotransmitters and circuit mechanisms (Lau et al., 2013; Kaplan & Sadock, 2009, 1432-4).

Although early pneumoencephalography studies had suggested ventricular enlargement and cortical abnormalities (Jakobi & Winkler, 1927), the psychiatric community had to wait nearly fifty years until more credible evidence could be obtained.  The development of computed tomography (CT) scanning and functional magnetic resonance imaging (fMRI) helped to usher in a new era in brain research, and for the first time evidence of the neurobiological correlates of schizophrenia began to emerge.  In 1976, CT scans of seventeen institutionalized patients with chronic schizophrenia were shown to have significant ventricular enlargement and related cognitive deficits in comparison with normal, age-matched controls (Johnstone et al., 1976; Tanaka et al., 1981).  In 1990, a study of fifteen pairs of monozygotic twins discordant for schizophrenia also revealed significant enlargement of the third and lateral ventricles, and smaller anterior hippocampi (Suddath et al, 1990).  While these early studies were groundbreaking, they were met with some criticism due to the possibility that structural changes in the brain could also be attributed to treatment, such as long-term neuroleptic therapy, electroconvulsive therapy, and insulin-induced coma (Weinberger et al., 1979).

Although there is evidence in animal and human models that long-term use of antipsychotic medications can contribute to loss of total brain tissue volume (Ho et al., 2011), these changes are also thought to be a result of a primary disease process (Navari, 2009; Moncrieff, 2010).  Several studies conducted on treatment-naïve patients experiencing their first psychotic episode have demonstrated hypofrontality and ventricular enlargement (Weinberger et al., 1982; Andreasen et al., 1992; Andreasen et al., 1997).  Interestingly, these volumetric changes are not thought to be due to loss of neurons, but are secondary to decreased dendritic density and spine formation (Glantz & Lewis, 2000), resulting in reduced neuronal size, thereby increasing overall cortical density (Harrison, 1999; Selemon, 2004).

While the hypofrontality hypothesis is conceptually attractive and has achieved prominence in the psychiatric literature, findings have been inconsistent (Gur, 1995).  Andreasen (1997) has pointed to conceptual and semantic problems with the term “hypofrontality,” and has suggested that the neuropathology of schizophrenia is more subtle than this terms allows.

Although our understanding of schizophrenia remains far from complete, scientists have made considerable progress in recent years in uncovering the pathology and etiology of this most severe mental illness.  Still, the question of whether our research “bakes any bread” in terms of clinical diagnosis remains.  Our most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) highlights the differences in cerebral architecture, white-matter connectivity, and gray-matter volume in various regions of the prefrontal and temporal cortices (APA, 2013).  However, none of these changes have attained diagnostic significance, and clinicians are left wanting for a radiological, laboratory, or psychometric test for this disorder (APA, 2013).  We can only hope that our continued research efforts and critical development of new research questions will lead to a breakthrough.



American Psychiatric Association.  (2013). Diagnostic and Statistical Manual of Mental Disorders: DSM-5 (5th ed.). Washington, D.C.: American Psychiatric Publishing.

Andreasen NC, Rezai K, Alliger R, Swayze VW, Flaum M, Kirchner P, Cohen G, O’Leary DS. (1992). Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia: assessment with xenon 133 single-photon emission computed tomography and the tower of london. Archives of General Psychiatry, 49, 943-958. doi:10.1001/archpsyc.1992.01820120031006

Andreasen NC, O’Leary DS, Flaum M, Nopoulos P, Watkins GL, Boles Ponto LL, Hichwa RD. (1997). Hypofrontality in schizophrenia: Distributed dysfunctional circuits in neuroleptic-naïve patients. Lancet (London, England), 349, 1730-1734. doi:10.1016/S0140-6736(96)08258-X

Andreasen NC. (2000). Schizophrenia: The fundamental questions. Brain Research Reviews, 31, 106-112. doi:10.1016/S0165-0173(99)00027-2

Ebmeier KP, Lawrie SM, Blackwood DH, Johnstone EC, Goodwin GM. (1995). Hypofrontality revisited: A high resolution single photon emission computed tomography study in schizophrenia. Journal of Neurology, Neurosurgery and Psychiatry, 58, 452-456. doi:10.1136/jnnp.58.4.452

Freud, S. (1924).  Neurosis and psychosis.  The standard edition of the complete psychological works of Sigmund Freud, volume XIX (1923-1925): The Ego and the Id and other works, 147-154.

Glantz LA, & Lewis DA. (2000). Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Archives of General Psychiatry, 57, 65-73. doi:10.1001/archpsyc.57.1.65

Gur RC. (1995). Hypofrontality in schizophrenia: RIP. Lancet (London, England), 345, 1383-1384. doi:10.1016/S0140-6736(95)92591-0

Harrison PJ. (1999). The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain, 122, 593-624. doi:10.1093/brain/122.4.593

Higgins ES, & George MS. (2013). The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior and Mental Illness. Philadelphia: Lippincott Williams & Wilkins.

Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. (2011). Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia. Archives of General Psychiatry, 68, 128-137. doi:10.1001/archgenpsychiatry.2010.199

Jacobi W & Winkler H. (1927).  Encephalographische studien an schizophrenen.  Arch. Psychiat. Nervenkr. 81, 299 – 332.

Johnstone EC, Crow TJ, Frith CD, Husband J, Kreel L. (1976).  Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet (London, England), 2, 924-926. doi:10.1016/S0140-6736(76)90890-4

Klerman GL. (1978) The evolution of a scientific nosology. In Schizophrenia: Science and Practice (Ed. Shershow JC.). Cambridge, Mass: Harvard University Press, 104-105.

Lau CIW, Han-Cheng H, Jung-Lung L, Mu-En. (2013). Does the dopamine hypothesis explain schizophrenia? Reviews in the Neurosciences, 24, 389-400. doi:10.1515/revneuro-2013-0011

Moncrieff J. (2009). A critique of the dopamine hypothesis of schizophrenia and psychosis. Harvard Review of Psychiatry, 17, 214-225. doi:10.1080/10673220902979896

Moncrieff J.  (2010). A systematic review of the effects of antipsychotic drugs on brain volume. Psychological Medicine, 40, 1409-1422. doi:10.1017/S0033291709992297

Navari SDP. (2009). Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings. Psychological Medicine, 39, 1763-1777. doi:10.1017/S0033291709005315

Selemon L. (2004). Increased cortical neuronal density in schizophrenia. The American Journal of Psychiatry, 161, 1564-1564. doi:10.1176/appi.ajp.161.9.1564

Suddath RL, Christison GW, Torrey EF, Casanova MF, Weinberger DR. (1990). Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. The New England Journal of Medicine, 322, 789-794. doi:10.1056/NEJM199003223221201

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van Rossum JM. (1966). The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Archives Internationales De Pharmacodynamie Et De Therapie, 160, 492-494.

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The Neurobiology of Depression

As we are amidst the holiday season, it seems appropriate to begin this post on the etiology of depression by debunking the myth that along with pumpkin pie, the holidays carry with them a spike in episodes of major depression disorder. Rather, the Center for Disease Control and Prevention reports the lowest rates of suicide attempts are during the winter months (O’connor, 2005). Our current understanding of the etiology of depressive disorders is quite complex and has come a long way, as we have progressed from focusing on the dysfunction of single neurotransmitter systems, to studying more intricate neural circuits, dysfunctions in neuroregulatory mechanisms, and the neurobiological effects of trauma.

Monoamine hypothesis: The serendipitous discovery of the therapeutic effects of tricylics and MAOIs in the 1950s led to the monoamine hypothesis. This theory characterizes depression as a disorder of serotonin (5HT), norepinephrine (NE), and dopamine (DA) concentrations and their receptors. While the evidence implicating monoamines support abnormalities in their neurotransmission, studies have failed to reveal these changes as central to the pathophysiology of depression. Overall, the data does not support that drug-free patients with major depression have a consistent reduction in cerebrospinal fluid concentrations of 5-hydroxyindoleacetic-acid (5HIAA), the main metabolite of 5HT. However, there is evidence linking low CSF 5HIAA levels to patients with histories of aggressive behaviors, impulsivity, and dangerous suicide attempts. Similarly, evidence of altered CSF concentrations of the major metabolite of NE is not consistent in depressed patients. While there is consistent data supporting low CSF levels of the DA metabolite, homovanillic acid, in depressed patients, the most convincing data supporting the monoamine hypothesis has come from research involving the depletion of the monoamines. Studies using tryptophan depletion, a precursor amino acid of 5HT, to induce low brain 5HT function have failed to alter mood in those not vulnerable to mood disorders, however patients who are vulnerable to mood disorders do show clinical depressive symptomatology. Studies that lower the synthesis of NE and DA by inhibiting a precursor of both catecholamines via the drug alpha-methyl-para-tyrosine (AMPT) have produced similar results. Thus, it seems that monoamine depletion does not produce depressive symptoms in healthy subjects, whereas patients who are vulnerable to depressive disorders, as evidence by past or family history, will experience a relapse in symptoms with low monoamine function. (Cowen, 2012).

While abnormalities in the monoamines alone are not sufficient to cause clinical depression, it seems that in vulnerable populations, a diminished function of 5HT, NE, and DA plays a definite role in the pathophysiology of depression. This may be due to pre-existing deficits in mood regulating neural circuits that predispose vulnerable populations to react abnormally to monoamine deficits (Cowen, 2012). Recent studies examining the impact of monoamine function on these circuits has focused on their effects in activating intracellular cascades and stimulating gene expression. 5HT and NE help regulate second messenger cascades, such as the cyclic AMP (cAMP) cascade, resulting in transduction cascades and the up-regulation of specific target genes, including the brain derived neurotrophic factor (BDNF).

Neurotrophic hypothesis: Neurotrophins, such as BDNF, provide for the function and survival of cortical neurons. This is relevant to etiology of depression in that evidence shows that a disruption in neurogenesis and nerve factor growth play an important role in the pathophysiology of depressive disorders. Moreover, postmortem analysis of suicidal patients with depression shows a marked reduction in BDNF in the prefrontal cortex and hippocampus (Higgins, 2013). This reduction has been linked to the production of excess cortisol. In patients with depression, there is an increased activity of the HPA axis due to a hyper expression of the corticotrophin releasing hormone (CRH) and reduced feedback inhibition. Dysregulation within the HPA axis predisposes these patients to a heightened response to chronic stress and it is this state of hypercortisolemia that has been found to be neurotoxic and cause decreased hippocampal BDNF mRNA. Stress-induced down regulation of BDNF results in a reduction in the size of neurons and volumetric loss in patients with depression. This can be seen in CT and MRI studies that show consistent structural deficits in the hippocampus, prefrontal cortex, anterior cingulate, and basal ganglia (Cowen, 2012). Thus, enhancing BDNF gene expression likely has powerful neuroprotective effects on structural plasticity and reversal of the neurotoxic effects of chronic stress or genetic vulnerability. This has given rise to the hypothesis that the therapeutic use of monoamine potentiating treatments can reverse the neuronal damage caused by stress-induced precipitation of mood disorders through enhancing intracellular mechanisms that increase BDNF and neurogenesis (Vaidya, 2001).

Immune hypothesis: There is increasing evidence of a high prevalence of depression and comorbid chronic medical illnesses that has led to the belief that depression is mediated by immune dysregulation and inflammatory processes. Recent research has shown activation of the immune response in depressed patients, particularly in the release of certain cytokines. In a study by Dowlati et al. (2010), the cytokines IL-6 and tumor necrosis factor alpha were increased in depressed subjects compared to controls. Cytokines stimulate the HPA axis, resulting in increased cortisol secretion. Cortisol normally suppresses HPA activity through negative feedback inhibition at the level of the hypothalamus and pituitary, however there is evidence of glucocorticoid resistance occurring in patients with depression. The loss of sensitivity to cortisol signaling leads to unchecked stimulation of HPA activity by the cytokines and this immune dysregulation may be one way in which inflammation induces depressive symptoms. This state of impaired immunity provides a framework in which psychological or immunological stress leads to a state of chronic inflammation in vulnerable individuals. These unchecked inflammatory processes are associated with increasing risk for comorbid depression and medical diseases. Moreover, the depression symptomatology that includes poor sleep, weight loss and malnutrition, inactivity, and the potential for health harming behaviors, such as alcohol abuse, may itself contribute to this decompensatory immune process. (Blume, 2011).

In summary, as evidenced by some of the theories stated above, the etiology of depression is a complex processes, involving dysregulation of interconnecting neural circuits and neural responses to emotion or stress. Our increasing understanding of how genetic, environmental, and interpersonal factors interconnect in depressive disorders is leading to new clinical research and more effective interventions.

Blume, Joshua Blume, Steven Douglas,Dwight Evans. (2011). Immune suppression and immune activation in depression. Brain, Behavior, and Immunity, 25, 221-229. doi:10.1016/j.bbi.2010.10.008

Cowen, P., Harrison, P., Burns, T. (2012). Shorter Oxford Textbook of Psychiatry. Oxford: Oxford University Press.

Cowen, P., Sharp, T., Lau, Y.F. J. (2013). Behavioral Neurobiology of Depression and Its Treatment.New York: Springer.

Higgins, E.S., George, M.S. (2013). The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior and Mental Illness. Philadelphia: Lippincott Williams & Wilkins.

O’Connor, A. (2005). The Claim: Depression Rates Rise During the Holidays. The New York Times.

Sadock, B.K., Sadock, V.A. (2007). Synopsis of Psychiatry. Philapdelpha, PA: Lippincott Williams & Wilkins.

Vaidya, V. A., & Duman, R. S. (2001). Depression – emerging insights from neurobiology. British Medical Bulletin, 57, 61-79. doi:10.1093/bmb/57.1.61

Electroconvulsive Therapy: Barbarism and Mystery

Sufferers and their families, caring clinicians and money-hungry drug companies alike have searched endlessly for reliable and consistent treatment modalities for depression.  From Freud’s earliest attempts to psychoanalyze and talk through the disorder to the FDA’s recent approval of the upcoming SSRI, Viibryd (Vilazodone), treating depression has been an ongoing battle with a fascinating and sometimes controversial history.  Much of the spotlight in recent years has been on these SSRIs and other miracle medications that frequently help relieve the neurovegetative symptoms depression wreaks on its victims.  However, the population oft not thought of is the treatment-resistant group, the sizable portion of severely depressed individuals that trial numerous drugs with no effect.  Researchers estimate that 10-30% of patients diagnosed with major depression will not respond to the antidepressants (Joffe, Levitt & Sokolov, 1996), which leads us to the question: how do we care for these poor souls?

For nearly 75 years, the gold standard in dealing with treatment-resistant depression is to literally shock them out of it.  Introduced in the 1930’s and continuously modified for safety and efficacy since, electroconvulsive therapy (ECT) has become a meticulously studied treatment modality for severe depression (Greenberg & Kellner, 2006).  The procedure, which sends enough electrical current into the brain to induce a 20-second long grand mal seizure, typically results in a favorable outcome for the severely depressed patient and somehow, zero criminal reports against the perpetrator.  To the lay, this sounds both barbaric and archaic, while certainly congering up the image of Jack Nicholson’s character writhing about torturously in One Flew Over the Cuckoo’s Nest.  Despite Hollywood’s sensationalist dramatization, the procedure is painless and wildly efficacious, producing robust response rates anywhere in the neighborhood of 60-90%, dependent on the study you read (Abrams, 2002; Greenberg & Kellner, 2006; Hermann et al., 1995).  These statistics propose that ECT is the most effective treatment available for severe depression.

Given reports of its effectiveness and the multitude of research done on the topic, one would assume that its mechanism of action (MOA) could be easily found using a simple Google search; however, no one knows definitively how it works.  Rudimentary explanations posit that the electrical stimulus may “reset” the brain to a healthier default setting, but just where and how does this reset occur?  Some interesting studies have looked closely at the serotonergic receptor 5-HT1A before and after ECT with this “resetting” hypothesis, as there is a large body of literature on 5-HT1A’s involvement in major depression (Hirvonen et al., 2008; Parsey et al., 2006; Parsey et al., 2010; Savitz, Lucki & Drevets, 2009).

Lanzenberger et al. (2013) demonstrated global reductions in 5-HT1A binding potential following a successful and responsive course of ECT, with the most significant reductions occurring in brain structures known to often malfunction in major depression like the hippocampus, amygdala, orbitofrontal cortex, anterior cingulate cortex and insula.  Though conflicting research (Goodfellow, Benekareddy, Vaidya & Lambe, 2009; Tsuji, Takeda & Matsumiya, 2001) explains that increased 5-HT1A activation and binding potential is protective against MDD, the data from Lanzenberger et al. (2013) was corroborated at least in part by an earlier study by Burnet, Sharp, LeCorre & Harrison (1999) on rats.  Decreased serotonin receptor 5-HT1A expression was observed at the CA4 region of the hippocampus in Burnet et al. (1999) following single and repeated electroconvulsive stimulation (ECS); however, expression was found to have increased at other hippocampal structures, such as the dentate gyrus.

The data above certainly suggests that the MOA behind ECT has something to do with stabilizing the 5-HT1A receptor.  However, some studies presented above proposed that greater 5-HT1A binding potential is a protective factor (Goodfellow et al., 2009; Tsuji, Takeda & Matsumiya, 2001) while the other finds that successful ECT induces less binding potential (Lanzenberger et al., 2013).  This is an obvious contradiction, but what if we look at this controversial receptor from a functional point of view?  Let’s take into consideration that 5-HT1A receptor’s important job as an autoreceptor at the synapse, which could lead to an explanation of the findings from Lanzenberger et al. (2013).

As a presynaptic autoreceptor, 5-HT1A has been known to regulate inhibition of serotonergic firing (Albert, 2012; Lanzenberger et al., 2013).  In this role, a high binding potential of 5-HT1A would cause great restriction of serotonin release into the synapse since autoreceptor binding is now increasingly encouraged.  When free serotonin binds to the autoreceptor, a negative feedback loop inhibits further serotonin release.  Perhaps the 5-HT1A autoreceptors of the severely depressed patients in Lanzenberger et al. (2013) were “reset” by ECT to a lower, healthier number and binding potential that discourages autoreceptor binding, boosting free serotonin levels and relieving treatment-resistant depression.  To support this assumption, research into the role that reducing or completely knocking out 5-HT1A autoreceptors has on increasing serotonin has been produced in both animal and human models (Bortolozzi et al., 2004; He et al., 2001).

Although resetting faulty 5-HT1A receptors alone has been highlighted here as a major component in how ECT works in treatment-resistant depression, other mechanisms are assuredly involved.  Research has found implication for the role of dopaminergic neurotransmission alterations in the striatum as a potential MOA of ECT as well (Costain, Cowen, Gelder & Grahame-Smith et al., 1982; Landau et al., 2011) and others have postulated that through eliciting high levels of ATP, ECT improves these refractory depressive symptoms (Sadek, Knight & Burnstock, 2011).  With or without a definite MOA, ECT remains the gold standard in breaking not only treatment-resistant depression but many other refractory psychiatric illnesses like schizophrenia, mania and catatonia, while doing so in a safe and relatively side-effect-free manner.



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