Mecanismele neurobiologice în depresia postpsihotică

Case presentation

C.N. is a 29-year-old woman with no psychiatric history prior to October 2024. She is unmarried, childfree, and recently relocated back to her family residence after living abroad for numerous years. She resides in an urban environment with her mom, stepdad and little brother. She has a boyfriend with whom she lived abroad, a relationship her mother did not approved. Several months before the first admission, she was sexually assaulted, but she chose not to pursue psychiatric support or report the incident to the authorities. C.N. completed a bachelor’s degree in economic science, but she has not maintained consistent employed since completing her studies. No additional somatic conditions were reported in her medical history examination.

C.N. presented at hospital admission with a sudden onset of clastic behavior and verbal aggression, accompanied by paranoid ideation and increased suspiciousness, a decline in daily functioning, which manifested after an intrafamilial dispute, but not involving a significant impairment in perceiving reality. The physical exams and paraclinical tests did not relieve medical or toxic causes of psychosis. She was diagnosed with acute and transient psychotic disorder “under observation”. During this admission, her treatment consisted of risperidone 3 mg/day, alprazolam 2 mg/day, and sodium valproate 600 mg/day. Moreover, during the hospitalization, the clinical psychologist applied brief therapeutic sessions both to the patient alone and together with her mother. It is worth mentioning that the patient did not want to elaborate on the circumstances in which the rape took place in Germany a few months before and, thus, a specific psychological intervention was not possible.

Both the pharmacologic and psychotherapeutic treatments had good results, with a significant improvement of her behavioral problems and positive symptoms permitting her discharge after a week. In the first admission, the mentioned diagnosis of acute and transient psychotic disorder “under observation” wasn’t clarified, because the patient did not show up for checkup sessions, and we were unable to monitor the positive symptoms.

In March 2025, she was again hospitalized. This time, however, she was brought in by the police after having demonstrated psychomotor agitation, aggressive behavior directed toward her family and neighbors, persecutory delusions and delusional behavior (she scratched a car in the parking lot). She claimed to have stopped her medication a few weeks prior to this presentation, purportedly due to concerns about side effects and the medication’s necessity. At the time of her admission, she was irritable, incoherent, and seemed to be responding to visual and auditory hallucinatory experiences. She was diagnosed again with acute and transient psychotic disorder, and she was treated with risperidone 4 mg/day, alprazolam 2 mg/day and sodium valproate 600 mg/day, with good results, within days, her positive psychotic symptoms subsided.

In the post-remission stage of acute psychosis, a new clinical picture developed. C.N. became withdrawn, she experienced sudden and intense mood swings, expressed persistent irritability, intrusive shame-infused self-criticism, and anxiety regarding social and professional reintegration. Accompanying these symptoms, there were a loss of motivation, anhedonia and a sense of hopelessness concerning the future. Her score on the depression scale suggested a moderate depressive episode which allowed for her discharge.

At home, her depressive symptoms worsened, and suicidal ideation became prevalent. The patient socially withdrew and isolated herself, oversleeping and self-neglecting. She was diagnosed with postpsychotic depression. After being readmitted, C.N. began antidepressive therapy with escitalopram 10 mg/day, while continuing with a low dose of risperidone. She was supervised for two weeks of hospitalization and achieved full remission of depressive symptoms. Within weeks, the patient found a new job and successfully integrated socially and professionally.

In this case, the diagnosis must be further monitored. There is a possibility that the evolution of symptoms, both psychotic and depressive, will stop. But there is also the possibility that the mentioned symptoms will continue or reappear, and then we can talk about the development of schizoaffective disorder, depressive type.

Discussion

Neurobiological factors in postpsychotic depression

Postpsychotic depression is not merely an emotional reaction to psychosis. It is a nosological entity driven by lasting changes in chemistry, function brain structure that happens during a psychotic episode and persists after remission.

One hypothesis comes from the association between depression and chronic stress. The neuroendocrinological factors associated with postpsychotic depression (PPD) specifically relate to the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. This dysregulation is characterized by sustained elevated levels of corticosteroids, especially of cortisol, due to the overactive HPA axis triggered by psychotic episodes. Sustained hypercortisolism results in central corticotropin releasing hormone (CRH) insufficiency, which may contribute to the onset of depressive symptoms⁽¹⁾. Such individuals often exhibit impaired HPA axis glucocorticoid receptor (GR) signaling (and, therefore, GR) function which makes it resistant to negative feedback mechanism. Negative events and stress further affect the expression and function of GR receptors, also negatively impacting the HPA axis activity⁽²⁾. Such findings support the existence of a neuroendocrine dysfunction in PPD and altered states of mood and cognition.

Neuroimaging continues to show widespread chan­ges across the brain in regions critical for mood and cognition, an overall reduction in grey matter volume, and disrupted neural connections. During the acute phase of psychosis, the prefrontal cortex – especially the dorsolateral (dlPFC) and ventromedial (vmPFC) regions – shows hypoactivity. Reduced dlPFC engagement weakens problem-solving abilities and increases rumination, leaving patients more vulnerable to depression, while persistent vmPFC underactivity provokes feelings of sadness, hopelessness and mood instability. Even though some recovery is attainable in a few but not all patients, the vmPFC region’s sustained hypoactivity leads to a range of mood disorders, including depression^(3,4). This correlation stands out in PPD.

Following the acute phase of psychosis, the combination of hippocampal atrophy and overactivity of the amygdala – specifically, its basolateral nucleus – drives the ongoing symptoms^(5,6). The hyperreactive amygdala heightens emotional responses and threat perceptions. Stress-related changes reinforce this activity by increasing connections within the amygdala. At the same time, hippocampal shrinkage weakens its ability to regulate the amygdala and contextualize memories⁽⁶⁾. This makes intrusive and distressing recollections harder to control. Patients are often seen struggling to differentiate between past traumas and present safety. Diminished connectivity between the prefrontal cortex, amygdala and hippocampus further disrupts the coordination between emotional regulation, memory and cognitive control⁽⁷⁾.

These underscored circuit changes are accentuated by neurochemical shifts. Reduced NMDA receptor activity weakens inhibitory control over excitatory neurons, leading to excess glutamate release⁽⁸⁾. Glutamate overstimulation of the amygdala increases dopaminergic firing in the mesolimbic system, with reduced dopamine supply to the prefrontal cortex⁽⁹⁾. The reduction of dopamine in the prefrontal cortex weakens emotional control, while high glutamate levels in the limbic system sustains hyperreactivity. The astrocytic glutamate imbalance is often prolonged due to insufficient astrocyte glutamate clearance. Compensatory changes of dampened dopamine activity from antipsychotic treatment could leave mesolimbic circuits sensitized, while mesocortical circuits remain chronically low in dopamine^(9,10). These systems cannot be recalibrated due to insufficient BDNF, as well as the altered metabotropic glutamate receptor signaling⁽¹¹⁾.

This combination leads to a neurobiological state that is marked by overactive emotional circuits, weak regulatory control, and a disrupted chemical balance^(5,12). This results in perception toward negative cues, maintains low mood and anhedonia, and heightens sensitivity to stress. Other neurotransmitter changes include reduced serotonin 5-HT_2A receptor binding in prefrontal and limbic areas and lower cortical GABA, which also promote a cycle of rumination and depressive symptoms in the post-psychotic phase⁽⁹⁾.

Conclusions

C.N.’s case demonstrates the interplay of circuits, pathways, neurotransmitter systems and stress responsive systems involved in the development of postpsychotic depression. The mechanisms that arise as a consequence of psychosis pose distinct interplay of restricted neural pathways, stress, neurotransmitter systems and neuroplasticity which, once identified, allows the application of psychopharmacological treatment that exercises both mood and emotional regulation in postpsychotic states. The combination of neurobiology and clinical treatment offers the best chance of achieving complete functional recovery in patients emerging from psychosis. Postpsychotic depression is being increasingly redefined as a neurobiological syndrome that deserves equal attention alongside the acute psychotic episode itself.    

Corresponding author: Lavinia Duica E-mail: laviniaduica@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

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