The Wistar Hannover rat (WHR) is a strain commonly used for toxicity studies but rarely used in studies investigating depression neurobiology. In this study, we aimed to characterise the behavioural responses of WHR to acute and repeated antidepressant treatments upon exposure to the forced swim test (FST) or learned helplessness (LH) test. WHR were subjected to forced swimming pre-test and test with antidepressant administration (imipramine, fluoxetine, or escitalopram) at 0, 5 h and 23 h after pre-test. WHR displayed high immobility in the test compared to unstressed controls (no pre-swim) and failed to respond to the antidepressants tested. The effect of acute and repeated treatment (imipramine, fluoxetine, escitalopram or s-ketamine) was then tested in animals not previously exposed to pre-test. Only imipramine (20 mg/kg, 7 days) and s-ketamine (acute) reduced the immobility time in the test. To further investigate the possibility that the WHR were less responsive to selective serotonin reuptake inhibitors, the effect of repeated treatment with fluoxetine (20 mg/kg, 7 days) was investigated in the LH model. The results demonstrated that fluoxetine failed to reduce the number of escape failures in two different protocols. These data suggest that the WHR do not respond to the conventional antidepressant treatment in the FST or the LH. Only s-ketamine and repeated imipramine were effective in WHR in a modified FST protocol. Altogether, these results indicate that WHR may be an interesting tool to investigate the mechanisms associated with the resistance to antidepressant drugs and identify more effective treatments.

Given the high prevalence and adverse outcomes associated with generalized anxiety disorder (GAD), development and expansion of effective treatment modalities are important. The present study compared the effectiveness of cognitive behavior therapy targeting intolerance of uncertainty (CBT-IU) and selective serotonin reuptake inhibitors (SSRIs) for treating GAD. A total of 30 Iranian patients with GAD (Mage = 25.16 ± 6.73) were randomised to receive either CBT-IU (n = 15) or SSRI (n = 15). Measures included the Structured Clinical Interview for DSM-5 (SCID-5), Penn State Worry Questionnaire (PSWQ), Why Worry-II (WW-II), Intolerance of Uncertainty Scale (IUS), and Negative Problem Orientation Questionnaire (NPOQ). Repeated measures analysis of variance tested differential treatment outcomes. The results of intention-to-treat (ITT) analysis indicated that although both CBT-IU and SSRI were effective treatments for GAD, CBT-IU produced significantly better results than SSRI at post-treatment. This clinical trial provides preliminary cross-cultural support for the treatment of GAD using CBT-IU, with findings suggesting that this non-medication intervention reduces GAD symptoms.

The medium- to long-term consequences of COVID-19 are not yet known, though an increase in mental health problems are predicted. Multidisciplinary strategies across socio-economic and psychological levels may be needed to mitigate the mental health burden of COVID-19. Preliminary evidence from the rapidly progressing field of psychedelic science shows that psilocybin therapy offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and maladaptive habitual patterns of cognition and behaviour, notably depression, addiction and obsessive compulsive disorder. The COMPASS Pathways (COMPASS) phase 2b double-blind trial of psilocybin therapy in antidepressant-free, treatment-resistant depression (TRD) is underway to determine the safety, efficacy and optimal dose of psilocybin. Results from the Imperial College London Psilodep-RCT comparing the efficacy and mechanisms of action of psilocybin therapy to the selective serotonin reuptake inhibitor (SSRI) escitalopram will soon be published. However, the efficacy and safety of psilocybin therapy in conjunction with SSRIs in TRD is not yet known. An additional COMPASS study, with a centre in Dublin, will begin to address this question, with potential implications for the future delivery of psilocybin therapy. While at a relatively early stage of clinical development, and notwithstanding the immense challenges of COVID-19, psilocybin therapy has the potential to play an important therapeutic role for various psychiatric disorders in post-COVID-19 clinical psychiatry.

Panic disorder is a chronic condition for many patients and can be socially, emotionally and occupationally disabling. Until recently, clomipramine and alprazolam were the only drugs approved for its treatment. While widely used in the US and Europe, both belong to drug classes (tricyclics and benzodiazepines) with well-recognised side effects that can be problematic and thus limit their use. Recently, paroxetine became the first selective serotonin reuptake inhibitor to receive approval and licensing for panic disorder.

The short- and long-term efficacy and tolerability of paroxetine in panic disorder has been established in clinical trials of almost 1,000 patients meeting Diagnostic and Statistical Manual (DSM)-IIIR criteria for panic disorder, with or without agoraphobia. In a 12-week double-blind study of 120 panic patients receiving standardised cognitive therapy, paroxetine was significantly more effective than placebo in reducing panic attack frequency. In a 12-week placebo-controlled comparison in 367 panic patients, paroxetine was at least as effective as clomipramine and better tolerated. There was also some evidence that paroxetine had an earlier onset of action than clomipramine.

A 9-month extension of the placebo-controlled comparison with clomipramine showed that the efficacy of paroxetine and clomipramine is maintained when treatment is continued into the longer term. In a relapse prevention study, 105 responders to 3 months' treatment with paroxetine or placebo were re-randomised, either to continue existing treatment or to receive placebo for 3 months. Only 5% of patients who continued to take paroxetine experienced a relapse compared with 30% of those who switched to placebo (P = 0.002). Paroxetine was generally well tolerated. In the short-term trials, the frequency of withdrawals due to adverse events (7.3%) was lower than that for placebo (11.4%) or clomipramine (14.9%). In the longer term, the dropout rate due to adverse events increased in the clomipramine group (19.0%) but was unchanged in the paroxetine group (7.4%). Since most patients with panic disorder will require prolonged treatment, the long-term tolerability of paroxetine and its lack of potential for dependence are important advantages that will encourage good compliance with treatment and improve the quality of life of patients.

Panic disorder is widespread in Australia, often in combination with other psychiatric conditions such as agoraphobia or major depression. Pharmacotherapy for panic disorder in Australia commenced with benzodiazepines, and later progressed to tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). More recently, treatment has moved towards use of the selective serotonin reuptake inhibitors (SSRIs), which are effective and better tolerated. Paroxetine is the first drug of this class to receive approval for treatment of panic disorder in Australia.

We aimed to identify biomarkers to guide the decision to add selective serotonin reuptake inhibitors (SSRI) to psychological treatment for social anxiety disorder (SAD). Forty-eight patients with SAD underwent functional magnetic resonance imaging and collection of clinical and demographic variables before treatment with cognitive–behavioural therapy, combined on a double-blind basis with either escitalopram or placebo for 9 weeks. Pre-treatment neural reactivity to aversive faces in the dorsal anterior cingulate cortex (ACC), but not clinical/demographic variables, moderated clinical outcomes. Cross-validated individual-level predictions accurately identified 81% of responders/non-responders. Dorsal ACC reactivity is thus a potential biomarker for SAD treatment selection.

The mode of action of serotonin in depression is unclear. We tested the modulation of hippocampal long-term plasticity, a model for learning and memory, by 5-HT and found a selective impairment of long-term depression resulting in a positive modification of synaptic network properties. We hypothetize a role for long-term plasticity in emotional regulation and the pathophysiology of affective disorders.

Although the mechanism by which antidepressants (ADs) may increase the risk of suicide-related outcomes is unknown, it has been hypothesised that some adverse effects, including akathisia, insomnia and panic attacks, as well as an early energising effect that might allow patients with depression to act on suicidal impulses, may have a key role. Considering that these adverse effects are dose-related, it might be hypothesised that the risk of suicidal behaviour is similarly related to the AD dose. This research question has recently been addressed by a propensity score-matched observational cohort study that involved 162 625 patients aged 10–64 years with a depression diagnosis who initiated therapy with citalopram, sertraline or fluoxetine. In this commentary, we discuss the main findings of this study in view of its methodological strengths and limitations, and we suggest possible implications for day-to-day clinical practice.

A possible link between prenatal exposure to the selective serotonin reuptake inhibitors (SSRIs) and development of autism spectrum disorders (ASDs), previously suggested by two case-control studies, was not confirmed by a recent cohort study that followed for 5–10 years more than 600,000 births. However, this study failed to demonstrate that SSRI exposure during pregnancy is safe in terms of child development outcomes, as an increased risk of ASDs cannot be completely ruled out. In the present article, the main strengths and weaknesses of this study are briefly analysed, including a possibility of confounding by indication.