We now recognise that withdrawal symptoms from antidepressants are common, and can be severe and long-lasting in some people. Many withdrawal symptoms overlap with symptoms of anxiety or depression, making it difficult to distinguish withdrawal from relapse. We describe how their onset soon after dose reduction, the association of psychological with physical symptoms, their prompt response to reinstatement, and their typical ‘wave’ pattern of onset, peak and resolution can help distinguish withdrawal symptoms from relapse. We also examine evidence that suggests that antidepressant withdrawal symptoms are misdiagnosed as relapse in discontinuation studies aimed at demonstrating the ability of antidepressants to prevent future relapse (relapse prevention properties). In these discontinuation studies people have their antidepressants stopped abruptly, or rapidly, making withdrawal symptoms very likely, and little effort is made to measure withdrawal symptoms or distinguish them from relapse. We conclude that there is currently no robust evidence for the relapse prevention properties of antidepressants, and current guidance might need to be re-evaluated.

Most clinically-used antidepressants acutely increase monoamine levels in synaptic clefts, while their therapeutic effects often require several weeks of administration. Slow neuroadaptive changes in serotonergic neurons are considered to underlie this delayed onset of beneficial actions. Recently, we reported that sustained exposure of rat organotypic raphe slice cultures containing abundant serotonergic neurons to selective serotonin (5-HT) reuptake inhibitors (citalopram, fluoxetine and paroxetine) caused the augmentation of exocytotic serotonin release. However, the ability of other classes of antidepressants to evoke a similar outcome has not been clarified. In this study, we investigated the sustained actions of two tricyclic antidepressants (imipramine and desipramine), one tetracyclic antidepressant (mianserin), three 5-HT and noradrenaline reuptake inhibitors (milnacipran, duloxetine and venlafaxine) and one noradrenergic and specific serotonergic antidepressant (mirtazapine) on serotonin release in the slice cultures. For seven of nine antidepressants, sustained exposure to the agents at concentrations of 0.1–100 μm augmented the level of increase in extracellular serotonin. The rank order of their potency was as follows: milnacipran>duloxetine>citalopram>venlafaxine>imipramine>fluoxetine>desipramine. Neither mirtazapine nor mianserin caused any augmentation. The highest augmentation by sustained exposure to milnacipran was partially attenuated by an α1-adrenoceptor antagonist, benoxathian, while the duloxetine-, venlafaxine- and citalopram-mediated increases were not affected. These results suggest that inhibition of the 5-HT transporter is required for the enhancement of serotonin release. Furthermore, the potent augmentation by milnacipran is apparently due to the accompanied activation of the α1-adrenoceptor.

Objective – To determine the most cost-effective oral therapy for the treatment of Major Depressive Disorder (MDD) in Italy. Method – We conducted a pharmacoeconomic evaluation based on a decision analytic model that examined the treatment of major depressive disorder (MDD) in Italy. The analysis compared the serotonin norepinephrine reuptake inhibitor (SNRI), venlafaxine extended-release (venlafaxine XR), to selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). A meta-analysis was performed to determine the clinical rates of success. The meta-analytic rates were applied to the decision analytic model to calculate the expected cost and expected outcomes for each anti-depressant comparator. Cost-effectiveness was determined using the expected values for both a successful outcome, and a composite measure of outcome termed ‘symptom-free days’. A policy analysis was conducted to estimate the financial impact to the Servizio Sanitario Nazionale (SSN). Results – Treatment of MDD with venlafaxine XR yielded the highest overall efficacy rates for outpatients (73.7%) versus SSRIs (61.4%) and TCAs (59.3%), and inpatients (62.3%) versus SSRIs (58.6%) and TCAs (58.2%). Venlafaxine XR had the lowest dropout rates due to lack of efficacy (4.8%) versus SSRIs (8.4%) and TCAs (6.8%), and adverse drug reactions (10.9%) versus SSRIs (17.4%) and TCAs (23.1%). Initiating treatment of MDD with venlafaxine XR yielded the lowest expected cost for outpatients and for inpatients. The total resulting savings for the SSN at a 5% venlafaxine XR utilization was estimated between L 963 million and L 3,210 million. Conclusion – This study confirms that venlafaxine XR is generally a cost-effective treatment of MDD. Additionally, the results of this investigation suggest that increased utilization of venlafaxine XR will favorably impact the SSN.

Obtaining drugs for use in basic and preclinical research has become increasingly difficult and in many instances is dependent upon the company's interest in the proposed research. In this paper, we describe a simple procedure for extracting the antidepressants sertraline, paroxetine, fluoxetine, venlafaxine, citalopram, escitalopram, duloxetine and atomoxetine from their readily available pharmaceutical preparations. With the exception of citalopram, escitalopram and duloxetine in which the free base was the final product, the hydrochloride salt forms of these drugs were prepared. This procedure provides these antidepressants in gram quantities in recovered yields ranging from 53% to 100% at over 99% purity and is in principle applicable to other drugs as well.

A case of venlafaxine associated visual hallucinations is described. The underlying neurochemical pathophysiology is explored and recommendations for management of patients who experience this side effect are discussed.